MXPA06000160A - 4-(methyl sulfonyl amino) phenyl analogues as vanilloid antagonist showing excellent analgesic activity and the pharmaceutical compositions comprising the same - Google Patents
4-(methyl sulfonyl amino) phenyl analogues as vanilloid antagonist showing excellent analgesic activity and the pharmaceutical compositions comprising the sameInfo
- Publication number
- MXPA06000160A MXPA06000160A MXPA/A/2006/000160A MXPA06000160A MXPA06000160A MX PA06000160 A MXPA06000160 A MX PA06000160A MX PA06000160 A MXPA06000160 A MX PA06000160A MX PA06000160 A MXPA06000160 A MX PA06000160A
- Authority
- MX
- Mexico
- Prior art keywords
- phenyl
- methylsulfonylamino
- propionamide
- fluoro
- group
- Prior art date
Links
- -1 4-(methyl sulfonyl amino) phenyl Chemical class 0.000 title claims abstract description 457
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 16
- 230000000202 analgesic Effects 0.000 title claims abstract description 10
- 230000003042 antagnostic Effects 0.000 title description 18
- 239000005557 antagonist Substances 0.000 title description 11
- 150000001875 compounds Chemical class 0.000 claims abstract description 163
- 208000002193 Pain Diseases 0.000 claims abstract description 24
- 230000036407 pain Effects 0.000 claims abstract description 10
- 208000005298 Acute Pain Diseases 0.000 claims abstract description 8
- 208000000094 Chronic Pain Diseases 0.000 claims abstract description 8
- 206010029331 Neuropathy peripheral Diseases 0.000 claims abstract description 7
- 210000003491 Skin Anatomy 0.000 claims abstract description 7
- 208000006820 Arthralgia Diseases 0.000 claims abstract description 6
- 208000006673 Asthma Diseases 0.000 claims abstract description 6
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 claims abstract description 6
- 210000001508 Eye Anatomy 0.000 claims abstract description 6
- 208000002551 Irritable Bowel Syndrome Diseases 0.000 claims abstract description 6
- 206010027599 Migraine Diseases 0.000 claims abstract description 6
- 208000008085 Migraine Disorders Diseases 0.000 claims abstract description 6
- 210000004400 Mucous Membrane Anatomy 0.000 claims abstract description 6
- 206010052639 Nerve injury Diseases 0.000 claims abstract description 6
- 208000004296 Neuralgia Diseases 0.000 claims abstract description 6
- 208000004550 Postoperative Pain Diseases 0.000 claims abstract description 6
- 208000000399 Procedural Pain Diseases 0.000 claims abstract description 6
- 206010038683 Respiratory disease Diseases 0.000 claims abstract description 6
- 210000003932 Urinary Bladder Anatomy 0.000 claims abstract description 6
- 230000004770 neurodegeneration Effects 0.000 claims abstract description 6
- 201000008175 pain disease Diseases 0.000 claims abstract description 6
- 239000000085 vanilloid receptor antagonist Substances 0.000 claims abstract description 6
- 206010021972 Inflammatory bowel disease Diseases 0.000 claims abstract description 5
- 208000006641 Skin Disease Diseases 0.000 claims abstract description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 260
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 112
- QLNJFJADRCOGBJ-UHFFFAOYSA-N Propanamide Chemical compound CCC(N)=O QLNJFJADRCOGBJ-UHFFFAOYSA-N 0.000 claims description 99
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 93
- 229940080818 propionamide Drugs 0.000 claims description 93
- 125000004432 carbon atoms Chemical group C* 0.000 claims description 69
- 239000002253 acid Substances 0.000 claims description 45
- 239000011780 sodium chloride Substances 0.000 claims description 40
- 125000004435 hydrogen atoms Chemical class [H]* 0.000 claims description 39
- 125000006185 3,4-dimethyl benzyl group Chemical group [H]C1=C(C([H])=C(C(=C1[H])C([H])([H])[H])C([H])([H])[H])C([H])([H])* 0.000 claims description 38
- UMGDCJDMYOKAJW-UHFFFAOYSA-N Thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 claims description 37
- 150000003839 salts Chemical class 0.000 claims description 32
- 125000005843 halogen group Chemical group 0.000 claims description 29
- 239000001257 hydrogen Substances 0.000 claims description 29
- 229910052739 hydrogen Inorganic materials 0.000 claims description 29
- 125000000217 alkyl group Chemical group 0.000 claims description 28
- 125000003277 amino group Chemical group 0.000 claims description 26
- ZVVCQVGMUKTANK-SSDOTTSWSA-N CS(=O)(=O)NC1=CC=C(C=C1)[C@@H](C)NC(=S)N Chemical compound CS(=O)(=O)NC1=CC=C(C=C1)[C@@H](C)NC(=S)N ZVVCQVGMUKTANK-SSDOTTSWSA-N 0.000 claims description 22
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 22
- 125000003352 4-tert-butyl benzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])*)C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 20
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 20
- HNQIVZYLYMDVSB-UHFFFAOYSA-N methanesulfonimidic acid Chemical compound CS(N)(=O)=O HNQIVZYLYMDVSB-UHFFFAOYSA-N 0.000 claims description 17
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 14
- 125000006512 3,4-dichlorobenzyl group Chemical group [H]C1=C(Cl)C(Cl)=C([H])C(=C1[H])C([H])([H])* 0.000 claims description 13
- 229910052799 carbon Inorganic materials 0.000 claims description 13
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 13
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 13
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 13
- 125000006283 4-chlorobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1Cl)C([H])([H])* 0.000 claims description 12
- 125000003545 alkoxy group Chemical group 0.000 claims description 12
- 125000000623 heterocyclic group Chemical group 0.000 claims description 12
- WSWLBAXHHGNVNQ-UHFFFAOYSA-N 1-[4-(methanesulfonamido)phenyl]cyclopropane-1-carboxylic acid Chemical compound C1=CC(NS(=O)(=O)C)=CC=C1C1(C(O)=O)CC1 WSWLBAXHHGNVNQ-UHFFFAOYSA-N 0.000 claims description 11
- 150000003973 alkyl amines Chemical class 0.000 claims description 11
- UHNKGFIFLKUJKY-UHFFFAOYSA-N benzylazanide Chemical group [NH-]CC1=CC=CC=C1 UHNKGFIFLKUJKY-UHFFFAOYSA-N 0.000 claims description 11
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- DYJHBSVQSMBUOQ-UHFFFAOYSA-N FC=1C=C(C=CC1NS(=O)(=O)C)C(C)NC(=S)N Chemical compound FC=1C=C(C=CC1NS(=O)(=O)C)C(C)NC(=S)N DYJHBSVQSMBUOQ-UHFFFAOYSA-N 0.000 claims description 9
- YMGUBTXCNDTFJI-UHFFFAOYSA-N cyclopropanecarboxylic acid Chemical compound OC(=O)C1CC1 YMGUBTXCNDTFJI-UHFFFAOYSA-N 0.000 claims description 9
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- 230000000694 effects Effects 0.000 claims description 9
- JXDHDLHQQQYACY-UHFFFAOYSA-N 2-[3-fluoro-4-(methanesulfonamido)phenyl]-2-methylpropanoic acid Chemical compound OC(=O)C(C)(C)C1=CC=C(NS(C)(=O)=O)C(F)=C1 JXDHDLHQQQYACY-UHFFFAOYSA-N 0.000 claims description 8
- 125000005907 alkyl ester group Chemical group 0.000 claims description 8
- JBSLANHIBKBQGE-UHFFFAOYSA-N 2-cyclopropylacetamide Chemical compound NC(=O)CC1CC1 JBSLANHIBKBQGE-UHFFFAOYSA-N 0.000 claims description 7
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 claims description 7
- YWISNUJQLNHIBT-UHFFFAOYSA-N 1-[4-(methanesulfonamido)phenyl]ethylurea Chemical compound NC(=O)NC(C)C1=CC=C(NS(C)(=O)=O)C=C1 YWISNUJQLNHIBT-UHFFFAOYSA-N 0.000 claims description 5
- 206010017886 Gastroduodenal ulcer Diseases 0.000 claims description 5
- 206010020751 Hypersensitivity Diseases 0.000 claims description 5
- 206010037660 Pyrexia Diseases 0.000 claims description 5
- 201000005794 allergic hypersensitivity disease Diseases 0.000 claims description 5
- 125000006367 bivalent amino carbonyl group Chemical group [H]N([*:1])C([*:2])=O 0.000 claims description 5
- 230000009610 hypersensitivity Effects 0.000 claims description 5
- 125000002528 4-isopropyl benzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])*)C([H])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 4
- 125000004217 4-methoxybenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1OC([H])([H])[H])C([H])([H])* 0.000 claims description 4
- 125000000590 4-methylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 claims description 4
- 125000001318 4-trifluoromethylbenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])*)C(F)(F)F 0.000 claims description 4
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- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 4
- WPPFGBIUGCNVBO-UHFFFAOYSA-N N-[3,3-bis(4-fluorophenyl)prop-2-enyl]-2-[3-fluoro-4-(methanesulfonamido)phenyl]propanamide Chemical compound C=1C=C(NS(C)(=O)=O)C(F)=CC=1C(C)C(=O)NCC=C(C=1C=CC(F)=CC=1)C1=CC=C(F)C=C1 WPPFGBIUGCNVBO-UHFFFAOYSA-N 0.000 claims description 3
- 239000003085 diluting agent Substances 0.000 claims description 3
- 125000006189 4-phenyl benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 2
- CXENCFIXOJDBHM-UHFFFAOYSA-N N-[3-(3,4-dimethylphenyl)propyl]-2-[4-(methanesulfonamido)phenyl]-2-methylpropanamide Chemical compound C1=C(C)C(C)=CC=C1CCCNC(=O)C(C)(C)C1=CC=C(NS(C)(=O)=O)C=C1 CXENCFIXOJDBHM-UHFFFAOYSA-N 0.000 claims description 2
- DGEZNRSVGBDHLK-UHFFFAOYSA-N [1,10]phenanthroline Chemical compound C1=CN=C2C3=NC=CC=C3C=CC2=C1 DGEZNRSVGBDHLK-UHFFFAOYSA-N 0.000 claims description 2
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- FLZIMWQQPVNOQB-UWJYYQICSA-N [(2S)-2-[[(1S)-1-[4-(methanesulfonamido)phenyl]ethyl]carbamothioylamino]-3-phenylpropyl] 2,2-dimethylpropanoate Chemical compound C([C@@H](COC(=O)C(C)(C)C)NC(=S)N[C@@H](C)C=1C=CC(NS(C)(=O)=O)=CC=1)C1=CC=CC=C1 FLZIMWQQPVNOQB-UWJYYQICSA-N 0.000 claims 1
- FOJDWLDFVVPKDW-UHFFFAOYSA-N [2-[(3,4-dimethylphenyl)methyl]-3-[[2-[3-fluoro-4-(methanesulfonamido)phenyl]-2-methylpropanoyl]amino]propyl] 2,2-dimethylpropanoate Chemical compound C1=C(C)C(C)=CC=C1CC(COC(=O)C(C)(C)C)CNC(=O)C(C)(C)C1=CC=C(NS(C)(=O)=O)C(F)=C1 FOJDWLDFVVPKDW-UHFFFAOYSA-N 0.000 claims 1
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Abstract
The present invention relates to novel 4-(methylsulfonylamino) phenyl analogue as a potent vanilloid receptor antagonist and the pharmaceutical compositions comprising the same. The inventive compound can be useful for analgesics to prevent, alleviate or treat pain diseases or inflammatory disease comprising pain, acute pain, chronic pain, neuropathic pain, post-operative pain, migraine, arthralgia, neuropathies, nerve injury, diabetic neuropathy, neurodegeneration, neurotic skin disorder, stroke, urinary bladder hypersensitiveness, irritable bowel syndrome, a respiratory disorder such as asthma or chronic obstructive pulmonary disease, irritation of skin, eye or mucous membrane, fervescence, stomach-duodenal ulcer, inflammatory bowel disease, inflammatory disease and urgent urinary incontinence.
Description
ANALOGUES OF 4-HYDROCHLORINE) PHENYLENE AS VANILLOID ANTAGONISTS THAT SHOW EXCELLENT ANALGESIC ACTIVITY AND PHARMACEUTICAL COMPOSITIONS THAT INCLUDE THEMSELVES.
TECHNICAL FIELD The present invention relates to novel analogs of 4- (methylsulfonyllamino) phenyl as vanilloid angiogonists which exhibit excellent analgesic activity and to the pharmaceutical compositions comprising the same.
BACKGROUND ART The vanilloid receptor (VR1) is a member of the transient receptor potential (TRP) superfamily. Members of this family are cationic channel proteins not activated by potential that play critical roles in processes ranging from sensory physiology to vasorelaxation and male fertility. They share structural similarities such as six transmembrane segments and an oligomeric structure (Montell, O. et al., Cell, 108, page 595, 2002). The vanilloid or capsaicin receptor (VR1 or TRPV1) has been cloned from rat dorsal root ganglia (DRG), human, chicken, guinea pig, and rabbit (Szallasi, A. et al., Pharmacol. , 51, p 159, 1999, Caterina, MJ et al., Nature, 389, p.816, 1997, Hayes, P. et al., Pain, 88, p 205, 2000. Jordt et al., Cell. , 108, pp. 421, 2002; Savidge, J. et al., Neuropharmacology, 43, p.450, 2002; Gawa, NR et al., J. Biol. Chez., In the printing press, 2004). Vanilloid receptor homologs have also been cloned but are not believed to be vanilloid sensitive (Gunthorpe, M. J. et al., Trends in Pharmacol, Sci, 23, p.m., 183, 2002). VR1, which is expressed predominantly in thin, unmyelinated sensory nerve fibers (C fibers) and small A fibers in the dorsal, trigeminal, and nodular ganglia, is a molecular integrator of nociceptor stimuli. VR1 is activated by protons, heat, natural exogenous ligands such as capsaicin (CAP) or resiniferatoxin (RTX), and endogenous substances such as anandamide and the lipoxygenase product 12-HPETE (Tominaga M. et al., Neuron, 21, p. 531; 1998; Caterina, MJ et al., Nature, 389, pp. 816, 1997; Walpole O SJ et al., Capsaicin in the Study of Pain, Academic Press, San Diego, CA., page 63, 1993; Appendino, G. et al., Life Sci., 60, p.681, 1997; Zygmunt, PM et al., Nature, 400, p.452, 1991; Hwang S., et al., Proc.
Nati Acad. Sci. U.S.A., 97, p. 6155, 2000). Since VR1 functions as a non-selective cationic channel with high Ca2 + permeability, its activation by these agents leads to an increase in intracellular Ca2 + which results in the excitation of the primary sensory neurons and ultimately the central perception of pain. The chronic stimulation of VR1 leads to the desensitization / defunctionalization of neurons, which is probably reflected in multiple mechanisms. The participation of VR1 in both pathological and physiological states suggests that blockade of this receptor, through desensitization or antagonism, would have considerable therapeutic utility. Among its therapeutic objectives, pain is of particular interest. Validation of VR1 as a molecular target for the treatment of chronic pain was confirmed using transgenic mice lacking functional VR1 receptors. These mice showed alteration in the reception of thermal and inflammatory pain (Caterina, M. J. et al., Science, 288, p.306, 2000). The therapeutic advantage of VR1 antagonism over desensitization after agonism is that it avoids the initial excitatory effect that precedes desensitization. The initial acute pain associated with capsaicin treatment has proven to be limiting toxicity. Following the discovery of capsazepine as the first VR1 antagonist (Walpole, O SJ et al., J. Med. Chem., 37, pp. 1942, 1994), several antagonists have been reported to be unachievable with both related and non-agonist related structures. (Walpole, CSJ et al., J. Med. Chem., 37, pp. 1942, 1994). Among them, 5-iodo-RTX, SC0030, halogenated capsaicin analogues, BCTC, SB-366791, 7-hydroxynaphthalen-1-yl-urea, and IBTU were characterized as important competing antagonisms of VR1 (Wahl, P. et al. al., Mol. Pharmacol., 59, page 9, 2001; Seabrook, G.R. et al., J. Pharmacol. Exp. Ther. 303, p. 1052, 2002; Wang, Y. et al., Mol. Pharmacol., 62, p. 947, 2002; Suh, Y-G. et al., Bioorg. Med. Chem. Lett., 13, p. 4389, 2003; Appendino, G. et al., Br. J. Pharmacol., 139, p. 1417, 2003; Valenzano, K. J. et al., J. Pharmacol. Exp. Ther., 306, p. 377, 2003; Pomonis, J. D. et al., J. Pharmacol. Exp. Ther., 306, p. 387, 2003; Sun, Q. et al., Bioorg. Med. Chem. Lett., 13, p. 3611, 2003; Gunthorpe, M. J. et al., Neuropharm., 46, p. 133, 2004; McDonnell, M. E. et al., Bioorg. Med. Chem. Lett., 14, p. 531, 2004; Toth, A. et al., Mol. Pharm., 65, p.282, 2004). It has previously been reported that isosteric substitution of the phenolic hydroxyl group in potent vanilloid receptor agonists (Lee, J. et al., Chem., 9, P. 19, 2001) by the alkylsulfonamido group provides a series of compounds that are antagonists. Effective of the action of capsaicin on rat VR1 expressed heterologously in Chinese hamster ovary cells (CHO). As a protoype, N- [2- (3,4-dimethylbenzyl) -3-pivaloyloxypropyl-N '- [4- (methylsulfonylammon) benzyl] thiourea (1) showed a high binding affinity with a value of K; of 29.3 nM for the inhibition of [3H] RTX binding and a potent antagonism with an IC5o value of 67 nM for the inhibition of 45Ca2 + uptake in response to capsaicin, presenting partial agonism (Wang, Y. et al., Pharm., 64, page 325, 2003). The 2,3-fluoro analogue showed a very potent antagonism with Cl50 = 7.8 nM and analgesic activity in the test of induced convulsions ("writhing test") (Lee, J. et al., Med. Chem., 46, page 3116, 2003).
1 = H 2 R = F The present inventors have endeavored by all means to discover novel analgesic agents based on the above studies and have finally completed the present invention by the synthesis of novel analogs of 4- (methylsulfonylamino) phenyl as vanilloid antagonists. showing excellent analgesic activity and the pharmaceutical compositions comprising the same.
DESCRIPTION OF THE INVENTION In this regard, the present invention provides novel compounds represented by the following formula (I), the pharmaceutically acceptable salt or the isomer thereof:
wherein, A is CONH, NHCO, NHC (= S) NH, NHC (= O) NH; R1 to R4 is independently at least one selected from hydrogen, halogen atom, cyano group, nitro group, lower alkylamine, lower alkoxy group having from 1 to 3 carbon atoms, carboxylic acid, hydroxamic acid, alkyl ester group having from 1 to 6 carbon atoms, alkylamide group having from 1 to 6 carbon atoms, benzylamide group, five or six membered heterocyclic ring; R5 and R6 are independently at least one selected from hydrogen, hydroxyl group, amino group, linear or branched alkyl group having from 1 to 6 carbon atoms, cycloalkyl group having from 1 to 6 carbon atoms and phenyl or benzyl group optionally Substituted with at least one selected from halogen atom, amine group and alkyl group having from 1 to 6 carbons, provided that R5 and R6 are not simultaneously a hydrogen atom; B is a group selected from
wherein R7 to R7 are independently at least one selected from hydrogen, halogen atom and linear or branched alkyl group having from 1 to 6 carbon atoms optionally substituted with more than one halogen atom, C is a selected group of alkyl, alkenyl and alkynyl group having from 1 to 5 carbon atoms, which may include one or more heteroatoms, m, n, p, q, rys is an integer from 0 to 3; an asterisk mark (*) and a C1 ^ mark) indicate a chiral carbon atom, and a double bond or single bond chain, respectively. Examples of "alkyl group" used herein include, but are not limited to, methyl, ethyl, propyl, and the like, and examples of "heterocyclic ring" used herein include, but are not limited to, pyrrole, pyrazole, pyrazine , purine, pyridine, piperazine, piperidine, tazol, morpholine, dioxane and the like. Preferable groups in the general formula (I) of the present invention are the group in which R5 or R6 is methyl, ethyl, propyl, isopropyl, phenyl or benzyl and R7 or R8 is isopropyl, t-butyl or sec-butyl group, but they are limited to them. The compounds of general formula (I) of the present invention comprise all the compounds represented by the following formulas (I) to (V) according to the definition of group A. Accordingly, the present invention provides novel compounds represented by the following formula (II), the pharmaceutically acceptable salt or the isomer thereof: wherein, Ri to R is independently at least one selected from hydrogen, halogen atom, cyano group, nitro group, lower alkylamine, lower alkoxy group having 1 to 3 carbon atoms, carboxylic acid, hydroxamic acid, alkyl ester group having 1 to 6 carbon atoms, alkylamide group having 1 to 6 carbon atoms, benzylamide group, five or six membered heterocyclic ring; R5 and R6 are independently at least one selected from hydrogen, hydroxyl group, amino group, linear or branched alkyl group having from 1 to 6 carbon atoms, cycloalkyl group having from 1 to 6 carbon atoms and phenyl or benzyl group optionally substituted with at least one selected from halogen atom, amine group and alkyl group having from 1 to 6 carbons, provided that R5 and R6 are not simultaneously a hydrogen atom; B is a group selected from group (1-1) to (I-6) defined in the general formula
(I); the asterisk * mark indicates a chiral carbon atom. In preferred embodiments of general formula (II), the most preferred compound is one selected from the group consisting of; N- (4-ferc-butylbenzyl) -2- [3-fluoro-4- (methylsulfonylamino) phenyl] propionamide (1-51,
KMJ-372), N- (4-Ierc-buylbenzyl) -2- [3-chloro-4- (methylsulfonylamino) phenyl] propionamide (1-52, KMJ-470), N- (4-fer-butylbenzyl) - 2- [3-bromo-4- (methylsulfonylamino) phenyl] propionamide (1-53, SH-173), N- (4-ferc-bulylbenzyl) -2- [3-iodo-4- (methylsulfonylamino) phenyl] propionamide (1-54, SH-168), N- (4-ert-butylbenzyl) -2- [3,5-difluoro-4- (methylsulfonylamino) phenyl] propionamide (1-55, SH-285), N- ( 4-urea-butylbenzyl) -2- [3-cyano-4- (methylsulfonyl-amino) phenyl] propionamide (1-56, SH-219), N- (4-ér-butyl-benzyl) -2- [3-ene-buzoxycarbonyl] -4- (methylsulfonylamino) phenyl] propionamide (1-57,
KMJ-806), N- (4-ert-butylbenzyl) -2- [3-carboxyl-4- (methylsulfonylamino) phenyl] propionamide (1-58, KMJ-788), N- (4-ert-butylbenzyl) - 2- [3-methoxycarbonyl-4- (methylsulfonylamino) phenyl] propionamide (1-59, KMJ-838), N- (4-ert-butylbenzyl) -2- [3- (benzylamino) carbonyl-4- (methylsulfonylamino) phenyl] propionamide (1-60, KMJ-836), N- (4-ert-buty-benzyl) -2- [3-piperidino-4- (methylsulfonylamino) phenyl] propionamide (1-61, YS-65), N- (4-Yerc-butylbenzyl) -2- [3-morfoin-4- (methylsulfonylamino) phenyl] propionamide (1-62, YS-49), N- (4-fer-butylbenzyl) -2- [3- (N -Boc) piperazino-4- (methylsulfonylamino) phenyl] propionamide (1-63, YS-76), N- (4-ert-butylbenzyl) -2- [3-piperazino-4- (methylsulfonylamino) phenyl] propionamide (1 -64, YS-79), N- (4-ferc-butylbenzyl) -2- [3-methoxy-4- (methylsulphonylamino) phenyl] propionamide (1-65, CHK-717), N- (4-ene- butylbenzyl) -2- [2-f luoro-4- (methylsulfonylamino) phenyl] propionamide (1-66, KMJ-708), N- (4-fer-buylbenzyl) -2- [2-chloro-4- (methylsulfonyl amine) phenyl] propionamide (1-67, KMJ-698), N- (4- urea-butylbenzyl) -2- [4- (methylsulfonylamino) phenyl] propionamide (2-7, KMJ-750), N- (4-chloro) -2- [4- (methylsulfonylamino) phenyl] propionamide (2-8, YS-85), N- (3,4-dichloro) -2- [4- (methylsulfonylamino) phenyl] propionamide (2-9, YS-97), N- (4-fer-butylbenzyl) - (2S ) -2- [3-fluoro-4- (methylsulfonylamino) phenyl] propionamide (3-5, SU-834), N- (4-fer-butylbenzyl) - (2R) -2- [3-fluoro-4- (Melylsulfonylamino) phenyI] propionamide (3-6, SU-824), N- (4-chlorobenzyl) -2- [3-fluoro-4- (methylsulfonylamino) phenyl] propionamide (4-1, SH-291), N - (4-chlorobenzyl-2- (3-chloro-4- (methylsulfonylamino) phenyl] propionamide (4-2, SH-290), N- (4-chlorobenzyl) 2- [3-bromo-4- (methylsulfonylamino) phenyl] propionamide (4-3, SH-335), N- (3,4-dichlorobenzyl) -2- [3-fluoro-4- (methylsulfonylamino) phenyl] propionamide (4-4, SH-94), N- (3,4-dichlorobenzyl) -2- [3-chloro-4- (methylsulfonylamino) phenyl] propionamide (4-5, SH-286), N- (3,4-dichlorobenzyl) -2- [3-bromo- 4- (methylsulfonylamino) phenyl] propionamide (4-6, SH-337), N- (4-methylbenzyl) -2- [3-fluoro-4- (methylsulfonylamino) phenyl] pr opionamide (4-7, SH-351), N- (4-isopropylbenzyl) -2- [3-fluoro-4- (methylsulfonylamino) phenyl] propionamide (4-8, KMJ-928), N- (4-methoxybenzyl) ) -2- [3-fluoro-4- (methylsulfonylamino) phenyl] proponamide (4-9, SH-353), N- (4-trif luoromethylbenzyl) -2- [3-f luoro-4- (methylsulfonylamino ) f-ethyl] propionamide (4-10, SH-93), N- (4-phenylbenzyl) -2- [3-fluoro-4- (methylsulfonylamino) phenyl] propionamide (4-11, KMJ-498), N- (1-naphthylmethyl) - [3-fluoro-4- (meilylsu-phenylamino) phenyl] propionamide (4-12, SH-92), N- (1,2,3,4-tetrahydro-1-naphthalenyl) -2- [ 3-fluoro-4- (methylsulfonylamino) phenyl] propionamide (4-13, SH-112), N- [2- (4-yerc-butylphenol) etiI] -2- [3-fluoro-4- (methylsulfonylamino) phenyl ] propionamide (4-14, KMJ-374), N- [3- (3, 4-dimethylphenyl) propyl] -2- [3-fluoro-4- (methylsulfonylamino) phenyl] propionamide (4-15, SU -770), N- [3- (3,4-dimethylphenyl) propyl] - (2R) -2- [3-f luoro-4- (methylsulfonylamino) phenyl] propionamide (4-16, SU-774), N- [3- (3,4-dimethylphenyl) propyl] - (2S) -2- [3-fluoro-4- (methylsulfonylamino) phenyl] propionamide (4-17, SU-776) , N- [3- (3,4-dimethylphenyl) -2-propenyl] -2- [3-fluoro-4- (methylsulfonylamino) phenyl] propionamide (4-18, KMJ-686), N- [3- ( 4-chlorophenyl) propyl] -2- [3-fluoro-4- (methylsulfonylamino) phenyl] propionamide (4-19), KMJ-518), N- [3- (4-chlorophenyl) -2-propenyl] -2- [3-fluoro-4- (methylsulfonylamino) phenyl] propioamide (4-20, KMJ-732), N -benzyloxy-2- [3-fluoro-4- (methylsulfonylamino) phenyl] propionamide (4-21, SH-109), N- (benzhydryl) -2- [3-fluoro-4- (methylsulfonylamino) phenyl] propionamide ( 4-22, SH-130), N- (2,2-diphenylethyl) -2- [3-fluoro-4- (methylsulfonylamino) phenyl] propionamide (4-23, SH-116), N- (3.3 -diphenylpropyl) -2- [3-fluoro-4- (methylsulfonylamino) phenyl] propionamide (4-24, KMJ-378), N- (3,3-diphenyl-2-propenyl) -2- [3-fluoro- 4- (methylsulfonylamino) phenyl] propionamide (4-25, KMJ-724), N- [3,3-di (4-methylphenyl) -2-propenyl] -2- [3-fluoro-4- (methylsulfonylamino) phenyl) ] propionamide (4-26, KMJ-908), N- [3,3-di (4-fluorophenyl) -2-propenyl] -2- [3-fluoro-4- (methylsulfonylamino) phenyl] propionamide (4-27) , SH-135), N- [2- (10,11-dihydro-5 H -dibenzo [a, d] cyclohepten-5-ylidene) ethyl] -2- [3-fluoro-4- (melylsulfonylamino) phenyl!] propionamide (4-28, SH-199), N- [2- (3,4-dimethylbenzyl) -3-pivaloxypropyl] -2- [4- (methylsulfonylamino) phenyl] propionamide (5-1, CH K-512), N- [2- (4-ert-butylbenzyl) -3-pivaloxypropyl] -2- [4- (methylsulfonylamino) phenyl] propionamide (5-2, CHK-514), 2- [3-fluorine -4- (methyl) -sulfonylamino) phenyl] -N- [2- (3,4-dimethylbenzyl) -3-pivaloxypropyljpropionamide (5-3, SU-542), 2- [3-fluoro-4- (methylsulfonamino) phenyl) ] -N- [2- (4-fer-butylbenzyl) -3-pivaloxypropyl] propionamide (5-4, SU-564), N- [2- (3,4-dimethylbenzyl) -3-pivaloxypropyl] -2- [3-methoxy-4- (methylsulfonyl) phenyl] proponamide (5-5, CHK-479), N- [2- (4-tert-butylbenzyl) -3-pivaloxypropyl] -2- [3- methoxy-4- (methylsulfonylamino) phenyl] proponamide (5-6, CHK-499), N- [2- (3,4-dimethylbenzyl) -3-pivaloxypropyl] -2- [3-chloro-4- ( methylisulfonyl) phenyl] propionamide (5-7, KNJ-472), N- [2- (4-ert-butylbenzyl) -3-pivaloxypropyl] -2- [3-chloro-4- (methylsulfonylamino) phenyl] propionamide (5 -8, KMJ-690), N - [(1 R) -1-benzyl-2- (pivaloxy) ethyl] - (2S) -2- [3-fluoro-4- (methylsulfonylamino) phenyl] propionamide (6- 1, SU-730), N - [(1S) -1-benzyl-2- (pivaloxy) ethyl] - (2S) -2- [3-fluoro-4- (methylsulfonylamino) phenyl] propionamide (6-2, SU-634), N - [(1S) -1-benzyl-2- (pivaloxy) ethyl] - (2R) -2- [3-fluoro-4- (methylsulfonylamino) phenyl] propionamide (6-3, SU- 636), N - [(1 R) -1-benzyl-2- (pivaloxy) ethyl] - (2R) -2- [3-f luoro-4- (methylsulfonylamino) phenyl] propionamide (6-4, SU- 728), N - [(2R) -2-benzyl-3- (pivaloxy) propyl] - (2S) -2- [3-fluoro-4-rneylsulfonylamino) phenyl] propionamide (6-5, SU-826), N - [(2S) -2-benzyl-3- (pivaloxy) propyl] - (2S) -2- [3-fluoro-4-Cmethylsulfonylamino) phenyl] propionamide (6-6, SU-830), N- [ (2S) -2-benzyl-3- (pivaloxy) propyl] - (2R) -2- [3-fluoro-4- (methylsulfonylamino) phenyl] propionamide (6-7, SU-838), N - [(2R ) -2-benzyl-3- (pivaloxy) propyl] - (2R) -2- [3-fluoro-4- (methylsulfonylamino) phenyl] propionamide (6-8, SU-818), N - [(2R) - 2- (4-Yerc-butyl) benzyl-3- (pivaloxy) propyl] - (2S) -2- [3-fluoro-4-methylmethyl] -lamino) phenyl] propionamide (6-9, MK-271), N - [(2S) -2- (4-ert-butyl) benzyl-3- (pivaloxy) propyl] - (2S) -2- [3-fluoro-4-methoxysulfonylamino) phenyl] (6-10, MK-272), N - [(2S) -2- (4-te / -c-buyl) benzyl-3- (pivaIoxi) propyl] - (2R) -2- [3-fluoro-4- (methylsulfonylamino) phenyl] propionamide (6-11, MK-450), N - [(2R) -2- (4-te? c -butyl) benzyl-3- (pivaloxy) propyl] - (2R) -2- [3-fluoro-4- (methylsulfonylamino) phenyl] propionamide (6-12, MK-452), N - [(2R) -2- (4-fer-buyl) benzyl-3- (pivaloxy) propyl] - ( 2S) -2- [3-chloro-4- (mlsylsulfonylamino) phenyl] propionamide (6-13, MK-453), N - [(2S) -2- (4-yerc-bufil) benzyl-3- (pivaloxy ) propyl] - (2S) -2- [3-chloro-4- (methylsulfonylamino) phenyl] propionamide (6-14, MK-451), 2- [3-fluoro-4- (methylsuphonyl amino) phenyl] -2 -methylpropionic (7-4, CHK-624), 2- [4- (methylsulfonylamino) phenyl] -2-methylpropionic acid (8-11), 2- [3-methoxy-4- (methylsulfonylamino) phenyl] -2 acid -methylpropionic (8-12), N- [2- (3,4-dimethylbenzyl) -3-pivaloxypropyl] -2- [4- (methylsulfonylamino) phenyl] -2-methylpropionamide (9-1, CHK, 520), N- [2- (3,4-dimethylbenzyl) -3-pivanedioxypropyl] -2- [3-fluoro-4- (methylsulfonylamino) phenyl] -2-methylpropionamide (9-2, CHK-543), N- [2 - (3,4-dimethylobenzyl) -3-pivaloxypropyl] -2- [3-methoxy-4- (methylsulfonylamino) phenyl] -2-methylpropionamide (9 -3, CHK-493), N- [3- (3,4-dimethylphenyl) propyl] -2- [4- (methylsulfonylamino) phenyl] -2-methylpropionamide (9-4, CHK-591), N- [3- (3,4-dimethylphenyl) propyI] -2- [3-fluoro-4- (methylsulfonylamino) phenyl] -2-methylpropionamide (9-5, CHK-656), N - [3- (3,4-Dimethylphenyl) propyl] -2- [3-methoxy-4- (methylsulfonylamino) phenyl] -2-meitylpropionamide (9-6, CHK-600), N- (4-yerc-butylbenzyl) ) -2- [4- (Methylsulfonyl) phenyl] -2-methylpropionamide (9-7, CHK-715), N- (4-ér-butylbenzyl) -2- [3-fluoro-4- (methylsulfonylamino) phenyl] -2-methylpropionamide (9-8, CHK-655), N- (4-fer-butylbenzyl) -2- [3-methoxy-4- (methylsulfonylamino) phenyl] -2-methylpropionamide (9-9), acid 1 - [3-fluoro-4- (mlsylsulfonylamino) phenyl] cyclopropanecarboxylic acid (10-5), 1- [4- (methylsulfonylamino) phenyl] cyclopropanecarboxylic acid (11-7, CHK-530), 1- [3-methoxy] 4- (methylsulfonylamino) phenyl] cyclopropanecarboxylic (11-8), N- [2- (3,4-dimethylbenzyl) -3-pivaloxypropyl] -1- [4- (meilylsulfonyllamino) phenyl] cyclopropanecarboxamide (12-1, CHK-533), N- [2- (3,4-dimethylbenzyl) -3-pivaloxypropyl] -1- [3-fluoro-4- (methylsulfonylamino) phenyl] cyclopropanecarboxylamide (12-2, CHK-538) , N- [2- (3,4-dimethylbenzyl) -3-pivaloxypropyl] -1- [3-methoxy-4- (methylsulfonylamino) phenyl] cyclopropanecarboxyamide (12-3, CHK-541), N- [3 - (3,4-Dimethyl-phenyl) propyl] -1- [4- (methylsulfonylamino) phenyl] cyclopropanecarboxamide (12-4, CHK-590), N- [3- (3,4-dimethylphenyl) propyl] - 1 - [3-f luoro-4- (methylsulfonyl amino) f-enyl] cyclopropanecarboxyamide (12-5), N- [3- (3,4-dimethylphenyl) propyl] -1- [3-methoxy-4- ( methylsulfonylamino) phenyl] cyclopropanecarboxyamide (12-6, CHK-632), N- (4-ert-butylbenzyl) -1- [4- (methylsulfonylamino) phenyl] cyclopropanecarboxyamide. (12-7, CHK-719), N- (4-ert-butylbenzyl) -1- [3-fluoro-4- (methylsulfonylamino) phenyl] -cyclopropanecarboxyamide (12-8, CHK-659), N- (4 -erc-butylbenzyl) -1- [3-methoxy-4- (methylsulfonylamino) f enylcyclopropanecarboxyamide (12-9, CHK-718). And the present invention provides novel compounds represented by the following formula (III):
wherein Ri to R4 is independently at least one selected from hydrogen, halogen atom, cyano group, nitro group, lower alkylamine, lower alkoxyl group having from 1 to 3 carbon atoms, carboxylic acid, hydroxamic acid, group alkyl ester having from 1 to 6 carbon atoms, alkylamide group having from 1 to 6 carbon atoms, benzylamide group, five or six membered heterocyclic ring, provided they are not all from Ri to R simultaneously a hydrogen atom; R5 and R6 are independently at least one selected from hydrogen, hydroxyl group, amino group, linear or branched alkyl group having from 1 to 6 carbon atoms, cycloalkyl group having from 1 to 6 carbon atoms and phenyl or benzyl group optionally substituted with at least one selected from halogen atom, amine group and alkyl group having from 1 to 6 carbons, provided that R5 and R6 are not simultaneously a hydrogen atom; B is a group selected from group (1-1) to (I-6) defined in the general formula
(I); the asterisk * mark indicates a chiral carbon atom. In preferred embodiments of general formula (III), the most preferred compound is one selected from the group consisting of; N- (4-tert-butylbenzyl) -N'-. { 1- [3-fluoro-4- (methylsulfonylamino) phenyl] ethyl} thiourea (15-1, LJO-328), N- (4-te / -c-butylbenzyl) -N'-1- [3-chloro-4- (methylsulfonylamino) phenyl] ethyl} thiourea (15-2, CHK-992), N- (4-ert-butylbenzyl) -N'-. { 1- [3-methoxy-4- (methylsulfonylamino) phenyl] ethyl} thiourea (15-3, CHK-575), N- (4-ert-butylbenzyl) -N'-. { 1- [3- (methoxycarbonyl) -4- (methylsulfonylamino) phenyl] etl} thiourea (15-4, YHS-187), N- (4-fer-butylbenzyl) -N'-. { 1- [3-carboxy-4- (meilylsu-phenylamino) phenyl] ethyl} thiourea (15-5, YHS-209), N- (4-eerc-bulylbenzyl) -N'-. { (1R) -1- [4- (Methylsulfonylamino) phenyl] ethyl} thiourea (16-5, SU-388), N- (4-fe / -c-butylbenzyl) -N, -. { (1S) -1- [4- (Meilylsu-phenylamino) phenyl] eyl} Iourea (16-6, SU-400), N- (4-ferc-butylbenzyl) -N, -. { (1 R) -1 - [3-f Iuoro-4- (methylsulfonylamino) phenyl] ethyl} thiourea (17-3, CJU-032), N- (4-ert-butylbenzyl) -N, -. { (1S) -1- [3-fluoro-4- (methylsulfonylamino) phenyl] ethyl} thiourea (17-6, CJU-039), N - [(2R) -2-benzyl-3- (pivaloyloxy) propyl] -N '- (1R) -1- [4- (methylsulfonylamino) phenyl] ethyl} thiourea (18-1, MK-229), N - [(2S) -2-benzyl-3- (pivaloyloxy) propyl] -N'-. { (1 R) -1 - [4- (Methylsulfonylamino) f-ethyl] ethyl} thiourea (18-2, MK-202), N - [(2R) -2-benzyl-3- (pivaloxylo) propyl] -N'-. { (1 S) -1 - [4- (Methylsulfonylamino) phenyl] ethyl} thiourea (18-3, MK-230), N - [(2S) -2-benzyl-3- (pivaloyloxyJpropylo-N'-NISIS-l-μ-ylsilylsulfonylamino-J-phenyl) vyiourea (18-4, MK-228), N- [ 2- (3,4-dimethylbenzyl) -3- (pivaloyloxy) propyl] -N'- { 1- [4- (methylsulfonyllamino) phenyl] etl.} Thiourea (18-5, LJO- 388), N- [2- (3,4-dimethylbenzyl) -3- (pivaloyloxy) propyl] -N'- { (1 R) -1- [4- (methylsulfonylamino) phenyl] ethyl.} Thiourea (18-6, SU-472), N - [(2R) -2- (3,4-dimethylbenzyl) -3- (pivaloiIoxi) propyl] -N'- { (1R) -1- [4- (methylsulfonylamino) phenyl] ethyl.} thiourea (18-7, SU-512), N - [(2S) -2- (3,4-dimethylbenzyl) -3- (pivaloyloxy) propyl] -N'- . {(1R) -1- [4- (Methylsulfonylamino) phenyl] ethyl} thiourea (18-8), N- [2- (4-phe / -c-butylbenzyl) -3- (pivaloyloxy) propyl ] -N'-yl- -methyl-sulphonylamino-phenyl-jettyl thiourea (18-9, LJO-401), N- [2- (4-ert-butyl-benzyl) -3- (pivaloyloxy) propyl] -N'- { 1 (R) - [4- (Methylsulfonylamino) phenyl] ethyl.} Thiourea (18-10, MK-296), N- [2 (R) - (4-ferc-buylbenzyl) -3- (pivaloyloxy) propiI] -N, - { 1 (R) - [4- (Methylsulfonylamino) phenyl] etl.} Thiourea (1. 8-11, MK-334), N- [2 (S) - (4-ert-butylbenzyl) -3- (pivaloyloxy) propyl] -N'-. { 1 (R) - [4- (Methylsulfonylamino) phenyl] ethyl} thiourea (18-12, MK-298), N - ^ - (S ^ -idimethylbenz-S-Ípivaloyloxypropylj-N'-tl-tS-fluoro ^ - (methylsulphonylamino) phenyl] elyl.} iourea (18-13 , LJO-344), N- [2- (4-yerc-buylbenzyl) -3- (pivaloyloxy) propyl] -N'- { 1 - [3-fluoro-4- (methylsulfonylamino) phenyl] ethyl. thiourea (18-14, LJO-366), N - [(2R) -3-phenyl-1-pivaloyloxy-2-propyl] -N '- [(R) - -methyl-4- (methylsulfonylamino) benzyl] thiourea (19-13, SU-692), N - [(2S) -3-phenyl-1-pivaloyloxy-2-propyl] -N '- [(R) - - methyl - 4- (methylsulfonylamino) benzyl] thiourea (19-14, SU-704), N - [(2R) -3-phenyl-1-pivaloyloxy-2-propyl] -N '- [(S) -a-methyl-4- (methylsulfonylamino) benzyl] thiourea (19-15), SU-720), N - [(2S) -3-phenyl-1-pivayloxy-2-propyl] -N '- [(S) - -methyl-4- (methylsulfonylamino) benzyl] thiourea (19- 16, SU-710), N- (4-ert-butylbenzyl) -N'-. { 1- [4- (Methylsulfonylamino) -3-f luorofenyl] propyl} thiourea (20-12, LJO-399), N- (4-yerc-butylbenzyl) -N'-yl - ^ - imethylsufonionaminoyl-S-fluorophenylj ^ -methylpropyl iourea (20-13, LJO-402), N- ( 4-Yerc-butylbenzyl-N '- ^ - methylmethylsulphonylamino-Sf luorofenyl] (phenyl) -methyl} thiourea (20-14, LJO-403), N- (4-fer-butyl-benzyl) -N, -. { 1- [4- (methylsulfonylamino) -3-fluorophenyl] -2-phenylethyl.] Thiourea (20-15, LJO-395), N- (4-ye / -c-butylbenzyl) -N'- { 1-methyI-1- [4- (methylsulphonylamino) phenyl] ethyl} thiourea (21-7, CHK-593), N- (4-ene-C-buylbenzyl) -N'-. meilyl 1- [3-fluoro-4- (methylisulfonyl amino) phenyl] ethyl} thiourea (21-8, CHK-660), N- (4-yerc-buylbenzyl) -N'-. {1-methyl} -1 - [3-methoxy-4- (methylsulfonylamino) phenyl] ethyl.} Thiourea (21 -9, CHK-629), N- (4-yerc-butylbenzyl) -N'- { 1 - [4 - (Methylsulphonylamino) phenyl] cyclopropyl.} thiourea (22-7, CHK-579), N- (4-yerc-butylbenzyl) -N'- { 1 - [3-f iuoro-4- (methylsulphonylamine ) phenyI] cyclopropyl.} thiourea (22-8), N- (4-tert-butylbenzyl) -N'- { 1 - [3-methoxy-4- (methylsulfonylamino) phenyI] cyclopropyl. thiourea (22-9, CHK-631). And the present invention provides novel compounds represented by the following formula (IV):
wherein Ri to R is independently at least one selected from hydrogen, halogen atom, cyano group, nitro group, lower alkylamine, lower alkoxy group having from 1 to 3 carbon atoms, carboxylic acid, hydroxamic acid, group alkyl ester having from 1 to 6 carbon atoms, alkylamide group having from 1 to 6 carbon atoms, benzylamide group, five or six membered heterocyclic ring; R5 and R6 are independently at least one selected from hydrogen, hydroxyl group, amino group, linear or branched alkyl group having from 1 to 6 carbon atoms, cycloalkyl group having from 1 to 6 carbon atoms and phenyl or benzyl group optionally substituted with at least one selected from halogen atom, amine group and alkyl group having from 1 to 6 carbons, provided that R5 and R6 are not simultaneously a hydrogen atom; B is a group selected from the group (1-1) to (I-6) defined in the general formula); the asterisk * mark indicates a chiral carbon atom. In preferred embodiments of general formula (IV), the most preferred compound is one selected from the group consisting of; N- (4-ert-butylbenzyl) -N, -. { 1- [4- (methylsulfonylamino) phenyl] etiI} urea (23-1, MK-82), N- (4-urea-butylbenzyl) -N, -. { 1- [3-fluoro-4- (melylsulfonylamino) phenyl] eyl} urea (23-2, MK-205).
And the present invention provides novel compounds represented by the following formula (V):
wherein, R) to R4 is independently at least one selected from hydrogen, halogen atom, cyano group, nitro group, lower alkylamine, lower alkoxy group having from 1 to 3 carbon atoms, carboxylic acid, hydroxamic acid, group alkyl ester having 1 to 6 carbon atoms, alkylamide group having 1 to 6 carbon atoms, benzylamide group, five or six membered heterocyclic ring; R5 and R6 are independently at least one selected from hydrogen, hydroxyl group, amino group, linear or branched alkyl group having from 1 to 6 carbon atoms, cycloalkyl group having from 1 to 6 carbon atoms and phenyl or benzyl group optionally substituted with at least one selected from halogen atom, amine group and alkyl group having from 1 to 6 carbons, provided that R5 and R6 are not simultaneously a hydrogen atom; B is a group selected from the group (1-1) to (1-6) defined in the general formula (0, the asterisk * indicates a chiral carbon atom.In a preferred embodiment of general formula (V), the more preferred compound is one selected from the group consisting of: N-. {1- [3-fIuoro-4- (methylsulfonylamino) pheny] ethyl} -3- (4-tert-7-butylphenyl) ) aceiamide (24-1, KMJ-586), N-1- [3-fluoro-4- (methylsulfonylamino) phenyl] ethyl] -3- (4-ert-butylphenyl) propanamide (24-2, KMJ- 552), N- { 1- [3-fluoro-4- (methylsulfonylamino) phenyl] ethyl.}. -3- (4-ert-butylphenyl) -2-propenamide (24-3, KMJ-570), N- {1- [3-fluoro-4- (methylsulfonylamino) phenyl] ethyl} -3- (3,4-dimethylphenyl) propanamide (24-4, CHK-602), N-. {1 - [3-fluoro-4- (methylsulfonylamino) phenyl] ethyl.}. -3- (3,4-dimethylphenyl) -2-propenamide
(24-5, CHK-651), N-. { 1- [3-fluoro-4- (mephsulfonylamino) phenyl] ethyl} -3- (4-chlorophenyl) -propanamide (24-6, KMJ-534), N-. { 1- [3-fIuoro-4- (methylsulfonylamino) phenyl] ethyl} -3- (4-chlorophenyl) -2-propenamide (24-7, KMJ-558), N-. { 1 - [3-fIuoro-4- (methylsulfonylamino) phenyl] ethyl} -3- (3,4-dimethylphenyl) butanamide (24-8, CHK-647). The term "salt" used in the present document includes all pharmaceutic salts well known in the art. The compounds of the invention represented by the general formulas (I) to (V) can be transformed into their pharmaceutically acceptable salts and solvates by the conventional method well known in the art. For the salts, the acid addition salt thereof formed by a pharmaceutically acceptable free acid thereof is useful and can be prepared by the conventional method. For example, after dissolving the compound in an excess amount of acid solution, the salts are precipitated by a water miscible organic solvent such as methanol, ethanol, acetone or acetonitrile to prepare the acid addition salt thereof and in addition the mixture of the equivalent amount of compound and diluted acid with water or alcohol such as monomethyl glycol ether, it can be heated and subsequently dried by evaporation or filtered under reduced pressure to obtain the dried salt form thereof. As the free acid of the method described above, an organic acid or an inorganic acid can be used. For example, an organic acid such as methanesulfonic acid, p-toluenesulfonic acid, acetic acid, trifluoroacetic acid, citric acid, maleic acid, succinic acid, oxalic acid, benzoic acid, lactic acid, glycolic acid, acid can be used herein. gluconic acid, galacturonic acid, glutamic acid, glutaric acid, glucuronic acid, aspartic acid, ascorbic acid, carbonyl acid, vanillic acid, hydroiodic acid and the like, and inorganic acids such as hydrochloric acid, phosphoric acid, sulfuric acid, nitric acid, tartaric acid and similar. In addition, the pharmaceutically acceptable metal salt form of the compounds of the invention can be prepared using a base. The alkali metal or alkaline earth metal salt thereof can be prepared by the conventional method, for example, after dissolving the compound in an excess amount of the solution of alkali metal hydroxide or alkaline earth metal hydroxide, the insoluble salts are filtered and submit the remaining filtrate to evaporation and dry to obtain the metal salt thereof. As the metal salt of the present invention, sodium, potassium or calcium salts are pharmaceutically suitable and the corresponding silver salt can be prepared by reacting the alkali metal salt or alkaline earth metal salt with a suitable silver salt such as silver nitrate. The pharmaceutically acceptable salt of the compound represented by the general formula (I) to (V) comprises all the acidic or basic salts that may be present in the compounds, if not specifically indicated herein. For example, the pharmaceutically acceptable salt of the present invention comprises the salt of the hydroxyl group such as the sodium, calcium and potassium salt thereof.; salt of the amino group such as the salt of hydrogen bromide salt, sulfuric acid salt, hidrogenosulfúrico acid salt, phosphate salt, hydrogen phosphate salt, dihydrophosphate, acetate salt, succinate salt, citrate salt, salt tartarate, lactal salt, mandelate salt, methanesulfonate salt (mesylate) and p-toluenesulfonate salt (tosylate) etc., which can be prepared by the conventional method known in the art. The term "isomer" as used herein includes all isomers, for example, stereoisomer, optically active isomer, racemic mixture, enantiomer and the like well known in the art. They can exist as optically different diastereomers since the compounds of the present invention have one or more asymmetric centers (*), accordingly, the compounds of the present nvención comprise all the optically active isomers, R or S stereoisomers and mixtures thereof. The present invention also comprises all or uses of the racemic mixture, one or more optically active isomers and mixtures thereof and preparation methods for preparing the isomers, for example, asymmetric synthesis, and isolation methods for isolating the isomers , for example, fractional recrystallization method, chromatographic method, well known in the art or the method disclosed herein. And, the present invention provides a method for preparing novel compounds represented by the general formulas (I) to (V) described herein which comprise the methods explained by the following examples or preferred embodiments. The compounds of the invention of formula (I) to (V) may be chemically synthesized by the methods explained by following reaction schemes below herein, which are merely exemplary and do not limit in any way the invention. The reaction schemes show the steps for preparing the representative compounds of the present invention, and the other compounds can also be produced by following the steps with appropriate modifications of reagents and starting materials, which are envisioned by those skilled in the art.
GENERAL SYNTHETIC PROCEDURES Scheme 1
SfeCl, Pradipa
As shown in Scheme 1 above, the reaction consists of five stages as follows: in a 1st step, the mixture of nitrobenzene having various substituents R1 to R and ethyl 2-halogenopropion, such as 2, is reacted. ethyl-chloropropionate, with a metal salt alkoxide solution, such as potassium-butoxide dissolved in DMF, dropwise at a temperature ranging from 0 ° C to room temperature, for a period ranging from 3 to 30 min., preferably 10 min. The reaction is stopped with acid, for example, 1 N HCl, diluted with water and extracted repeatedly with diethyl ether to obtain the organic solvent phase. The organic solvent phase is washed with water and saline water, dried, concentrated in vacuo and the residue is further purified by the flash column method to obtain the intermediate 2- (3-halo-4-nitrophenyl) propionate. of ethyl (1-1 to 1-12) by alkylation of the 4-position on the phenyl ring; in a 2- step, the propionate intermediate (1-1 to 1-12) is reduced with a reducing agent, for example, 10% Pd / C (hydrogenation reaction, method A) or Fe ion in the presence of acetic acid (method B). The resulting product is filtered and the filtrates are dried under vacuum and purified by the flash column method to obtain the intermediate 2- (4-amino-3-halophenyl) propionate ethyl (1-13 to 1-25). by reducing the nitro group to amino group; in a 3 iapa, the compound of propionalo (1-13 to 1-25) is reacted with sulfonyl halide, preferably methanesulfonyl chloride dissolved in pyridine solvent with stirring, and the resulting product is washed with water and purified with the ultrafast column chromatography method to obtain the intermediate 2- (3-halo-4 (methylsulfoniamino) phenyl) ethyl propionate (1-26 to 1-37) by a sulfonation process; in a fourth step, the propionate compound (1-26 to 1-37), dissolved in a mixed solvent mixed with water and THF, is reacted with a metal hydroxide such as lithium hydroxide, dropwise with stirring and acidified with an acid solution such as a 1 N HCl solution to obtain an organic phase. The organic phase is extracted and dried to yield the carboxylic acid compound (1-38 to 1-50) by a hydrolysis process; in a 5th step, 2- [3-halo-4- (methylsulfonylamino) phenyl] propionate is added dropwise to an EDC solution containing an amine compound such as 4-t-butylbenzylamine at a temperature ranging from 02C to room temperature, the resulting residue is stirred, filtered, concentrated and the resulting residue is further purified with the ultrafast column chromatography method obtaining the proposed final product, N- (4-t-butylbenzyl) -2- [2 or 3-substituted-4- (methylsulfonylamino) phenyl] propionamide (1-51 to 1-67), a derivative represented by the general formula (II) having a group B (I-2), by coupling the acid with the amine group.
H2? Fd-Ú As shown in scheme 2 above, the compound represented by the general formula (II) having a group A (NHCO), R5 (meyilo) and R6 (H) can be prepared by the following procedure: it is coupled 2- (4-nitrophenyl) propionic acid conventionally available with an amine (RNH2) to produce an amide (2-1 to 2-3) and the amide is reduced to produce an amine compound (2-4 to 2-6) . Finally, the amine is subjected to methylsulfonation obtaining the final product (2-7 to 2-9). The compound represented by the general formula (II) can comprise various optical isomers, for example, enantiomer, stereoisomer, diastereomer, etc., according to the B residue containing a chiral carbon, and the various isomers can be synthesized and isolated by the procedure explained through the following schemes 3 and 4.
Scheme 3
L-phenyle ninol
As shown in scheme 3 above, the carboxylic acid (1-19) obtained in scheme 1 is reacted with L-phenylalaninol in the presence of EDC to produce the amide (3-1). The amide is hydrolyzed with a strong acid such as sulfuric acid to obtain a specific R (3-3) isomer or S (3-4) form and is further reacted with amine producing enantiomers of form R (3-5) or S (3-6) optically active represented by the general formula (II) having the residue B 0-1).
Scheme 4
As depicted in scheme 4 above, the carboxylic acid (1-38 to 1-40) obtained in scheme 1 is reacted with an amine having appropriate substituents B in the presence of EDC to produce the proposed amide compound proposed. by the general formula (II) that has the remainder B (I-2).
Scheme 5
54 R? =? Rf = 3, - S- ftpH R2 fcBa '5-4 RpF RH B «? -d R | = 0CHa R ßjWiíes S-ft RJ = 0ÉHÍ R ^ fB l 5-7 R? = CP ^ = S, 4 -stS2 6 f? fCI KM-É &i As depicted in scheme 5 above, the carboxylic acid obtained in scheme 1 is reacted with an amine having appropriate substituents B in the presence of EDC to produce the amide compound proposal represented by the general formula (II) that has the remainder B (I-2).
Scheme 6
As depicted in Scheme 6 above, the carboxylic acid obtained in scheme 1 is reacted with an amine having suitable B substituents in the presence of EDC to produce the proposed optically active amide compound represented by the general formula (II) that is the reslo B (I-2) that contains a chiral carbon. The remainder B-NH2 (I-2) having enantiomers of form (R) or form (S) is reacted due to the chiral carbon located in position 2 with the form (R) or the form (S) of the carboxylic acid obtained in Scheme 1 to produce various stereoisomers, namely, acíivos, ie (1S, 2R), (1S, 2S), (1R, 2R) and (1R, 2S).
The compound having a lower alkyl group in R5 and R6 can be prepared by the following procedures shown in scheme 7 and scheme 8:
Scheme 7
For example, as depicted in Scheme 7 above, the compound having a halogen atom in any of Ri and R can be prepared as follows: The ester (1-13) is reacted with an appropriate alkylating agent, that is, methyl iodide, in the presence of DMF and hydrogenated metal such as NaH obtaining the dimethyloyl compound (7-1), and in addition similar reactions are carried out to the stages ranging from the 2- stage to the 4- step in scheme 1 to produce the compound represented by the general formula (II) having a dimethyl group (7-4).
Scheme 8
For example, the compound having a lower alkoxy group or hydrogen atom in any of Ri and R4 and methyl groups in both R5 and R6 can be prepared by the process depicted in scheme 8 above.
Scheme 9
For example, the compound having an NHCO group on the A moiety and methyl groups on both R5 and R6 can be prepared by the process depicted in scheme 9 above. As depicted in scheme 9 above, the carboxylic acid (8-11, 7-4, 8-12) is reacted with an amine having appropriate substituents B in the presence of EDC to produce the proposed compound represented by the formula general (II) having a NHCO group in residue B. Scheme 10
H ^ toC
The compound represented by the general formula (II) having a cycloalkane in R5 and R6 and halogen atoms in any of ñ and R4 can be prepared by the process represented in scheme 10.
Scheme 11
11-3 R? H S4 P.fsOCHs 1 ^ 2 Rf = t) ßHg íí4 sQ ft IfcCl ptridine
1 RF »ÜC • 11-B Rf OCH3
The compound represented by the general formula (II) having a cycloalkane in R5 and R6 and a methoxyl group in any of Ri and R can be prepared by the process depicted in scheme 11. For example, the ester is reacted (8- 3, 8-4) with a dihaloalkane reagent, such as 1,2-dibromomethane, in the presence of a metal hydride, such as NaH, to produce intermediate cycloalkyl compounds (11-2, 11-2) and are serial steps comprising reduction, mesylation and alkylation reactions to obtain the final carboxylic acid product (11-7, 11-8).
Scheme 12
As shown in scheme 12, the carboxylic acid product (11-7, 11-8) is reacted with an amine having an appropriate B-residue in the presence of EDC to obtain the final compound represented by the general formula ( II) having a cycloalkyl group in R5 and R6. The compound represented by the general formula (III) and the general formula (IV) having a methyl and hydrogen group in R5 and R6 can be prepared by the process depicted in schemes 13 to 15.
Scheme 13
As depicted in scheme 13 above, the reaction consists of four steps as follows: in a? -step, the 4-iodoamine compound (13-1 to 13-2) dissolved in pyridine is reacted with an agent of sulfonation, for example, methanesulfonyl chloride, with stirring. The resulting organic solvent phase is extracted, dried, concentrated in vacuo and the residue is further purified with the flash column chromatography method obtaining a sulfonylamine compound (13-3 to 13-4) by transformation of amine to group sulfonyl; in a 2- step, the sulfonylamine compound (13-3 to 13-4) dissolved in DMF is reacted with a metal acetate, preferably Pd (II) acetamide or TI (I) acetate, in the presence of DPPP ( 1, 3-bisdiphenylphosphinopropane) and butyl vinyl ether at a temperature ranging from 60 to 110 ° C for a period ranging from 5 to 24 hours and the reaction mixture is cooled to a temperature ranging from 0 C to room temperature. An acid solution such as 10% HCl is added thereto and stirred. The reaction mixture is diluted with ethyl acetate, washed with a solution of ammonium chloride, concentrated in vacuo and purified by the method of column chromatography to obtain a ketone compound (13-5 to 13-7).; in a 3rd step, the ketone compound and an acid halide salt in pyridine are dissolved and heated to a temperature ranging from 40 to 90 ° C, preferably 70 ° C, for a period ranging from 30 min. up to 5 hours The reaction mixture is cooled, diluted and the resulting organic phase is purified with the ultra-short column chromatography method obtaining oxime derivatives (13-8 to 13-10) by replacing the ketone with an oxime group; in an A-stage, the oxime derivatives are hydrogenated with a reducing agent, for example, 10% Pd / C dissolved in a lower alcohol, for example, methanol. The resultant is filtered and the filtrate is purified with the flash column chromatography method obtaining an intermediate amine compound (13-11 to 13-13) by reducing the nitro group to the amine group as can be observed in scheme 13.
Scheme 14
The compound having a chloro group or methoxyl group in any of Ri to R can be prepared by the process depicted in scheme 14.
Scheme 15
The thiourea compound represented by the general formula (III) and the urea compound of the general formula (IV) can be prepared by the process represented in scheme 15. As shown in scheme 15, the amine compound obtained in the scheme 14 and the isocyanate compound (B-NCS) or the cyanate compound (B-NCO) having an appropriate B moiety are dissolved in DMF and stirred at a temperature ranging from 0 ° C to the ambient temperature for a period of time. which ranges from 30 min to 4 hours, preferably 2 hours. The reaction mixture is diluted with water and the organic solvent phase is extracted, dried, concentrated under vacuum and purified by the flash column method to obtain the thiourea compound or proposed urea compounds (15-1 to 15-). 5, 18-1 to 18-6, 19-5 to 19-12, 23-1 to 23-2) by the coupling reaction.
Scheme 16
The stereoisomers of the compound represented by the general formula (III) and the general formula (IV) having hydrogen atoms in all of R-t to R4 can be prepared by the process depicted in scheme 16.
Scheme 17
The stereoisomers of the compound represented by the general formula (III) and the general formula (IV) having a halogen atom in any of Ri to R4 can be prepared by the process depicted in schemes 17 and 18. As depicted in the scheme 17 above, 3'-fluoro-4 (methylsulfonylamino) acetophenone is coupled with optically active sulfonamine of R-form or S-form respectively and reduced with a reducing agent, such as NaBH 4, to synthesize the sulfonamine isomers of Form R or Form S (17-1 and 17-4) respectively. In addition, these amine isomers are hydrolyzed under acidic conditions to obtain the optically active amine (17-2, 17-5). A procedure similar to the method in scheme 13 is carried out to obtain the (R) or (S) -thiourea represented by the general formula (III) or the urea represented by the general formula (IV), which are active (17-3) and 17-6).
Scheme 18
As shown in scheme 18, the amine is reacted with benzylamine in the presence of EDC to obtain the final compound thiourea represented by the formula (II) which is a group (I-2) in residue B.
Scheme 19
W4 E W R "ÍS S
134 * 1R.2R 10.6 1R.2R ^ Mz 19-S 1R, 2R R »NHÍ 1544 1RJ2S í $ .s iR, as IO 19-li 1RJS RBUHJ 1S-15 1SJ2R 19-7 -f S # S! RW? O2 49 ^ 1S.2R RBMHJ 1545 1S, 2S 15 1SJJS SMOJJ As depicted in scheme 19 above, the alcohol is reacted with pivaloyl halide, for example, pivaloyl chloride (Me3CCOCl), under acidic conditions obtaining the amine (19-1 and 19-2). In addition, the amine is reacted with 1,1-thiocarbonyldiimidazole (TCD) in the presence of the DMF solvent producing the isothiocyanate (19-3, 19-4). The isocyanate is reacted with (R) or (S) -alpha-methyl-4-nitrobenzylamine HCl in the presence of a base, for example, TEA, is reduced with a reducing agent, for example, Al-Hg, and it is subjected to mesylation obtaining the (1S, 2R), (1S, 2S), (1R, 2R) and (1R, 2S) -thiourea represented by the general formula (III) or the urea represented by the formula general (IV) (19-3 to 19-16).
The intermediate amine compound (13-11 to 13-13) can be prepared by the process depicted in the following scheme 20.
Scheme 20
28ß «" CHsCHg aw B ", PSW: ao-a R -CH? SH ^ afls .R ^ CMCCHsia« * R * Ph 28 1 R = CH; fh 94 R B CHJPN
2M2 R = CH £ CH3 2843 S «CHCCHá2 - £ 044 R« Pt *
As shown in scheme 20, 2-fluoro-4-iodoaniline is reacted with tetrakis (triphenylphosphine) palladium and tributyl vinyl tin in the presence of a catalytic amount of 2,6-di-fer-butyl-4- methylol enol to obtain 2-f luoro-4-vinylaniline (21 -1). The resulting compound is reacted with a sulfonating agent such as methanesulfonyl chloride in the presence of pyridine solvent to produce N- (2-lu-fluoro-4-vinylphenyl) methanesulfonamide (20-2) and oxidized with an oxidizing agent, for example osmium tetraoxide and sodium periodate, in the presence of a solvent of acetone-water mixture to give the aldehyde in the middle (20-3). In addition, the aldehyde compound is reacted with a Grignard reagent to obtain the intermediate alcohol (2-4 to 20-7) and is further reacted with DPPA (diphenylphosphorylazide) and DBU (1,8-diazabicyclo [5.4.0 ] undec-7-ene) in the presence of toluene solvent yielding an azide compound (20-8 to 20-11). Finally, the intermediate azide is reduced with a reducing agent such as Pd / C producing the proposed amine derivative (13-11 to 13-13) selectively. The thiourea compound represented by the general formula (III) or the urea compound represented by the general formula (IV) having methyl groups in both R5 and R6 can be prepared by the procedure shown in the following scheme 21.
Scheme 21
8-11 R = H fltíß 21-1 R = H 4 R = F 21 * 2 R3? . 8-12 R = Q? 21.3 OQHs
As depicted in scheme 21, the carboxylic acid compound (8-11, 7-4, 8-12) is reacted with DPPA (diphenylphosphorylazide) and a molecular sieve in the presence of base such as TEA and solvent is added organic and benzyl alcohol to the reaction mixture obtaining a carbamate (21-1 to 21-3) by the reaction of Curtis. The carbamate compound is subjected to a reduction process with a reducing agent such as Pd / C in H gas by obtaining an intermediate amine (21-4 to 21-6) and furthermore it undergoes the coupling reaction shown in the scheme 15 obtaining the proposed amine, which is reacted with benzylamine in the presence of EDC to obtain the final thiourea compound represented by the general formula (III) or the urea compound represented by the general formula (IV).
Scheme 22
reflux t-7 R = H 22-1 RsH. 18-7 F F 22-a -R = F 22-3 RsOCI ^
The thiourea compound represented by the general formula (III) or the urea compound represented by the general formula (IV) having a cyclopropyl group in sye can be prepared by the process shown in scheme 22. As depicted in scheme 22 , the carboxylic acid compound (8-11, 7-4, 8-12) is reacted with DPPA (diphenylphosphorylazide) and a molecular sieve in the presence of base such as TEA, and organic solvent and benzyl alcohol are added to the mixture. reaction obtaining a carbamate (22-1 to 22-3) by the Curtis reaction. The carbamate compound is subjected to a reduction process with a reducing agent such as Pd / C in H2 gas to obtain an intermediate amine (22-4 to 22-6) and furthermore it is subjected to the coupling reaction shown in the scheme 15 obtaining the proposed amine, which is reacted with benzylamine in the presence of EDC to obtain the final thiourea compound represented by the general formula (III) or the urea compound represented by the general formula (IV).
Scheme 23
1341 R = H ffj JJ The urea compound represented by the general formula (IV) having methyl or hydrogen in R5 and R6 can be prepared by the process shown in scheme 23. The present invention also provides a pharmaceutical composition comprising a compound of formula (I) to (V) or a pharmaceutically acceptable salt thereof as an active ingredient for a vanilloid receptor antagonist. The compound of formula (I) to (V) according to the present invention has potent analgesic and anilinflamalor activity, and the pharmaceutical composition of the present invention can be used, therefore, to alleviate or soothe acute, chronic or inflammatory pains or to suppress inflammation and to treat urgent urinary incontinence. The present invention also provides a pharmaceutical composition comprising the compound selected from the group consisting of compounds of formula (1) to (V) or the pharmaceutically acceptable salts thereof to prevent and bring diseases with pain or inflammatory diseases. Diseases with pain and inflammatory diseases comprise at least one selected from the group consisting of pain, acute pain, chronic pain, neuropathic pain, postoperative pain, migraine, arthralgia, neuropathies, nerve injury, diabetic neuropathy, neurodegeneration, neurotic skin disorder , stroke, hypersensitivity of the urinary bladder, irritable bowel syndrome, a respiratory disorder such as asthma or chronic obstructive pulmonary disease, irritation of the skin, eyes or mucous membrane, fever, gastroduodenal ulcer, inflammatory bowel disease and the like. The present invention also provides a pharmaceutical composition comprising the compound selected from the group consisting of compounds of formula (I) to (V) or pharmaceutically acceptable salts thereof for preventing and treating urgent urinary incontinence.
The pharmaceutical composition of the present invention comprises the compounds of the invention in an amount of between 0.0001 and 10% by weight, preferably from 0.0001 to 1% by weight, based on the total weight of the composition.
The present invention also provides a use of a compound selected from the group consisting of compounds of formula (I) to (V) or the pharmaceutically acceptable salts thereof as vanilloid receptor antagonists. According to another aspect of the present invention, there is also provided a use of compound (I) to (V) for the manufacture of medicaments used to alleviate or treat pain, acute pain, chronic pain, neuropathic pain, postoperative pain, migraine, arthralgia , neuropathies, nerve injury, diabetic neuropathy, neurodegeneration, neurotic skin disorder, stroke, hypersensitivity of the urinary bladder, irritable bowel syndrome, a respiratory disorder such as asthma or chronic obstructive pulmonary disease, irritation of the skin, eyes or mucous membrane, fever, gastroduodenal ulcer, inflammatory disease of the ininsíino or urgent urinary incontinence. The compound of formula (I) to (V) according to the present invention can be arranged as a pharmaceutical composition comprising pharmaceutically acceptable carriers, adjuvants or diluents. For example, 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 vehicles include physiological saline, polyethylene glycol, ethanol, vegetable oils, isopropyl myristate, etc., but are not limited thereto. For topical administration, the compounds of the present invention can be formulated in the form of ointments and creams. According to another aspect of the present invention, a method is also provided for alleviating or bringing pain, acute pain, chronic pain, neuropathic pain, postoperative pain, migraine, arthralgia, neuropathies, nerve injury, diabetic neuropathy, neurodegeneration, neurotic disorder of the skin, stroke, hypersensitivity of the urinary bladder, irritable bowel syndrome, a respiratory disorder such as asthma or chronic obstructive pulmonary disease, irritation of the skin, eyes or mucous membrane, fever, gastroduodenal ulcer, inflammatory bowel disease, inflammatory disease or urgent urinary incontinence, wherein the method comprises administering a therapeutically effective amount of the compound of formula (I) to (V) or the pharmaceutically acceptable salt thereof. Hereinafter, the following formulation methods and excipients are merely by way of example and do not limit the invention in any way. The compounds of the present invention in pharmaceutical forms can be used in the form of their pharmaceutically acceptable salts, and may also be used alone or in an appropriate association, as well as in combination with other pharmaceutically active principles. The compounds of the present invention can be formulated into injection preparations by dissolving, suspending or emulsifying them in aqueous solvents such as normal saline, 5% dextrose, or non-aqueous solvents such as vegetable oil, synthetic aliphatic acid glycerides, aliphatic acid esters superior or propylene glycol. The formulation may include conventional additives such as solubilizers, isotonic agents, suspension agents, emulsifying agents, stabilizers and preservatives. The desirable dose of the compounds of the invention varies depending on the condition and weight of the patient, the severity, the pharmacological form, the route and period of administration, and can be chosen by those skilled in the art. However, in order to obtain the desirable effects, it is generally recommended to administer an amount ranging between 0.0001-100 mg kg, preferably 0.001-100 mg / kg weight / day of the compounds of the invention, of the present invention. The dose can be administered once or divided into several times a day. As for the composition, the compounds should be present between 0.0001 and 10% by weight, preferably 0.0001 to 1% by weight, based on the total weight of the composition.
The pharmaceutical composition of the present invention can be administered to an animal subject such as mammals (rat, mouse, domestic animals or human) through several routes. All modes of administration are contemplated, for example, administration can be performed orally, rectally, or by intravenous, intramuscular, subcutaneous, intrathecal, epidural or intracerebroventricular injection. It is another object of the present invention to provide a use of the aforementioned compound of the present invention for the preparation of a therapeutic agent for the prevention and treatment of a pain disease or an inflammatory disease exhibiting vanilloid receptor antagonistic activity in the human or a mammal. Additionally, it is an object of the present invention to provide a method for irradiating or preventing a pain disease and an inflammatory disease exhibiting vanilloid receptor antagonist activity in a mammal comprising administering to said mammal an effective amount of the aforementioned compound of the present invention together with a pharmaceutically acceptable carrier thereof. It will be clear to those skilled in the art that various modifications and variations may be made in the compositions, use and preparations of the present invention without departing from the spirit or scope of the invention.
BEST MODE FOR CARRYING OUT THE INVENTION The present invention is explained more specifically by the following examples. However, it should be understood that the present invention was not limited to these examples in any way.
EXAMPLES Example 1: Preparation of α / - (4-ε-butylbenzyl) -2- [3-fluoro-4- (methylsulfonylamino) phenyl] propionamide (1-51, KMJ-372) Step 1-1. Preparation of ethyl 2- (3-fluoro-4-nitrophenyl) propionate (1-1, SU-654) To a solution of potassium f-butoxide (20 mmol) in DMF (20 mL) under stirring was added a Mixture of 2-fluoronitrobenzene (10 mmol) and ethyl 2-chloropropionate (10 mmol) at 0 ° C dropwise. After stirring for 10 min at 0 g, the mixture was quenched by a 1N HCl solution, diluted with water and extracted with diethyl ether several times. The combined organic phases were washed with water and brine, dried over MgSO, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel using EtOAc: hexanes (1:10) as eluent to give ethyl 2- (3-fluoro-4-nitrophenyl) propionate (1-1, SU-654). Yield 68%, yellow oil 1 H-NMR (CDCl 3) d 8.02 (dd, 1 H, J = 7.8, 8.0 Hz), 7.2-7.3 (m, 2 H), 4 , 14 (m, 2 H), 3.78 (q, 1 H, J = 7.1 Hz), 1.52 (d, 3 H, J = 7.1 Hz), 1.22 (t, 3 H, J = 7, 08 Hz). Stage 1-2. Preparation of ethyl 2- (4-amino-3-fluorophenyl) propionate (1-13, SU-656) A suspension of 2- (3-fluoro-4-nitrophenyl) propionate (1-1.5 mmol) was hydrogenated and 10% Pd-C (500 mg) in EtOH (30 ml) with a hydrogen balloon for 1 h and filtered through Celite. The filtrate was concentrated in vacuo and the residue was purified by flash chromatography on silica gel using EtOAc: hexanes (1: 4) as eluent to give the compound 2- (4-amino-3-f-fluorophenyl) propionate (1-13). , SU-656). 94% yield, colorless oil. 1 H-NMR (CDCl 3) d 6.96 (dd, 1 H, J = 1.7 Hz), 6.87 (dd, 1 H, J = 1.7, 8.3 Hz), 6.71 (dd, 1 H, J = 8.3, 11.9 Hz), 4.11 (m, 2 H), 3.58 (q, 1 H, J = 7.1 Hz), 3.45 (sa, 2 H) , 1, 43 (d, 3 H, J = 7.1 Hz), 1.20 (t, 3 H, J = 7. 05 Hz). Stage 1-3. Preparation of the ethyl compound 2- [3-fluoro-4- (methylsulphonylamino) phenyl] propionate (1-26, SU-658) A solution of 2- (4-amino-3-phlorophenyl) propionate (1-13) was dissolved , 4 mM) and pyridine (10 ml) with methanesulfonyl chloride (6 mM) and stirred at 0 C for 10 minutes. The combined organic phases were washed with H2O and the residue was purified by flash chromatography on silica gel with EtOAc / hexanes (1: 2) as eluent to give the compound 2- [3-fluoro-4- (methylsulfonylamino) phenyl] propionate. ethyl (1-26, SU-658). Yield 91%, white solid, mp = 81-C 1 H-NMR (CDCl 3) d 7.50 (t, 1 H, J = 8.3 Hz), 7.0-7.1 (m, 2 H) , 6.55 (sa, 1 H),
4.12 (m, 2 H), 3.68 (q, 1 H, J = 7.1 Hz), 3.02 (s, 3 H), 1, 48 (d, 3 H, J = 7, 1 Hz), 1, 22 (t, 3 H, J = 7.1 Hz). Stage 1-4. Preparation of the compound 2- [3-fluoro-4- (methylsulfonylamino) phenyl] propionic acid (1-38, SU-660) A solution of ethyl 2- [3-fluoro-4- (methylsulfonylamino) phenyl] propionate was treated (1-26, 2 mmol) in H2O and THF (1: 2, 30 ml) with lithium hydroxide (6 mmol) and stirred for 4 h at room temperature. The mixture was diluted with H2O and CH2Cl2, acidified by a 1N HCl solution and extracted with CH2Cl2 several times. The combined organic phases were washed with water and brine, dried over MgSO4 and concentrated in vacuo. The residue was crystallized by diethyl ether and N-hexane to give the compound 2- [3-fluoro-4- (methylisuphonyl-amino) phenyl] propionic acid (1-38, SU-660). Yield 97%, white solid, mp = 120 QC 1 H-NMR (CDCl 3) d 7.52 (t, 1 H, J = 8.04 Hz), 7.1-7.15 (m, 2 H), 6 , 60 (sa, 1 H), 3.73 (q, 1 H, J = 7.1 Hz), 3.03 (s, 3 H), 1.51 (d, 3 H, J = 7.1 Hz).
Stage 1-5. Preparation of? / - (4-fer-butylbenzyl) -2- [3-fluoro-4- (methylsulfonylamino) phenyl] propionamide (1-51, KMJ-372) A mixture consists of 2- [3-fluoro-4] acid - (methylsulfonylamino) phenyl] propionic (1-38, 10 mmol), 4---butylbenzylamine (12 mmol) and EDC (12 mmol) in CH 2 Cl 2 (20 mL) was stirred for 12 h at room temperature. The reaction mixture was filtered and the filtrate was concentrated. The residue was purified by flash chromatography on silica gel using EtOAc: hexanes as eluent to obtain? / - (4-fer-butylbenzyl) -2- [3-fluoro-4- (meli-sulphonyl) phenyl] propionamide (1-51, KMJ -372) having the following physicochemical properties: Yield 78%, white solid, mp = 52-54 QC 1 H-NMR (CDCl 3) d 7.48 (t, 1 H, J = 8.3 Hz), 7.32 (da, 2 H), 7.1-7.2 (m, 4 H), 6.73 (sa, 1 H), 5.83 (ta, 1 H), 4.36 (ddd of AB, 2 H), 3.52 (q, 1 H, J = 7.1 Hz), 3.00 (s, 3 H), 1.50 (d, 3 H, J = 7.1 Hz), 1.29 (s, 9 H). MS (FAB) m / z 407 (MH +) Example 2: Preparation of / V- (4-tert-butylbenzyl) -2- [3-chloro-4- (methylsulfonylamino) phenyl] propionamide (1-52 KMJ-470) By a procedure similar to that of Example 1 except for the use of 2-chloroniylbenzene as starting material, it was synthesized / V- (4-ferc-butylbenzyl) -2- [3-cynor-4- (methylsulfonylamino) phenyl] propionamide having the following physicochemical properties: Yield of 68%, white solid, mp = 126-129 ° C 1 H-NMR (CDCl 3) d 7.60 (d, 1 H, J = 8.2 Hz), 7, 43 (d, 1 H, J = 2 Hz), 7.34 (da, 2 H,), 7.24 (dd, 1 H, J = 8.2, 2 Hz), 7.14 (day, 2) H), 6.75 (sa, 1 H), 5.68 (a, 1 H), 4.38 (ddd of AB, 2 H), 3.50 (q, 1 H, J = 7.1 Hz ), 3.01 (s, 3 H), 1.52 (d, 3 H, J = 7.1 Hz), 1.30 (s, 9 H) MS (FAB) m / z 423 (MH +) Example 3: Preparation of - (4-eerc-buylbenzyl) -2- [3-bromo-4- (methylsulfonylamino) phenyl] propionamide (1-53 SH-173) By a procedure similar to that of Example 1 except for the use of 2-bromonitrobenzene as a starting material a, V- (4-yerc-butylbenzyl) -2- [3-bromo-4- (methylsulfonylamino) phenyl] propionamide having the following physicochemical properties was synthesized: Yield of 76%, white solid, mp = 66 -67 ° C 1 H-NMR (CDCl 3) d 7.55-7.6 (m, 2 H), 7.33 (d, 2 H, J = 8.1 Hz), 7.27 (dd, 1 H , J = 1, 8, 8.6 Hz), 7.12 (d, 2 H, J = 8.1 Hz), 6.80 (sa, 1 H), 5.91 (ta, 1 H), 4.36 (ddd of AB, 2 H), 3.50 (q, 1 H, J = 7.1 Hz), 2.98 (s, 3 H), 1, 50 (d, 3 H, J = 7.1 Hz), 1.29 (s, 9 H)
MS (FAB) m / z 467 (MH +) Example 4: Preparation of / V- (4-ert-Butylbenzyl) -2- [3-iodo-4 (methylsulfonylamino) phenyl] propionamide (1-54 SH-168) Median a procedure similar to that of Example 1 except for the use of 2-iodonitrobenzene as starting material, was synthesized? / - (4-tert-butylbenzyl) -2- [3-iodo-4- (methylsulfonylamino) phenyl] propionamide having the following physicochemical properties: Yield of 75%, white solid, mp = 71 ° C 1 H-NMR (CDCl 3) d 7.80 (d, 1 H, J = 2 Hz), 7.59 (d, 1 H, J = 8.3 Hz), 7.3-7.37 (m, 3 H), 7.13 (d, 2 H, J = 8.1 Hz), 6.60 (sa, 1 H), 5, 67 (ta, 1 H), 4.39 (ddd of AB, 2 H), 3.48 (q, 1 H, J = 7.1 Hz), 3.01 (s, 3 H), 1.52 (d, 3 H, J = 7.1 Hz), 1.30 (s, 9 H) MS (FAB) m / z 515 (MH +) Example 5: Preparation of / V- (4-fer-butylbenzyl) -2- [ 3,5-difluoro-4- (methylsulfonylamino) phenyl] propionamide (1-55 SH-285) By a procedure similar to that of Example 1 except for the use of 2,6-difluoroniiobenzene as a starting material, N- was synthesized ( 4-tert-butylbenzyl) -2- [3,5-difluoro-4- (methylsulfonylamino) phenyl] propionamide having the following physicochemical properties: Yield 70%, white solid, mp = 80-81 ° C 1 H-NMR (CDCl 3) d 7.35 (dt, 2 H), 7.15 (da, 2 H), 6.99 (dt, 2 H), 6.16 (sa, 1 H), 5.76 (ta, 1 H), 4.38 (ddd of AB, 2 H), 4.12 (q, 1 H, J = 7.1 Hz), 3.02 (s, 3 H), 1, 50 (d, 3 H, J = 7.1 Hz), 1.30 (s, 9 H) MS (FAB) m / z 425 (MH +) Example 6: Preparation of α / - (4-ér-butylbenzyl) -2- [3 -cyano-4- (methylisulfonylamino) phenyl] propionamide (1-56 SH-219) By a procedure similar to that of Example 1 except by the use of 2-cyanonitrobenzene as a starting material,? / - (4-ert-butylbenzyl) -2- [3-cyano-4- (methylsulfonylamino) phenyI] propionamide was synthesized having the following physicochemical properties: Yield 30 %, white solid, mp = 102-105 ° C 1 H-NMR (CDCl 3) d 7.67 (d, 1 H, J = 8.4 Hz), 7.63 (d, 1 H, J = 1.8 Hz), 7.58 (dd, 1 H), 7.35 (day, 2 H), 7.15 (day, 2 H), 5.73 (ta, 1 H), 4.38 (ddd of AB) , 2 H), 3.51 (q, 1 H, J = 7.1 Hz), 3.11 (s, 3 H), 1.53 (d, 3 H, J = 7.1 Hz), 1 , 31 (s, 9 H) MS (FAB) m / z 414 (MH +) Example 7: Preparation of V- (4-ferc-buiylbenzyl) -2- [3- (f-butoxycarbonyl) -4- (methylsulfonyl) phenyl] propionamide (1-57 KMJ-806) By a procedure similar to that of Example 1 except for the use of 2-fer-butoxycarbonyl-nitrobenzene as a starting material,? - (4-ert-butylbenzyl) -2- was synthesized [3- (β-buloxycarbonyl) -4- (methylsulfonylamino) phenyl] propionamide having the following physicochemical properties: Yield 53%, white solid, mp = 75-77 ° C 1 H-NMR (CDCIg) d 7.90 (d, 1 H, J = 2.2 Hz), 7.67 (d, 1 H, J = 8.6 Hz), 7.50 (dd, 1 H, J = 8.6, 2.2 Hz), 7.33 (da, 2 H), 7.13 (day, 2 H), 5.74 (ta, 1 H), 4.38 (ddd of AB, 2 H), 3.55 (q, 1 H, J = 7.1 Hz), 3.04 (s, 3 H), 1.60 (s, 9 H), 1.53 (d, 3 H, J = 7.1 Hz), 1.30 (s, 9 H) MS (FAB) m / z 489 (MH +) Example 8: Preparation of? / - (4-fer-butylbenzyl) -2- [3 -carboxyl-4- (methylsulfoniamino) phenyl] propionamide (1-58 KMJ-788) Compound 1-58 was prepared from? / - (4-fer-butylbenzyl) -2- [3- (f-butoxycarbonyl) -4- (methylsulfonylamino) phenyl] propionamide (1-57) by hydrolysis of trifluoride acid. Yield of 74%, white solid, mp = 180-183 ° C 1 H-NMR (CD 3 OD) d 8.45 (rt, 1 H), 8.12 (d, 1 H, J = 2.2 Hz), 7 , 64 (d, 1 H, J = 8.6 Hz), 7.56 (dd, 1 H, J = 8.6, 2.2 Hz), 7.30 (day, 2 H), 7.11 (da, 2 H), 4.29 (sa, 2 H), 3.69 (q, 1 H, J = 7.1 Hz), 3.04 (s, 3 H), 1.46 (d, 3 H, J = 7.1 Hz), 1.27 (s, 9 H) MS (FAB) m / z 433 (MH +) Example 9: Preparation of? / - (4-fer-butylbenzyl) -2- [ 3- (methoxycarbonyl) -4- (methylsuphonyl amino) phenyl] propionamide (1-59 KMJ-838) By a procedure similar to that of Example 1 except for the use of 2-methoxycarbonyl-nitrobenzene as a starting material, N- was synthesized ( 4-tert-butylbenzyl) -2- [3 (methoxycarbonyl) -4- (mephsulfonylamino) pheny1] propionamide (1-59) which has the following physicochemical properties: Yield of 79%, white solid, mp = 142-144 ° C 1 H-NMR (CDCl 3) d 10.38 (s, 1 H), 8.03 (d, 1 H, J = 2.2 Hz), 7.70 (d, 1 H, J = 8.6 Hz) , 7.51 (dd, 1 H, J = 8.6, 2.2 Hz), 7.33 (da, 2 H), 7.13 (day, 2 H), 5.69 (ta, 1 H ), 4.38 (ddd of AB, 2 H), 3.94 (s, 3 H), 3.53 (q, 1 H, J = 7.1 Hz), 3.05 (s, 3 H), 1.54 (d, 3 H, J = 7, 1 Hz), 1.30 (S, 9 H) MS (FAB) m / z 447 (MH +) Example 10: Preparation of? / - (4-tert-butylbenzyl) -2- [3- (benzylamino) carbonyl- 4- (methylsulfonylamino) phenyl-propionamide (1-60, J-836)? / - (4-Fer-butylbenzyl) -2- [3- (benzylamino) carbonyl-4- (mlsylsulfonylamino) phenyl] propionide (1-60) was prepared ) from 1-58 by coupling general amine with benzylamine. 88% yield, white solid, mp = 79-81 ° C 1 H-NMR (CDCl 3) d 7.65 (d, 1 H, J = 8.6 Hz), 7.61 (d, 1 H, J = 2.2 Hz), 7.3-7.38
(m, 8 H), 7,11 (day, 2 H), 5,84 (ta, 1 H), 4,60 (d, 2 H, J = 6 Hz), 4,35 (ddd of AB, 2 H), 3.48 (q, 1 H, J = 7.1 Hz), 2.97 (s, 3 H), 1.50 (d, 3 H, J = 7.1 Hz), 1, 29 (s, 9 H) MS (FAB) m / z 522 (MH +) Example 11: Preparation of? / - (4-ert-butylbenzyl) -2- [3-piperidino-4- (methylsulfonyl amino) phenyl] propionamide (1-61 YS-65) By a procedure similar to that of Example 1 except for the use of 2-piperidinonii-benzene as a starting material, was it synthesized? - (4-ferc-butylbenzyl) -2- [3-piperidino-4- (methylsulfonylamino) phenyl] propionamide having the following physicochemical properties: Yield 86%, white solid, mp = 125 ° C 1 H-NMR (CDCl 3) d 7.78 (sa, 1 H,), 7.45 (d, 1 H, J = 8.4 Hz), 7.31 (day, 2 H),
7.15 (d, 1 H, J = 2 Hz), 7.10 (da, 2 H), 7.05 (dd, 1 H, J = 8.4, 2 Hz), 5.59 (ta, 1 HOUR),
4.38 (d of AB, 2 H, J = 5.7 Hz), 3.52 (q, 1 H, J = 7.1 Hz), 3.04 (s, 3 H), 2.75 ( m, 4 H),
1.65-1.75 (m, 4 H), 1.6 (m, 2 H), 1.52 (d, 3 H, J = 7.1 Hz), 1.29 (s, 9 H) MS (FAB) m / z 472 (MH +) Example 12: Preparation of? / - (4-tert-buylbenzyl) -2- [3-morpholino-4- (methylsulfonylamino) phenyl] propionamide (1-62 YS-49) By a procedure similar to that of Example 1 except for the use of 2-morpholino-nihrobenzene as the starting material, / V- (4-fer-butylbenzyl) -2- [3-morpholino-4- (methylsulfonylamino) phenyl] was synthesized] propionamide having the following physicochemical properties: Yield of 84%, white solid, mp = 78 ° C 1 H-NMR (CDCl 3) d 7.69 (sa, 1 H), 7.46 (d, 1 H, J = 8.2 Hz), 7.32 (day, 2 H), 7.18
(d, 1 H, J = 1.8 Hz), 7.08-7.15 (m, 3 H), 5.63 (ta, 1 H), 4.38 (d of AB, 2 H, J = 5.5 Hz), 3.85 (m, 4 H), 3.52 (q, 1 H, J = 7.1 Hz), 3.08 (s, 3 H), 2.84 (m, 4 H), 1.52 (d, 3 H, J = 7.1 Hz), 1.29 (s, 9 H) MS (FAB) / 77 / z474 (MH +) Example 13: Preparation of? / - ( 4-fer-butylbenzyl) -2- [3- (N -boc) piperazino-4- (methylsulfonylamino) phenyl] propionamide (1-63 YS-76) By a procedure similar to that of Example 1 except for the use of 2- (NBoc) piperazine-nitrobenzene as starting material, N- (4-tert-butylbenzyl) -2- [3- (Nboc) piperazino-4- (methylsulfonyllamino) phenyl] propionamide having the following properties was synthesized. physicochemical: Yield of 88%, white solid, mp = 103 ° C 1 H-NMR (CDCl 3) d 7.66 (sa, 1 H), 7.46 (d, 1 H, J = 8.2 Hz), 7 , 32 (day, 2 H), 7.15
(d, 1 H, J = 1.8 Hz), 7.08-7.13 (m, 3 H), 5.60 (ta, 1 H), 4.38 (ddd of AB, 2 H), 3.58 (m, 4 H), 3.49 (q, 1 H, J = 7.1 Hz), 3.08 (s, 3 H), 2.79 (m, 4 H), 1.55 (d, 3 H, J = 7.1 Hz), 1.49 (s, 9 H), 1.30 (s, 9 H) MS (FAB) m / z 573 (MH +) Example 14: Preparation of? / - (4-tert-butylbenzyl) -2- [3-piperazino-4- (mephsulfonylamino) phenyl] proponamide (1-64 YS-79) Use a procedure similar to that of Example 1 except for the use of 2-piperazino- Nitrobenzene as starting material, was synthesized? / - (4-ér-butylbenzyl) -2- [3-piperazino-4- (methylsulfonylamino) phenyl] propionamide having the following physicochemical properties: Yield of 96%, white solid, mp = 92 ° C 1 H-NMR (CDCl 3) d 7.46 (d, 1 H, J = 8.3 Hz), 7.32 (da, 2 H), 7.18 (d, 1 H, J = 1 , 8 Hz), 7.08-7.13 (m, 3 H), 5.60 (ta, 1 H), 4.38 (d of AB, 2 H, J = 5 Hz), 3.52 ( q, 1 H, J = 7.1 Hz), 3.06 (s, 3 H), 3.03 (m, 4 H), 2.80 (m, 4 H), 1.52 (d, 3 H, J = 7.1 Hz), 1.29 (s, 9H) MS (FAB) m / z 473 (MH +) Example 15: Preparation n / - (4-FERC-butylbenzyl) -2- [3-methoxy-4- (meíilsulfonilamino) phenyl] propionamide (1-65, CHK 717) Using a method similar to Example 1 except for using acid
2- [3-methoxy-4- (methylsulfonylamino) phenyl] propionic as a starting material, was synthesized? - (4-ferc-butylbenzyl) -2- [3-methoxy-4- (methylsulfonylamino) phenyl] propionamide having the following physicochemical properties: Yield of 83%, white solid, mp = 74-76 ° C 1H- NMR (CDCIg) d 7.1-7.5 (m, 5 H), 6.85-6.9 (m, 2 H), 6.75 (sa, 1 H), 5.75 (t, 1) H), 4.39 (ddd of AB, 2 H), 3.85 (s, 3 H), 3.54 (q, 1 H, J = 7.1 Hz), 2.94 (s, 3 H) ), 1.53 (d, 3 H, J = 7.1 Hz), 1.31 (s, 9 H) MS (FAB) m / z419 (MH +) Example 16: Preparation of? / - (4-urea) -butylbenzyl) -2- [2-fluoro-4- (methylsulfonylamino) phenyl] propionamide (1-66 KMJ-708) By a procedure similar to that of Example 1 except for the use of 3-fluoronitrobenzene as starting materialwas synthesized? / - (4-ferc-butylbenzyl) -2- [2-fluoro-4- (methylsulfonylamino) phenyl] propionamide having the following physicochemical properties: Yield of 63%, white solid, mp = 111-113 ° C 1 H-NMR (CDCl 3) d 7.3-7.38 (m, 3 H), 7.28 (sa, 1 H), 7.15 (da, 2 H), 7.02 (dd, 1 H , J = 11, 4, 2.2 Hz), 6.87 (dd, 1 H, J = 8.4, 2.2 Hz), 5.88 (ta, 1 H), 4.41 (ddd of AB, 2 H), 3.84 (q, 1 H, J = 7.1 Hz), 3.00 (s, 3 H), 1.52 (d, 3 H, J = 7.1 Hz), 1.30 (s, 9 H) MS (FAB) m / z 407 (MH +) Example 17: Preparation of? - (4-Ierc-butylbenzyl) -2- [2-chloro-4- (methylsulfonylamino) phenyl] propionamide (1-67 KMJ-698) By a procedure similar to that of Example 1 except for the use of 3-fluoroniienobenzene as the material of departure, was it synthesized? - (4-ferc-butylbenzyl) -2- [2-chloro-4- (methylsulfonylamino) phenyl] propionamide having the following physicochemical properties: Yield 46%, white solid, mp = 134-136 ° C 1 H-NMR (CDCl 3) d 7.44 (d, 1 H, J = 8.4 Hz), 7.34 (da, 2 H), 7.29 (d, 1 H, J = 2.2 Hz), 7, 15 (day, 2 H), 7.07 (dd, 1 H, J = 8.4, 2.2 Hz), 5.88 (ta, 1 H), 4.40 (ddd of AB, 2 H) , 3.84 (q, 1 H, J = 7.1 Hz), 3.00 (s, 3 H), 1.52 (d, 3 H, J = 7.1 Hz), 1, 30 (s) , 9 H) MS (FAB) m / z 423 (MH +) Example 18: Preparation of? / - (4-tert-butylbenzyl) -2- [4- (methylisulfonic acid)] propionamide (2-7, KMJ-750) Step 18-1. Preparation of? / - (4-fer-bulletin-benzyl) -2- (4-niiophenol) propionamide (2-1. KMJ-738) By a procedure similar to that of Example 1-5 except for the use of 2- (4-nitrophenyl) -propionamide as a starting material, was synthesized? / - (4-etr-butylbenzyl) -2- (4-nitrophenyl) propionamide having the following physicochemical properties: Yield of 84%, white solid , mp = 146-148 ° C 1 H-NMR (CDCl 3) d 8.16 (dt, 2 H), 7.49 (dt, 2 H), 7.32 (dt, 2 H), 7.10 (dt) , 2 H), 5.86 (ta, 1 H), 4.37 (ddd, 2 H), 3.64 (q, 1 H, J = 7.1 Hz), 1.55 (d, 3 H) , J = 7.1 Hz), 1.29
(s, 9 H) Stage 18-2. Preparation of? / - (4-ér-butylbenzyl) -2- (4-aminophenyl) propionamide (2-4 KMJ-740) By a procedure similar to that of Example 1-2 except for the use of N- (4 -erc-butylbenzyl) -2- (4-nitrophenyl) propionamide as starting material, was synthesized? / - (4-etr-butylbenzyl) -2- (4-aminophenyl) propionamide having the following physicochemical properties: Yield 95 % yield, colorless oil 1H-NMR (CDCIg) d 7.31 (dt, 2 H), 7.05-7.1 (m, 4 H), 6.65 (di, 2 H), 5.66 ( ta, 1 H), 4.34 (ddd, 2 H), 3.66 (sa, 2 H), 3.49 (q, 1 H, J = 7.1 Hz), 1.51 (d, 3 H, J = 7.1 Hz), 1.29 (s, 9 H) Step 18-3. Preparation of W- (4-ferc-butylbenzyl) -2- [4- (methylsulfonylamino) phenyjpropionamide (2-7, KMJ-750) By a procedure similar to that of example 1-3 except for the use of N- (4- ferc-butylbenzyl) -2- (4-aminophenyl) propionamide as starting material, was synthesized / V- (4-ér-butylbenzyl) -2- [4- (methylsulfonylamino) phenyl] propionamide having the following physicochemical properties: 93%, white solid, mp = 77-79 ° C 1 H-NMR (CDCl 3) d 7.32 (dt, 2 H), 7.27 (dt, 2 H), 7.18 (dt, 2 H) , 7.11 (dt, 2 H), 6.96 (sa, 1 H), 5.73 (ta, 1 H), 4.38 (ddd, 2 H), 3.55 (q, 1 H, J = 7.1 Hz), 2.98 (s, 3 H), 1.52 (d, 3 H, J = 7.1 Hz), 1.29 (s, 9 H) EM (El) m / z 388 (M +) Example 19: Preparation of? - (4-chlorobenzyl) -2- [4- (methylsulfonylamino) phenyl] propionamide (2-8, YS-85) By a procedure similar to that of example 18 except for the use of 4-chlorobenzylamine as a starting material, it was synthesized ? - (4-chlorobenzyl) -2- [4- (methylsulfonylamino) phenyl] propionamide having the following physicochemical properties: Yield 94%, white solid, mp = 164 ° C 1 H-NMR (CDCl 3) d 7.24 -7.32 (m, 4 H), 7.18 (dt, 2 H), 7.10 (dt, 2 H), 6.59 (sa, 1 H), 5.70 (ta, 1 H) , 4.37 (ddd, 2 H), 3.56 (q, 1 H, J = 7.1 Hz), 3.01 (s, 3 H), 1.53 (d, 3 H, J = 7 , 1 Hz) MS (El) m / z 366 (M +) Example 20: Preparation of? / - (3,4-dichlorobenzyl) -2- [4- (methylsulfonylamino) phenyl] propionamide (2-9, YS-97 ) By a procedure similar to that of Example 18 except for the use of 3,4-dichlorobenzylamine as a starting material,? / - (3,4-dichlorobenzyl) -2- [4- (methylsulfonylamino) phenyl] propionamide having the following physicochemical properties: Yield of 96%, white solid, mp = 130 ° C 1 H-NMR (CDCl 3) d 7.18-7.38 (m, 5 H), 7.01 (d, 1 H), 6 , 38 (sa, 1 H), 5.68 (ta, 1 H), 4.35 (d, 2 H, J = 5.8 Hz), 3.58 (q, 1 H, J = 7.1) Hz), 3.02 (s, 3 H), 1.53 (d, 3 H, J = 7.1 Hz) MS (El) m / z 400 (M + Example 21: Preparation of? / - (4-tert-butylbenzyl) - (2S) -2- [3-fluoro-4- (methylsulfonylamino) phenyl] propionamide (3-5, SU-834) Step 21- 1. ? / - [(lS) -1-Benzyl-2-hydroxyethyl] - (2S) -2- [3-fIuoro-4 (methylsulfonylamino) phenyl] propionamide (3-1, SU-632-H) A mixture of acid 2- [3-fluoro-4- (meilylsulfonicamino) phenyl] propionic (100 mg, 0.234 mmol) and L-phenylalaninol (71 mg, 0.468 mmol) in CH 2 Cl 2 (3 mL) was refluxed for 3 h and concentrated in vacuo. . The residue was dissolved in MeOH (2 mL) and purified by flash column chromatography on silica gel using EtOAc: hexanes (2: 1) to EtOAc: MeOH (20: 1) as eluent giving? / - [(1S) -1-benzyl-2-hydroxyethyl] - (2S) -2- [3-fluoro-4- (methylsulfonylamino) phenyl] propionamide. mp = 150-153 ° C, [a] = -20.36 (c 1.00, MeOH) 1 H-NMR (CD3OD) d 7.36 (t, 1 H, J = 8.5 Hz), 7, 0-7.28 (m, 7 H), 4.07 (m, 1 H), 3.56 (q, 1 H, J = 7.3 Hz), 3.48 (dd, 2 H, J = 1.2, 5.1 Hz), 2.9-3.0 (m, 4 H), 2.71 (dd, 1 H, J = 9, 14 Hz), 1.27 (d, 3 H, J = 7.05 Hz) Step 21-2. (2S) - [3-fluoro-4- (methylsulfonylamino) pheny1] propionic acid (3-3j SU-668) A solution of? / - [(1S) -1-benzyl-2-hydroxyethyl] - (2S) ) -2- [3-Fluoro-4- (methylsulfonylamino) phenyl] propionamide (100 mg, 0.234 mmol) in 3 N H2SO4 (1 mL) and 1,4-dioxane (1 mL) was heated to 100 ° C for 5 hours. hy cooled to room temperature. The solution was diluted with water and extracted with CH2Cl2 several times. The combined organic phases were washed with water, dried over MgSO 4, and concentrated in vacuo to give (2S) - [3-fluoro-4- (methylsulfonylamino) phenyl] propionic acid. Yield 73% 1 H-NMR (CDCIg) d 7.52 (t, 1 H, J = 8.3 Hz), 7.1-7.2 (m, 2 H), 6.68 (sa, 1 H), 3.73 (q, 1 H, J = 7.3 Hz), 3.03 (s, 3 H), 1.51 (d, 3 H, J = 7.3 Hz) [a] = +29.76 (c1.00, CHCl3) Step 21-3. ? / - (4-Phenobutylbenzyl) - (2S) -2- [3-fluoro-4- (methylsulfonylamino) phenyl] propionamide (3-5, SU-834) By a procedure similar to that of Example 1-5 except for the use of (2S) - [3-fluoro-4- (methylsulfonylamino) phenyl] propionic acid as the starting material, was synthesized? / - (4-etr-butylbenzyl) - (2S) -2- [3-fluoro-4 - (Methylsulfonylamino) phenyl] propionamide having the following physicochemical properties: Yield of 98%, white solid, mp 52 ~ 54 ° C [a] = -15.5 (c 0.5, CHCl 3) 1 H-NMR (CDCl 3 ) d 7.51 (t, 1 H, J = 8.3 Hz), 7.33 (m, 2 H), 7.06-7.2 (m, 4 H),
6.58 (sa, 1 H), 5.73 (ta, 1 H), 4.38 (ddd of AB, 2 H, J = 5.5, 14.6 Hz), 3.52 (q, 1) H, J = 7.1 Hz), 3.02 (s, 3 H), 1.52 (d, 3 H, J = 7.1 Hz), 1.30 (s, 9 H) EM (FAB) m / z 407 (MH +) Example 22: Preparation of? / - (4-ferc-butylbenzyl) - (2R) -2- [3-fluoro-4- (methylsuphonyl amino) phenyl] propionamide (3-6, SU-824 ) Stage 22-1. ? / - [(1S) -1-Benzyl-2-hydroxyethyl- (2R) -2- [3-fluoro-4- (methylsulfonylamino) phenyl] propionamide (3-2, SU-632-L) By a similar procedure To that of Example 10, N - [(1S) -1-benzyl-2-hydroxyethyl] - (2R) -2- [3-fluoro-4- (methylsulfonylamino) phenyl] propionamide having was synthesized. the following physicochemical properties: mp = 164-166 ° C, [a] = -25.48 (c 1.00, MeOH) 1 H-NMR (CD3OD) d 7.33 (t, 1 H, J = 8.5 Hz), 6.9-7.12 (m, 7 H), 4.12 (m, 1 H), 3.5-3.6 (m, 3 H), 2.98 (s, 3 H) , 2.88 (dd, 1 H, J = 5.1, 14 Hz), 2.71 (dd, 1 H, J = 9.3, 14 Hz), 1.36 (d, 3 H, J = 7.05 Hz) Step 22-2. (2R) - [3-Fluoro-4- (methylsulfonylamino) phenyl] propionic acid (3-4, SU-732) By a procedure similar to that of Example 10-2 except for the use of (2R) - [3- fluoro-4- (methylsulfonylamino) phenyl] propionic as the starting material, (2R) - [3-fluoro-4- (methylsulfonylamino) phenyl] propionic acid having the following physicochemical properties was synthesized: The spectral datum of this compound are identical to those of 3-3. [ce] = -29.25 (c 1.00, CHCl3) Step 22-3. ? / - (4-tert-butylbenzyl- (2R) -2- [3-fluoro-4- (methylsulfonylamino) phenyl] propionamide (3-6, SU-824) By a procedure similar to that of Example 10-3, synthesized N- (4-tert-butylbenzyl) - (2R) -2- [3-fluoro-4- (methylsulfonylamino) phenyl] propionamide having the following physicochemical properties: Yield of 96%, white solid, mp = 52 ~ 54 ° C [a] = +18.4 (c 0.5, CHCl3) The spectral data are identical to those of compound 3-5 EM (FAB) m / z 407 (MH +) Example 23: Preparation of / V- (4- chlorobenzyl) -2- [3-fluoro-4- (methylsulfonylamino) phenyjpropionamide (4-1, SH-291) By a procedure similar to that of Example 1-5 except for the use of 2- [3-fluoro-4-] (meilylsulfonyl) phenyl] propionic (1-39) with the corresponding 4-chlorobenzylamine compound as the starting material, N- (4-chlorobenzyl) -2- [3-fluoro-4- (methylsulfonylamino) phenyl] propionamide was synthesized having the following physicochemical properties: Yield of 98%, white solid, mp = 129-130 ° C 1H -NMR (CDCl 3) d 7.53 (t, 1 H, J = 8.3 Hz), 7.25-7.3 (m, 2 H), 7.06-7.2 (m, 4 H) , 6.44 (sa, 1 H), 5.67 (ta, 1 H), 4.37 (ddd of AB, 2 H), 3.53 (q, 1 H, J = 7.1 Hz), 3.03 (s, 3 H), 1.52 (d, 3 H, J = 7.1 Hz) MS (FAB) m / z 385 [M-Hf Example 24: Preparation of? - (4-chlorobenzyl) -2- [3-chloro-4- (mephsulfonylamino) phenyl] propionamide (4-2, SH-290) By a procedure similar to that of example 1-5 except for the use of acid 2- [ 3-fluoro-4- (methylsulfonylamino) phenyl] propionic (1-39) with the corresponding 4-chlorobenzylamine compound as the starting material, was synthesized? F- (4-chlorobenzyl) -2- [3-chloro-4- ( methylsulfonylamino) phenyl] propionamide having the following physicochemical properties: Yield 98%, white solid, mp = 134-135 ° C 1 H-NMR (CDCl 3) d 7.61 (d, 1 H, J = 8.3 Hz) , 7.41 (d, 1 H, J = 1.2 Hz), 7.2-7.3 (m, 3 H), 7.13 (d, 2 H), 6.73 (sa, 1 H ), 5.68 (ta, 1 H), 4.38 (ddd of AB, 2 H), 3.52 (q, 1 H, J = 7.1 Hz), 3.02 (s, 3 H) 1.52 (d, 3 H, J = 7.1 Hz) MS (FAB) m / z 402 (MH +) Example 25: Preparation of / V- (4-chlorobenzyl) -2- [3-bromo-4 - (Methylsulphonylamino) phenyl] propionamide (4-3, SH-335) By a procedure similar to that of Example 1-5 except for the use of 2- [3-bromo-4- (methylisulfonyl) phenyl] propionic acid ( 1-40) with the corresponding 4-chlorobenzylamine compound as the starting material, N- (4-chlorobenzyl) -2- [3-bromo-4- (methylsulfonylamino) phenyl] propionamide having the following physicochemical properties was synthesized: 88%, white solid, mp = 147 ° C 1 H-NMR (CDCl 3) d 7.60 (d, 1 H, J = 8.4 Hz), 7.57 (d, 1 H, J = 1, 2 Hz), 7.24-7.32
(m, 3 H), 7.13 (d, 2 H), 6.74 (s a, 1 H), 5.73 (ta, 1 H), 4.36 (ddd of AB, 2 H), 3.52 (q, 1 H, J = 7.1 Hz), 3.01 (s, 3 H), 1.52 (d, 3 H, J = 7.1 Hz) MS (FAB) m / z 446 (MH +) Example 26: Preparation of? / - (3,4-dichlorobenzyl) -2- [3-fluoro- 4- (Methylsulfonylamino) phenyl] propionamide (4-4, SH-94) By a procedure similar to that of Example 1-5 except for the use of 2- [3-fIuoro-4- (methylsulfonylamino) phenyl] ] propionic (1-38) with the corresponding 3,4-dichlorobenzylamine compound as the starting material, N- (3,4-dichlorobenzyl) -2- [3-fluoro-4- (methylsulfonylamino) phenyl] propionamide was synthesized having the following physicochemical properties: Yield of 76%, white solid, mp = 130-133 ° C 1 H-NMR (CDCl 3) d 7.53 (t, 1 H, J = 8.3 Hz), 7.36 (d , 1 H), 7.23 (d, 1 H), 7.16 (dd, 1 H), 7.10 (day, 1 H), 7.02 (dd, 1 H), 6.51 (d. , 1 H), 5.76 (ta, 1 H), 4.36 (d of AB, 2 H), 3.54 (q, 1 H, J = 7.1 Hz), 3.03 (s, 3 H), 1.52 (d, 3 H, J = 7.1 Hz) MS (FAB) m / z 419 (MH +) Example 27: Preparation of? - (3,4-dichlorobenzyl) -2- [3-chloro-4- (methylsulfonylamino) phenyI] propionamide (4-5, SH-286) By a procedure similar to that of example 1-5 except for the use of acid 2 - [3-chloro-4- (methylsulfonylamino) phenyl] propionic (1-39) with the corresponding 3,4-dichlorobenzylamine compound as a starting material, was synthesized? - (3,4-dichlorobenzyl) -2- [3-chloro-4- (methylsulfonylamino) phenyl] propionamide having the following physicochemical properties: Yield 85%, white solid, mp = 129-130 ° C 1 H-NMR (CDCl 3) d 7.59 (d, 1 H, J = 8.4 Hz), 7.41 (d, 1 H), 7.36 (d, 1 H), 7.2-7.25 (m , 2 H), 7.03 (dd, 1 H), 6.78 (sa, 1 H), 5.91 (ta, 1 H), 4.35 (d of AB, 2 H, J = 6 Hz ), 3.54 (q, 1 H, J = 7.0 Hz), 3.02 (s, 3 H), 1.52 (d, 3 H, J = 7.0 Hz) EM (FAB) m / z 435 (M +) Example 28: Preparation of? / - (3,4-dichlorobenzyl) -2- [3-bromo-4- (methylsulfonylamino) phenyl] proponamide (4-6, SH-337) By a procedure similar to that of Example 1-5 except for the use of 2- [3-bromo-4- (methylsulfonylamino) phenyl] propionic acid (1-40) with the corresponding 3,4-dichlorobenzylamine compound as a starting material, was synthesized N- (3,4-dichlorobenzyl) -2- [3-bromo-4- (methylsulfonylamino) phenyl] propionamide having the following physicochemical properties: Yield 98%, white solid, mp = 161-162 ° C 1 H-NMR (CDCI g) d 7.62 (d, 1 H, J = 8.4 Hz), 7.57 (d, 1 H, J = 1.8 Hz), 7.37 (d, 1 H, J = 8, 4 Hz), 7.2-7.3 (m, 2 H), 7.04 (dd, 1 H, J = 1, 8 & amp;; 8.2 Hz), 6.75 (sa, 1 H), 5.75 (ta, 1 H), 4.37 (d of AB, 2 H, J = 6 Hz), 3.53 (q, 1 H, J = 7.1 Hz), 3.02 (s, 3 H), 1.52 (d, 3 H, J = 7.1 Hz) MS (FAB) m / z 481 (MH +) Example 29: Preparation of? / - (4-methylbenzyl) -2- [3-fluoro-4- (methylsulfonylamino) phenyl] propionamide (4-7, SH-351) By a procedure similar to that of Example 1-5 except for the use of 2- [3-Fluoro-4- (methylsulfonylamino) phenyl] propionic acid (1-38) with the corresponding 4-methylbenzylamine compound as the starting material, N- (4-methylbenzyl) -2- [3-fluoro- 4- (Methylsulfonylamino) phenyl] propionamide having the following physicochemical properties: Yield of 96%, white solid, mp = 166 ° C 1 H-NMR (CDCl 3) d 7.51 (t, 1 H, J = 8.3 Hz), 7.05-7.2 (m, 6 H), 6.50 (sa, 1 H),
.66 (ta, 1 H), 4.36 (ddd of AB, 2 H), 3.51 (q, 1 H, J = 7.1 Hz), 3.02 (s, 3 H), 2 , 32 (s, 3 H), 1.52 (d, 3 H, J = 7.1 Hz) MS (FAB) m / z 365 (MH +) Example 30: Preparation of / V- (4-isopropylbenzyl) - 2- [3-fluoro-4- (methylsuphonyl-amino) phenyl] propionamide (4-8, KMJ-928) By a procedure similar to that of Example 1-5 except for the use of 2- [3-fluoro-4- ( methylsulfonylamino) phenyl] propionic (1-38) with the corresponding 4-isopropylbenzylamine compound as the starting material, was synthesized? / - (4-isopropylbenzyl) -2- [3-fluoro-4- (methylsulfonylamino) phenyl] propionamide having the following physicochemical properties: Yield of 69%, white solid, mp = 137-139 ° C 1 H-NMR (CDCl 3) d 7.49 (t, 1 H, J = 8.3 Hz), 7.05-7 , 2 (m, 6 H), 6.70 (sa, 1 H), 5.80 (a, 1 H), 4.36 (ddd of AB, 2 H), 3.52 (q, 1 H) , J = 7.1 Hz), 3.00 (s, 3 H), 2.88 (m, 2 H), 1.51 (d, 3 H, J = 7.1 Hz), 1.22 ( d, 6 H) MS (FAB) m / z 393 (MH +) Example 31: Preparation of? / - (4-methoxybenzyl) -2- [3-fluoro-4- (m ethylsulphonylamino) phenyl] propionamide (4-9, SH-353) by a procedure similar to that of Example 1-5 except for the use of 2- [3-fluoro-4 (methylsulfonylamino) phenyl] propionic acid (1-38) with the corresponding 4-methoxybenzylamine compound as a starting material, N- (4-methoxybenzyl) -2- [3-fluoro-4- (methylsulfonylamino) phenyl] propionamide was synthesized having the following physicochemical properties: Yield of 96%, white solid , mp = 138 ° C 1 H-NMR (CDCl 3) d 7.48 (t, 1 H, J = 8.3 Hz), 7.05-7.2 (m, 4 H), 6.82 (d, 2 H), 6.69 (sa, 1 H), 5.80 (ta, 1 H), 4.33 (ddd of AB, 2 H), 3.78 (s, 3 H), 3.52 ( q, 1 H, J = 7.1 Hz), 3.01 (s, 3 H), 1.51 (d, 3 H, J = 7.1 Hz) MS (FAB) m / z 381 (MH +) Example 32: Preparation of? / - (4-trifluoromethylbenzyl) -2- [3-fluoro-4- (methylsulfonylamino) phenyl] propionamide (4-10, SH-93) By a procedure similar to that of Example 1-5 except for the use of 2- [3-fluoro-4- (methylsulfonylamino) phenyl] propionic acid (1-38) with the 4-trifluoro compound The corresponding methylbenzylamine as starting material was synthesized? / - (4-trifluoromethylbenzyl) -2- [3-fluoro-4- (methylsulfonylamino) phenyl] propionamide having the following physicochemical properties: Yield of 81%, white solid, mp = 150-152 ° C 1 H-NMR (CDCl 3) d 7.5-7.6 (m, 3 H), 7.26 (d, 2 H), 7.05-7.2 (m, 2 H) , 5.86 (ta, 1 H), 4.46 (ddd of B, 2 H), 3.56 (q, 1 H, J = 7.1 Hz), 3.02 (s, 3 H), 1.52 (d, 3 H, J = 7.1 Hz) MS (FAB) m / z 419 (MH +) Example 33: Preparation of? / - (4-biphenylmethyl) -2- [3-fluoro-4- (methylsulfonylamino) phenyl] propionamide (4-11, KMJ-498) By a procedure similar to that of Example 1-5 except for the use of 2- [3-fluoro-4- (methylsulfonylamino) phenyl] propionic acid (1-38) ) with the corresponding 4-phenylbenzylamine compound as the starting material,? / - (4-biphenylmethyl) -2- [3-fluoro-4- (methylsulfonylamino) phenyl] propionamide having the following physicochemical properties was synthesized: Yield 78% , white solid, mp = 155-157 ° C 1 H-NMR (CDCl 3) d 7.1-7.58 (m, 12 H), 6.45 (sa, 1 H), 5.71 (ta, 1 H), 4.45 (ddd, 2 H ), 3.55 (q, 1 H, J = 7.1 Hz), 3.01 (s, 3 H), 1.54 (d, 3 H, J = 7.1 Hz) EM (FAB) m / z 427 (MH +) Example 34: Preparation of? / - (1-naphilylmethyl) -2- [3-fluoro-4- (methylsulfonylamino) phenyl] propionamide (4-12, SH-92) By a procedure similar to that of Example 1-5 except for the use of 2- [3-fluoro-4- (methylsulfonylamino) phenyl] propionic acid (1-38) with the corresponding 4-chlorobenzylamine compound as starting material, was synthesized? - (1-naphthylmethyl) ) -2- [3-fIuoro-4- (methylsulfonylamino) phenyl] propionamide having the following physicochemical properties: 79% yield, white solid, mp = 159-161 ° C 1 H-NMR (CDCl 3) d 7.75 -7.9 (m, 3 H), 7.3-7.5 (m, 5 H), 7.16 (dd, 1 H), 7.04 (day, 1 H), 6.52 (day) , 1 H), 5.69 (ta, 1 H), 4.86 (ddd, 2 H), 3.49 (q, 1 H, J = 7.1 Hz), 2.96 (s, 3 H) ), 1.51 (d, 3 H, J = 7.1 Hz) MS (FAB) m / z 401 (MH +) Example 35: Preparation of? / - (1,2,3,4-tetrahydro-1- na phthalene ??) - 2- [3-fluoro-4- (methylsulfonylamino) phenyl] propionamide (4-13, SH-112) Using a procedure similar to that of Example 1-5 except for the use of 2- [3-fluoro-4- (methylsulfonylamino) phenyl] propionic acid (1-38) with compound 1,2,3, 4-Tetrahydro-1-naphthalenamine corresponding as starting material, N- (1, 2,3,4-tetrahydro-1-naphthalenyl) -2- [3-fluoro-4- (methylsulfonylamino) phenyl] propionamide was synthesized which has the following physicochemical properties: Yield of 73%, white solid, mp = 116-117 ° C 1 H-NMR (CDCl 3) d 7.51 (m, 1 H), 6.8-7.2 (m, 6 H), 6.53 (sa, 1 H), 5.62 (day, 1 H), 5.15 (m, 1 H), 3.51 (q, 1 H, J = 7.1 Hz) , 3.00 (s, 3 H), 2.75 (m, 2 H), 1.7-1.9 (m, 4 H), 1.53 (d, 3 H, J = 7.1 Hz ) MS (FAB) m / z 391 (MH +) Example 36: Preparation of / V- [2- (4-f-butylphenyl) ethyl] -2- [3-fluoro-4- (methylsulfonylamino) phenyl] propionamide (4) -14, KMJ-374) by a procedure similar to that of example 1-5 except for the use of 2- [3-fluoro-4- (methylsulfonylamino) phenyl] propionic acid (1-38) with compound 2- (4-f-butyl) ethylamine corr As starting material, N- [2- (4-t-butylphenyl) ethyl] -2- [3-fluoro-4- (methylsulfonylamino) phenyl] propionamide was synthesized having the following physicochemical properties: 64% yield, solid white, mp = 124-126 ° C 1 H-NMR (CDCl 3) d 7.50 (t, 1 H, J = 8.3 Hz), 7.29 (day, 2 H), 6.95-7 , 15 (m, 4 H), 6.52 (sa, 1 H), 5.41 (ta, 1 H), 3.47 (m, 3 H), 3.03 (s, 3 H), 2 , 72 (t, 2 H, J = 6.8 Hz), 1.47 (d, 3 H, J = 7.3 Hz), 1, 31 (s, 9 H) EM (FAB) m / z 421 (MH +) Example 37: Preparation of - [3- (3,4-dimethylphenyl) propyl] -2- [3-fluoro-4- (methylsulfonylamino) phenyl] propionamide (4-15, SU-770) By a similar procedure to that of Example 1-5 except for the use of 2- [3-fluoro-4- (methylsulfonylamino) phenyl] propionic acid (1-38) with the corresponding racemic 3- (3,4-dimethylpheny!) propylamine propylamine as the starting, V / [3- (3,4-dimethylphenyl) propyl] -2- [3-fluoro-4- (methylsulfonylamino) phenyl] propionamide having the following physicochemical properties was synthesized : Yield 95%, white solid, mp = 128-130 ° C, 1 H-NMR (CDCl 3) d 7.50 (t, 1 H, J = 8.3 Hz), 7.13 (dd, 1 H, J = 1.95, 11.2 H), 7.0-7.07 (m, 2 H), 6.83-6.92 (m, 2 H), 6.57 (sa, 1 H), 3.41 (q, 1 H, J = 7.1 Hz), 3.2-3.3 (m, 2 H), 3.01 (s, 3 H), 2.51 (t, 2 H, J = 7.6 Hz), 2.22 (s, 6 H), 1.7-1.8 (m, 2 H), 1.45 (d, 3 H,
J = 7.1 Hz) MS (FAB) m / z 407 (MH +) Example 38: Preparation of? - [3- (3,4-dimethylphenyl) propyl] - (2R) -2- [3-fluoro-4- (methylsulfonylamino) phenyl] propionamide (4-16, SU-774) By a procedure similar to that of Example 1-5 except for the use of 2- [3-fluoro-4 (methylsulfonylamino) phenyl] propionic acid (1-38) with the 3- (3,4-dimethy-phenyl) propyl] -R-amine compound as the material for starting, N- [3- (3,4-dimethylphenyl) propyl] - (2R) -2- [3-fluoro-4 (methylsulfonylamino) phenyl] propionamide having the following physicochemical properties was synthesized: Yield of 96%, white solid, mp = 128-130 ° C The spectral data of compound 4-16 are identical to those of compound 4- 15. [a] = -4.23 (c 0.25, CHCl3) MS (FAB) m / z 407 (MH +) Example 39: Preparation of / V- [3- (3,4-dimethylphenyl) propyl] - (2S) -2- [3-fluoro-4- (methylsulfonylamino) phenyl] propionamide (4-17, SU-776) Mediate a procedure similar to that of Example 1-5 except for the use of 2- [3-fluoro-4- (methylsulfonylamino) phenyl] propionic acid (1-38) with the compound 3- (3,4- dimetilfe niI) propyl] -S-amine as the starting material, was synthesized? / - [3- (3,4-dimethy-phenyl) propyl] - (2S) -2- [3-fluoro-4 (methylsulfonylamino) phenyl] propionamide which has the following physicochemical properties: Yield of 95%, white solid, mp = 128-130 ° C The spectral data of compound 4-17 are identical to those of compound 4-15. [a] = +4.34 (c 0.25, CHCl3) MS (FAB) m / z 407 (MH +) Example 40: Preparation of A / - [3- (3,4-dimethylphenyl) -2-propenyl] -2- [3-Fluoro-4- (methylsulfonylamino) phenyl] propionamide (4-18, KMJ-686) By a procedure similar to that of Example 1-5 except for the use of 2- [3-fluoro-4-] (Methylsulfonylamino) phenyl] propionic (1-38) with the corresponding 3- (3,4-dimethy-phenyl) -2-propenylamine as the starting material, N- [3- (3,4-dimethylphenyl) -2- was synthesized propenyl] -2- [3-fluoro-4- (methylsulfonylamino) phenyl] propionamide having the following physicochemical properties: Yield 78%, white solid, mp = 144-146 ° C 1 H-NMR (CDCl 3) d 7, 52 (t, 1 H, J = 8.3 Hz), 7.0-7.2 (m, 5 H), 6.58 (sa, 1 H), 6.37 (d, 1 H, J = 15.8 Hz), 6.06 (di, 1 H, J = 6.2, 15.8 Hz), 5.57 (ai, 1 H), 3.9-4.02 (m, 2 H) , 3.53 (q, 1 H, J = 7.1 Hz), 3.01 (s, 3 H), 2.24 (s, 6 H), 1.52 (d, 3 H, J = 7 , 1 Hz) MS (FAB) m / z 405 (MH +) Example 41: Preparation of / V- [3- (4-chlorophenyl) propyl] -2- [3-fluoro-4- (met ilsulfonylamino) phenyl] propionamide (4-19, KMJ-518) by a procedure similar to that of Example 1-5 except for the use of 2- [3-fluoro-4- (methylsulfonylamino) pheny1] propionic acid (1-38) with the corresponding 3- (4-chlorophenyl) propylamine compound as the starting material, was it synthesized? - [3- (4-chlorophenyl) propyl] -2- [3-fluoro-4- (methylsulfonylamino) phenyl] propionamide which has the following physicochemical properties: Yield 70%, white solid, mp = 141-143 ° C 1H -NRM (CDCI3) d 7.51 (t, 1 H, J = 8.3 Hz), 7.02-7.25 (m, 6 H), 6.52 (sa, 1 H), 5.38 (ta, 1 H), 3.44 (q, 1 H, J = 7.1 Hz), 3.24 (ddd, 2 H), 3.02 (s, 3 H), 2.55 (t, 2 H, J = 7.5 Hz), 1.76 (m, 2 H), 1.47 (d, 3 H, J = 7.1 Hz) MS (FAB) m / z 413 (MH +) Example 42 : Preparation of / V- [3- (4-chlorophenyl) -2-propen? ] -2- [3-fluoro-4- (methylsulfonylamino) phenyjpropionamide (4-20, KMJ-732) Mediate a procedure similar to that of Example 1-5 except for the use of 2- [3-fluoro-4- ( methylsulfonylamino) phenyl] propionic (1-38) with the corresponding 3- (4-chlorophenyl) propenylamine compound as a starting material, was synthesized / V- [3- (4-chlorophenyl) -2-propenyl] -2- [3 -fluoro-4- (methylsulfonylamino) phenyl] propionamide having the following physicochemical properties: Yield of 72%, white solid, mp = 151-153 ° C 1 H-NMR (CDCl 3) d 7.52 (t, 1 H, J = 8.3 Hz), 7.08-7.3 (m, 6 H), 6.60 (sa, 1 H), 6.37 (d, 1 H, J = 15.8 Hz), 6 , 10 (dt, 1 H, J = 6.2, 15.8 Hz), 5.61 (1 a, 1 H), 3.9-4.1 (m, 2 H), 3.54 (q , 1 H, J = 7.1 Hz), 3.02 (s, 3 H), 1.52 (d, 3 H, J = 7.1 Hz) Example 43: Preparation of? -benzyloxy-2- [3-fluoro-4- (mephsulfonylamino) phenyl] propionamide (4-21), SH-109) By a procedure similar to that of Example 1-5 except for the use of 2- [3-fluoro-4- (methylsulfonylamino) phenyl] propionic acid (1-38) with the corresponding benzyloxyamine compound as starting material , was synthesized? / - benzyloxy-2- [3-fluoro-4- (methylsulfonylamino) phenyl] propionamide having the following physicochemical properties: Yield 76%, white solid, mp = 182-183 ° C 1 H-NMR ( CDCl 3) d 7.94 (s, 1 H), 7.49 (t, 1 H, J = 8.3 Hz), 7.25-7.35 (m, 5 H), 7.12 (dd, 1 H, J = 2, 11.2 Hz), 7.02 (dd, 1 H, J = 2, 8.2 Hz), 6.52 (sa, 1 H), 4.87 (s, 2 H) ), 3.35 (q, 1 H, J = 7.1 Hz), 3.02 (s, 3 H), 1.46 (d, 3 H, J = 7.1 Hz) EM (FAB) m / z 367 (MH +) Example 44: Preparation of? / -benzhydryl-2- [3-fluoro-4- (methylsulfonylamino) phenyl] propionamide (4-22, SH-130) By a procedure similar to that of Example 1-5 except for the use of 2- [3-fluoro-4- (methylsulfonylamino) phenyl] propionic acid (1-38) with the corresponding benzhydrylamine compound as the material of departure, was it synthesized? -benzhydril-2- [3-fluoro-4- (methylsulfonylamino) phenyl] propionamide having the following physicochemical properties: Yield of 79%, white solid, mp = 160-161 ° C 1 H-NMR (CDCl 3) d 7.51 (t, 1 H, J = 8.3 Hz), 7.0-7.4 (m, 10 H), 6.20 (d, 1 H), 6.04 (ta, 1 H), 3, 58 (q, 1 H, J = 7.1 Hz), 3.00 (s, 3 H), 1.52 (d, 3 H, J = 7.1 Hz) EM (FAB) / 77 / z427 ( MH- ') Example 45: Preparation of α / - (2,2-diphenylethyl) -2- [3-fluoro-4- (methylsulfonylamino) phenyl] proponamide (4-23, SH-116) By a procedure similar to that of Example 1-5 except for the use of 2- [3-fluoro-4- (methylsulfonylamino) phenyl] propionic acid (1-38) with the corresponding 2,2-diphenylethylamine compound as a starting material, it was synthesized N-benzhydr? -2- [3-fluoro-4 (methylsulfonylamino) phenyl] propionamide having the following physicochemical properties: Yield 64%, white solid, mp = 129 ° C H-NMR (CDCl 3) d 7.42 (t, 1 H, J = 8.3 Hz), 7.1-7.3 (m, 10 H), 6.95 (dd, 1 H), 6.87 (d, 1 H), 6, 50 (sa, 1 H), 5.28 (rt, 1 H), 4.12 (t, 1 H), 3.75-3.95 (m, 2 H), 3.37 (q, 1 H, J = 7.1 Hz) , 3.01 (s, 3 H), 1.40 (d, 3 H, J = 7.1 Hz) MS (FAB) m / z 441 (MH +) Example 46: Preparation of? / - (3.3 -diphenylpropyl) -2- [3-fluoro-4- (methylsulfonylamino) phenyl] propionamide (4-24, KMJ-378) By a procedure similar to that of example 1-5 except for the use of 2- [3-fluoro acid] 4- (Methylsulfonylamino) phenyl] propionic (1-38) with the corresponding 2,2-diphenylpropylamine compound as the starting material, was synthesized? / - (3,3-diphenylpropyl) -2- [3-fluoro-4- (methylsulfonylamino) phenyl] propionamide having the following physicochemical properties: Yield of 76%, white solid, mp = 66-68 ° C 1 H-NMR (CDCl 3) d 7.51 (t, 1 H, J = 8 , 3 Hz), 7.0-7.3 (m, 12 H), 6.45 (sa, 1 H), 5.27 (ta, 1 H), 3.85 (t, 1 H, J = 7.8 Hz), 3.34 (q, 1 H, J = 7.1 Hz), 3.21 (ddd, 2 H), 3.01 (s, 3 H), 2.24 (dd, 2 H), 1.43 (d, 3 H, J = 7.1 Hz) MS (FAB) m / z 455 (MH +) Example 47: Preparation of? - (3,3-diphenyl-2-propenyl) -2- [3-fluoro-4- (methylsulfonylamino) phenyl] propionamide (4-25, KMJ-724) Use a procedure similar to that of Example 1-5 except for the use of 2- [3-fluoro-4- (methylsulfonylamino) phenyl] propionic acid (1-38) with the corresponding 3,3-diphenyl-2-propenylamine compound as a starting material, was synthesized? / - (3.3 -diphenyl-2-propenyl) -2- [3-fluoro-4- (methylsulfonylamino) phenyl] propionamide having the following physicochemical properties: Yield 78%, white solid, mp = 155-157 ° C 1H -NMR (CDCl 3) d 7.52 (t, 1 H, J = 8.3 Hz), 7.05-7.4 (m, 12 H), 6.50 (sa, 1 H),
6. 00 (t, 1 H, J = 7.0 Hz), 5.44 (ta, 1 H), 3.85-4.0 (m, 2 H), 3.46 (q, 1 H, J = 7.1 Hz),
3. 01 (s, 3 H), 1.48 (d, 3 H, J = 7.1 Hz) MS (El) m / z 452 (M +) Example 48: Preparation of N- [3,3-di (4 -methylphenyl) -2-propenyl] -2- [3-fluoro-4- (methylsulfonylamino) phenyl] propionamide (4-26, KMJ-908) By a procedure similar to that of example 1-5 except for the use of acid 2 - [3-fluoro-4- (methylsulfonylamino) phenyl] propionic (1-38) with the corresponding 3,3-di (4-methylphenyl) -2-propenylamine compound as a starting material, was synthesized? - [3,3-Di (4-methylphenyl) -2-propenyl] -2- [3-fluoro-4- (methylsulfonylamino) phenyl] propionamide having the following physicochemical properties: Yield of 72%, white solid, mp = 163-165 ° C 1 H-NMR (CDCl 3) d 7.49 (t, 1 H, J = 8.3 Hz), 6.95-7.2 (m, 10 H), 5.93 (t, 1 H, J = 7.0 Hz), 5.56 (rt, 1 H), 3.8-4.0 (m, 2 H), 3.47 (q, 1 H, J = 7.1 Hz ), 3.00 (s, 3 H), 2.34 (d, 6 H), 1.47 (d, 3 H, J = 7.1 Hz) MS (FAB) m / z 481 (MH +) Example 49: Preparation of? / - [3,3-di (4-fluorophenyl) -2-propenyl] -2- [3-fluoro-4- (methylsulfonylamino) phenyl] propionamide (4-27, SH-135) By a procedure similar to that of Example 1-5 except for the use of 2- [3-fluoro-4- (methylsulfonylamino) phenyl] propionic acid (1-38) with the compound 3,3-di (4-fluorophenyl) -2- corresponding propenylamine as starting material, was synthesized / V- [3,3-di (4-fluorophenyl) -2-propenyl] -2- [3-fluoro-4- (methylsulfonylamino) phenyl] propionamide having the following physicochemical properties : 78% yield, solid white co, mp = 57-60 ° C 1 H-NMR (CDCl 3) d 7.49 (t, 1 H, J = 8.3 Hz), 6.9-7.2 (m, 10 H), 6.72 (sa, 1 H), 5.92 (t, 1 H, J = 7.0 Hz), 5.58 (sa, 1 H), 3.8-4.0 (m, 2 H), 3, 48 (q, 1 H, J = 7.1 Hz), 3.02 (S, 3 H), 1.48 (d, 3 H, J = 7.1 Hz) MS (FAB) m / z 489 ( MH +) Example 50: Preparation of? / - [2- (10,11-dihydro-5H-dibenzo [a, d | cyclohepten-5-ylidene) ethyl] -2- [3-fluoro-4- (methylsulfonylamino) phen L] propionamide (4-28, SH-199) By a procedure similar to that of Example 1-5 except for the use of 2- [3-fluoro-4- (methylsulfonylamino) phenyl] propionic acid (1-38) with the corresponding 2- (10,11-dihydro-5W-dibenzo [a, d] cyclohepten-5-ylideethylamine as starting material was synthesized? / - [2- (10,11-dihydro-5 - / - dibenzo [α, δ] cyclohepten-5-ylidene) etl] -2- [3-fluoro-4- (methylsulfonylamino) phenyl] proponamide having the following physicochemical properties: Yield of 76%, white solid, mp = 67-69 ° C 1 H-NMR (CDCl 3) d 7.50 (t, 1 H, J = 8.3 Hz), 7.05-7.25 (m, 10 H), 6.49 (sa, 1 H), 5.80 (t, 1 H), 5.40 (rt, 1 H), 4.13 (m, 1 H), 3.71 (m, 1 H), 3.43 (q, 1 H, J = 7.1 Hz), 3.2-3.4 (m, 4 H), 3.01 (s, 3 H), 1.46 (d, 3 H, J = 7.1 Hz) EM (FAB ) m / z 479 (MH +) Example 51: Preparation of? / - [2- (3,4-dimethylbenzyl) -3-pivaloyloxypropyl] -2- [4- (methylsulfonylamino) phenyI] propionamide (5-1, CHK- 512)? / - [2- (3,4-dimethylbenzyl) -3-pivaloyloxypropyl] -2- [4- (meilylsulfonylamino) phenyl] propionamide was prepared by the procedure similar to that described in example 1-5 above . Yield 75%, white solid, mp = 112-115 ° C 1 H-NMR (CDCl 3) d 7.28 (m, 2 H), 7.16 (m, 2 H), 6.8-7.05 ( m, 3 H), 6.36 (sa, 1 H), 5.77 (ta, 1 H), 3.98 (m, 1 H), 3.77 (m, 1 H), 3.45 ( m, 1 H), 2.95-3.35 (m, 2 H), 2.97 (m, 3 H), 2.4-2.6 (m, 2 H), 2.1-2, 25 (m, 6 H), 2.04 (m, 1 H), 1.47 (d, 3 H), 1.20 (s, 9 H)
MS (FAB) m / z 503 (MH +) Example 52: Preparation of N- [2- (4-í-butylbenzyl) -3-pivaloyloxypropyl] -2- [4- (methylisulfonyl) phenyl] propionamide (5-2, CHK-514) N- [2- (4-í-Butylbenzyl) -3-pivaloyloxypropyl] -2- [4- (methylsulfonylamino) phenyl] propionamide was prepared by the procedure similar to that described in example 1-5 above. Yield 82%, white solid, mp = 97-100 QC 1 H-NMR (CDCl 3) d 7.0-7.35 (m, 7 H), 6.38 (sa, 1 H), 5.81 (s) , 1 H), 4.02 (m, 1 H), 3.78 (m, 1 H), 3.47 (m, 1 H), 3.34 (m, 1 H), 2.95-3 , 1 (m, 4 H,), 2.45-2.55 (m, 2 H), 2.09 (m, 1 H), 1.47 (d, 3 H), 1.30 (s, 9 H), 1.21 (s, 9 H) MS (FAB) m / z 531 (MH +) Example 53: Preparation of 2- [3-fluoro-4- (methylsulfonylamino) phenyl] -? - [2 (3, 4-dimethylbenzyl) -3-pivaloyloxypropyl] propionamide (5-3, SU-542) 2- [3-fluoro-4- (methylsulfonylamino) phenyl] -? / - [2- (3,4-dimethylbenzyl ) -3-pivaloyloxypropylpropionamide by the procedure similar to that described in Example 1-5 above. Yield 67%, white solid, mp = 46-48 ° C 1 H-NMR (CDCl 3) d 7.51 (dt, 1 H), 7.0-7.2 (m, 3 H), 6.8 -6.95 (m, 2 H), 6.58 (sa, 1 H), 5.91 (ta, 1 H), 4.05 (m, 1 H), 3.78 (m, 1 H) , 3.25-3.5 (m, 2 H), 2.9-3.1 (m, 4 H), 2.45-2.65 (m, 2 H), 2.15-2.3 (m, 6 H), 2.05 (m, 1 H), 1.46 (d, 3 H, J = 7.3 Hz), 1.22 (s, 1 H) EM (FAB) m / z 521 (MH +) Example 54: Preparation of 2- [3-fluoro-4- (methylsulfonylamino) phenyl] -? / - [2- (4-ert-butylbenzyl) -3-pivaloyloxypropyl] propionamide (5-4, SU- 564) 2- [3-Fluoro-4- (methylsulfonylamino) phenyl] - / V- [2- (4-etr-butylbenzyl) -3-pivaloyloxypropyl] propionamide was prepared by the procedure similar to that described in example 1 5 previous. Yield 82%, white solid, mp = 113-115 ° C 1 H-NMR (CDCl 3) d 7.50 (dt, 1 H), 7.30 (d, 2 H, J = 7.8 Hz), 7 , 15 (dt, 1 H), 7.02-7.1 (m, 3 H), 6.82 (sa, 1 H), 6.00 (1 a, 1 H), 4.06 (m, 1 H), 3.80 (m, 1 H), 3.3-3.5 (m, 2 H), 2.95-3.1 (m, 4 H), 2.5-2.6 (m. m, 2 H), 2.11 (m, 1 H), 1, 46 (d, 3 H, J = 7.3 Hz), 1.30 (s, 1 H), 1.22 (s, 1 H) MS (FAB) m / z 549 (MH +) Example 55: Preparation of? / - [2- (3,4-dimethylbenzyl) -3-pivaloyloxypropyl] -2- [3-methoxy-4- (methylsulfonylamino) phenyl ] propionamide (5-5, CHK-479)? / - [2- (3,4-Dimethylbenzyl) -3-pivaloyloxypropyl] -2- [3-methoxy-4- (methylsulfonylamino) phenyl] propionamide was prepared by procedure similar to that described in example 1-5 above. Yield 87%, white solid, mp = 54-57 ° C 1 H-NMR (CDCl 3) d 7.44 (m, 1 H), 6.7-7.05 (m, 5 H), 5.86 ( ta, 1 H), 3.98 (m, 1 H), 3.85 (m, 3 H), 3.78 (m, 1 H), 3.46 (m, 1 H), 2.95- 3.35 (m, 2 H), 2.90 (m, 3 H), 2.4-2.6 (m, 2 H), 2.1-2.25 (m, 6 H), 2, 04 (m, 1 H), 1.47 (d, 3 H), 1.19 (s, 9 H) MS (FAB) m / z 533 (MH +) Example 56: Preparation of? / - [2- ( 4-Ierc-butylbenzyl) -3-pivaloyloxypropyl] -2- [3-methoxy-4- (methylsulfonylamino) phenyl] propionamide (5-6, CHK-499) N- [2- (4-fer-butylbenzyl was prepared ) -3-pivaloyloxypropyl] -2- [3-methoxy-4- (methylsulfonylamino) phenyljpropionamide by the procedure similar to that described in example 1-5 above. Yield 80%, white solid, mp = 54-57 ° C 1 H-NMR (CDCl 3) d 7.46 (m, 1 H), 7.29 (m, 2 H), 7.03 (m, 2 H), 6.8-6.95 (m, 2 H), 6.72 (sa, 1 H), 5.83 (ta, 1 H), 4.02 (m, 1 H), 3.88 (m, 3 H), 3.78 (m, 1 H), 3.46 (m, 1 H), 3.33 (m, 1 H), 3.02 (m, 1 H), 2.92 (m, 3 H), 2.45-2.55 (m, 2 H), 2.05 (m, 1 H), 1.48 (d, 3 H), 1.30 (s, 9 H) 1.21 (s, 9 H) MS (FAB) m / z 561 (MH +) Example 57: Preparation of? / - [2- (3,4-dimethylbenzyl) -3-pivaloyloxypropyl] -2- [3-chloro -4- (Methylsulfonylamino) phenyl] propionamide (5-7, KMJ-472)? - [2- (3,4-Dimethylbenzyl) -3-pivaloyloxypropyl] -2- [3-chloro-4- ( methylsulfonylamino) fenirjpropionamide by the procedure similar to that described in example 1-5 above. Yield 62%, white solid, mp = 127-129 ° C 1 H-NMR (CDCl 3) d 7.60 (m, 1 H), 7.40 (m, 1 H), 7.22 (m, 1 H ), 6.8-7.05 (m, 3 H),
6.72 (sa, 1 H), 5.90 (ta, 1 H), 4.06 (m, 1 H), 3.80 (m, 1 H), 3.42 (m, 1 H), 3.30 (m, 1 H), 3.05 (m, 1 H), 2.99 (m, 3 H), 2.45-2.65 (m, 2 H), 2.15-2, 3 (m, 6 H), 2.05 (m, 1 H), 1.47 (m, 3 H), 1.22 (s, 9 H) MS (FAB) m / z 537 (M +) Example 58 : Preparation of? / - [2- (4-Ierc-butylbenzyl) -3-pivaloyloxypropyl] -2- [3-chloro-4- (methylsulfonylamino) phenyl] propionamide (5-8, KMJ-690) The / V- [2- (4-Fer-butylbenzyl) -3-pivaloyloxypropyl] -2- [3-chloro-4- (methylsulfonylamino) phenyl] propionamide by the procedure similar to that described in example 1-5 above. Yield 58%, white solid, mp = 142-144 ° C 1 H-NMR (CDCl 3) d 7.59 (m, 1 H), 7.42 (m, 1 H), 7.30 (m, 2 H ), 7.22 (m, 1 H), 7.06 (m, 2 H), 6.82 (da, 1 H), 5.98 (ta, 1 H), 4.07 (m, 1 H) ), 3.81 (m, 1 H), 3.43 (m, 1 H), 3.32 (m, 1 H), 3.04 (m, 1 H), 2.98 (s, 3 H) ), 2.5-2.6 (m, 2 H), 2.12 (m, 1 H), 1.46 (m, 3 H), 1.30 (s, 9 H), 1.22 ( s, 9 H) MS (FAB) m / z 563 (M + -1) Example 59: Preparation of? / - [(R) -1-benzyl-2- (pivaloyloxy) eyl] - (S) -2- [ 3-fluoro-4- (methylsulfonylamino) phenyl] propionamide (6-1, SU-730) The? / - [(R) -1-benzyl-2- (pivaloyloxy) etiI] - (S) -2- was prepared [3-fluoro-4- (methylsulfonylamino) phenyl] propionamide by the procedure similar to that described in example 1-5 above. Yield 96%, white solid, mp = 115 ° C, [a] = -1.75 (c 1, 00, CHCl 3) 1 H-NMR (CDCl 3) d 7.50 (t, 1 H, J = 8, 3 Hz), 6.95-7.25 (m, 7 H), 6.60 (sa, 1 H), 5.54 (d, 1 H, J = 7.8 Hz), 4.42 (m , 1 H), 4.04 (ddd of AB, 2 H), 3.43 (q, 1 H, J = 7.1 Hz), 3.04 (s, 3 H), 2.75 (dd of AB, 2 H), 1.43 (d, 3 H, J = 7.1 Hz), 1.19 (s, 9 H) MS (FAB) m / z 479 (MH) Example 60: Preparation of? - [(S) -1-Benzyl-2- (pivaloyloxy) ethyl] - (S) -2- [3-fluoro-4- (methylsulfonylamino) phenyl] propionamide (6-2, SU-634) The? - [(S) -1-Benzyl-2- (pivaloyloxy) ethyl] - (S) -2- [3-fluoro-4- (methylsulfonylamino) phenyl] propionamide by the procedure similar to that described in Example 1-5 previous.
Yield 98%, white solid, mp = 125 ~ 126 QC, [a] = -12.56 (c 1.00, CHCl 3) 1 H-NMR (CDCl 3) d 7.50 (t, 1 H, J = 8 , 3 Hz), 7.0-7.32 (m, 7 H), 6.48 (sa, 1 H), 5.60 (d, 1 H, J = 7.8 Hz), 4.38 ( m, 1 H), 4.00 (ddd of AB, 2 H), 3.43 (q, 1 H, J = 7.08 Hz), 3.02 (s, 3 H), 2.82 (ddd) of AB, 2 H), 1.44 (d, 3 H, J = 7.08 Hz), 1.13 (s, 9 H) MS (FAB) m / z 479 (MH +) Example 61: Preparation of? / - [(S) -1-Benzyl-2- (pivaloyloxy) ethyl] - (R) -2- [3-fluoro-4- (methylsulfonylamino) phenyl] propionamide (6-3, SU-636) The / V - [(S) -1-Benzyl-2- (pivaloyloxy) ethyl] - (R) -2- [3-fluoro-4- (methylsulfonylamino) phenyl] propionamide by the procedure similar to that described in example 1 5 previous. 95% yield, white solid, mp = 117 ~ 119 ° C, [] = +1.46 (c 1, 00,
The spectral data of compound 6-3 are identical to those of 6-1. MS (FAB) m / z 479 (MH +) Example 62: Preparation of? / - [(R) -1-benzyl-2- (pivaloyloxy) ethyl] - (R) -2- [3-fluoro-4- (methylsulfonylamino) phenyl] propionamide (6-4, SU-728) The? - [(R) -1-Benzyl-2 - (? Ivaloyloxy) ethyl] - (R) -2- [3-fluoro-4- (methylsulfonylamino) phenyl] propionamide by the procedure similar to that described in example 1-5 previous. Yield 93%, white solid mp 124-126 ° C, [a] = +11.8 (c 1.00, CHCl3)
The spectral data of compound 6-4 are identical to those of 6-2. MS (FAB) m / z 479 (MH +) Example 63: Preparation of N - [(2R) -2-benzyl-3- (pivaloyloxy) propyl] - (2S) -2- [3-fluoro-4- (methylsulfonylamino ) phenyl] proponamide (6-5, SU-826) The? / - [(2R) -2-benzyl-3- (pivaloyloxy) propyl] - (2S) -2- [3-fluoro-4] was prepared - (meilylsulfonylamino) phenyl] propionamide by the procedure similar to that described in example 1-5 above. Yield 87%, white solid, mp = 40-42 ° C 1 H-NMR (CDCl 3) d 7.51 (t, 1 H, J = 8.3 Hz), 7.06-7.32 (m, 7 H), 6.50 (sa, 1 H), 5.93 (ta, 1 H), 4.05 (dd, 1 H, J = 4, 11, 5 Hz), 3.76 (dd, 1 H) , J = 5, 11.5 Hz), 3.45 (q, 1 H, J = 7.1 Hz), 3.36 (dt, 1 H), 2.9-3.05 (m, 4 H) ), 2.58 (d, 2 H, J = 7.5 Hz), 2.09 (m, 1 H, CH), 1.47 (d, 3 H, J = 7.1 Hz), 1, 22 (s, 9 H) MS (FAB) m / z 493 (MH +) Example 64: Preparation of? / - [(2S) -2-benzyl-3- (pivaloyloxy) propyl] - (2S) -2- [ 3-fluoro-4- (methylsulfonylamino) phenyl] propionamide (6-6), SU-830) Was the? - [(2S) -2-Benzyl-3- (pivaloyloxy) propyl] - (2S) -2- [3-fluoro-4- (methylsulfonylamino) phenyl] propionamide by the procedure similar to that described in example 1-5 above . Yield 86%, white solid, mp = 92-94 ° C [a] = +5.8 (c 0.5, CHCl3) 1 H-NMR (CDCl 3) d 7.52 (t, 1 H, J = 8 , 25 Hz), 7.06-7.32 (m, 7 H), 6.52 (sa, 1 H), 5.92 (ta, 1 H), 4.08 (dd, 1 H, J = 4, 11, 5 Hz), 3.79 (dd, 1 H, J = 5, 11.5 Hz), 3.46 (q, 1 H, J = 7.1 Hz), 3.33 (dt, 1 H), 3.03 (dt, 1 H), 3.00 (s, 3 H), 2.48-2.62 (m, 2 H), 2.13 (m, 1 H), 1, 47 (d, 3 H, J = 7.1 Hz), 1.22 (s, 9 H) MS (FAB) m / z 493 (MH +) Example 65: Preparation of? / - [(2S) -2- benzyl-3- (pivaloyloxy) propyl] - (2R) -2- [3-fluoro-4- (methylsulfonylamino) phenyl] propionamide (6-7, SU-838) The? / - [(2S) -2 was prepared -benzyl-3- (pivaloyloxy) propyl] - (2R) -2- [3-fluoro-4- (methylsulfonylamino) phenyl] propionamide by the procedure similar to that described in example 1-5 above. Yield of 88%, white solid, mp = 40-42 ° C The spectral data of compound 6-7 are identical to those of compound 6-5
Example 66: Preparation of? / - [(2R) -2-benzyl-3- (pivaloyloxy) propyl] - (2R) -2- [3-fluoro-4- (methylisu-phenylamino) phenyl] propionamide (6-8, SU -S18)? / - [(2R) -2-Benzyl-3- (pivaloyloxy) propyl] - (2R) -2- [3-fluoro-4- (methylsulfonylamino) phenyl] propionamide was prepared by the procedure similar to described in Example 1-5 above. Yield of 89%, white solid, mp = 92 ~ 94 ° C [a] = -12.5 (c 0.5, CHCl3) The spectral data of compound 6-8 are identical to those of compound 6-6. Example 67: Preparation of α / - [(2R) -2- (4-í-butylbenzyl) -3- (pivaloyloxy) propyl] (2S) -2- [3-fluoro-4- (methylsulfonylamino) phenyl] propionamide ( 6-9, MK 271) The? / - [(2R) -2- (4-y-butylbenzyl) -3- (pivaloyloxy) propyl] - (2S) -2- [3-fluoro-4- ( methylsulfonylamino) phenyl] propionamide by the procedure similar to that described in example 1-5 above. Yield 90%, white solid, mp = 44-46 ° C 1 H-NMR (CDCl 3) d 7.51 (t, 1 H, J = 8.25 Hz), 7.31 (d, 2 H), 7.16 (dd, 1 H, J =
11, 2, 1.8 Hz), 7.03-7.1 (m, 3 H), 6.41 (sa, 1 H), 5.91 (ta, 1 H), 4.06 (dd, 1 H, J = 4,
11, 5 Hz), 3.78 (dd, 1 H, J = 5, 11, 5 Hz), 3.43 (q, 1 H, J = 7 Hz), 3.36 (ddd, 1 H), 2.9-3.05 (m, 4 H), 2.55 (d, 2 H, J = 7.5 Hz), 2.08 (m, 1 H), 1.46 (d, 3 H, J = 7 Hz), 1, 30 (s, 9
H), 1.22 (s, 9 H) MS (FAB) m / z 549 (MH +) Example 68: Preparation of? - [(2S) -2- (4-y-butylbenzyl) -3- (pivaloyloxy) propyl] - (2S) -2- [3-fIuoro-4- (methylsulfonylamino) phenyl] propionamide (6-10, MK-272) The? / - [(2S) -2- (4-y-butylbenzyl) was prepared ) -3- (pivaloyloxy) propyl] - (2S) -2- [3-fluoro-4- (methylsulfoniamino) phenyl] propionamide by the procedure similar to that described in example 1-5 above. Yield 92%, white solid, mp = 43-45 ° C [cf = +11.0 (c1.0, CHCl3) 1 H-NMR (CDCl3) d 7.52 (t, 1 H, J = 8 , 25 Hz), 7.30 (d, 2 H), 7.17 (dd, 1 H, J =
11.2, 1.8 Hz), 7.0-7.1 (m, 3 H), 6.50 (sa, 1 H), 5.90 (ta, 1 H), 4.08 (dd, 1 H, J = 4, 11.5
Hz), 3.81 (dd, 1 H, J = 5, 11, 5 Hz), 3.45 (q, 1 H, J = 7 Hz), 3.34 (ddd, 1 H), 2.9 -3.1 (m, 4 H), 2.53 (ddd of AB, 2 H), 2.12 (m, 1 H), 1.47 (d, 3 H, J = 7 Hz), 1, 30 (s, 9 H), 1.22 (S, 9 H) MS (FAB) m / z 549 (MH +) Example 69: Preparation of / V - [(2S) -2- (4-f-butylbenzyl) l) -3- (pivaloyloxy) propyl] - (2R) -2- [3-fluoro-4- (methylsulfonylamino) phenyl] propionamide (6-11, MK-450) The? - [(2S) -2- (4-γ-butylbenzyl) -3- (pivaloyloxy) propyl] - (2R) -2- [3-fluoro-4- (methylsulfony] amino) phenyl] propionamide by the procedure similar to that described in Example 1-5 above. Yield 87%, white solid, mp = 44-46 ° C [a] = -8.1 (c 1.0, CHCl3) MS (FAB) m / z 549 (MH +) The spectral data of compound 6-11 they are identical to those of compound 6-9. Example 70: Preparation of? / - [(2R) -2- (4-f-butylbenzyl) -3- (pivaloiIoxi) propyl] - (2R) -2- [3-fluoro-4- (methylsulfonylamino) phenyl ] propionamide (6-12, MK-452)? - [(2R) -2- (4-f-butylbenzyl) -3- (pivaloyloxy) propyl] - (2R) -2- [3-fluoro- 4- (Methylsulfonylamino) phenyl] propionamide by the procedure similar to that described in example 1-5 above.
90% yield, white solid, mp = 43-45 ° C [a] = -6.7 (e 1.0, CHCl3) MS (FAB) m / z549 (MH +) The spectral dampness of compound 6-12 is identical to those of compound 6-10. Example 71: Preparation of? / - [(2R) -2- (4-f-butylbenzyl) -3- (pivaloyloxy) propyl] - (2S) -2- [3-chloro-4- (methylsulfonylamino) phenyl] propionamide (6-13, MK-453) The? / - [(2R) -2- (4-f-butylbenzyl) -3- (pivaloyloxy) propyl] - (2S) -2- [3-chloro-4] was prepared - (Methylsulfonylamino) phenyl] propionamide by means of the procedure similar to that described in example 1-5 above. Yield 92%, white solid, mp = 61-63 ° C [a] = -3.18 (c 1.0, CHCl3) 1 H-NMR (CDCl 3) d 7.59 (d, 1 H, J = 8 , 4 Hz), 7.41 (d, 1 H, J = 2 Hz), 7.31 (d, 2
H) 7.22 (dd, 1 H, J = 8.4, 2 Hz), 7.07 (d, 2 H), 6.74 (sa, 1 H), 5.93 (ta, 1 H) , 4.06 (dd, 1 H, J = 4, 11.3 Hz), 3.79 (dd, 1 H, J = 4.8, 11, 3 Hz), 3.41 (q, 1. H , J = 7.1 Hz), 3.35
(ddd, 1 H), 2.95-3.05 (m, 4 H), 2.55 (d, 2 H, J = 7.5 Hz), 2.09 (m, 1 H), 1, 46 (d, 3 H, J =
7.1 Hz), 1.30 (s, 9 H), 1.22 (s), 9 H) MS (FAB) m / z 566 (MH +) Example 72: Preparation of? Í - [(2S) -2- (4-y-butylbenzyl) -3- (pivaloyloxy) propyl] - (2S) - 2- [3-Chloro-4- (methylsulfonylamino) phenyl] propionamide (6-14, MK-451) The? / - [(2S) -2- (4-y-butylbenzyl) -3- (pivaloyloxy) was prepared propyl] - (2S) -2- [3-chloro-4- (methylsulfonylamino) phenyl] propionamide by the procedure similar to that described in example 1-5 above. Yield 90%, white solid, mp = 55-57 ° C 1 H-NMR (CDCl 3) d 7.61 (d, 1 H, J = 8.4 Hz), 7.42 (d, 1 H, J = 2 Hz), 7.30 (d, 2 H), 7.23 (dd, 1 H, J = 8.4, 2 Hz), 7.05 (d, 2 H), 6.72 (sa, 1 H), 5.91 (ta, 1 H), 4.09 (dd, 1 H, J = 4, 11.3 Hz), 3.81 (dd, 1 H, J = 5, 11.3 Hz) , 3.43 (q, 1 H, J = 7.1 Hz), 3.34 (ddd, 1 H), 2.95-3.08 (, 4 H), 2.53 (ddd of AB, 2 H), 2.12 (m, 1 H), 1.47 (d, 3 H, J = 7.1 Hz), 1.30 (s, 9 H), 1.22 (s, 9 H) EM (FAB) m / z566 (MH +) Example 73: Preparation of 2- [3-fluoro-4- (methylsulfonylamino) phenyl] -2-methylpropionic acid (7-4, CHK-624) Step 73-1. Preparation of Ethyl 2- (3-fluoro-4-nitrophenyl-2-methylpropionamide (7-1 CHK-623) To a stirred solution of the 2- (4-amino-3-fluorophenyl) propylate propionate compound (1-13) , 10 mmol, 20 mmol) and NaH (12 mmol) in DMF (20 ml) was added a CH3I (15 mmol) at 0 ° C. dropwise, after stirring for 10 min at 0 ° C., the The mixture was diluted with water and extracted with diethyl ether several times, the combined organic phases were washed with water and brine, dried over MgSO 4, and concentrated in vacuo. The residue was purified by chromatography. of ultrafast column on silica gel using
EtOA. exes (1:10) as eluent to give ethyl 2- (3-fluoro-4-nitrophenyl) -2-methylpropionamide (7-1, CHK-623). Yield 84%, yellow oil 1 H-NMR (CDCl 3) d 8.04 (dd, 1 H, J = 7.8, 8.5 Hz), 7.24-7.31 (m, 2 H), 4 , 15 (q, 2
H, J = 7.1 Hz), 1.60 (S, 6 H), 1.21 (t, 3 H, J = 7.1 Hz) Step 73-2. Preparation of ethyl 2- (4-amino-3-fluorophenyl) -2-methylpropionamide (7-2
CHK-633 Using a procedure similar to that of Example 1-2 except for the use of ethyl 2- (3-fluoro-4-nitrophenyl) -2-methylpropionamide (7-1), 2- (4-amino- Ethyl 3-fluorophenyl) -2-methylpropionamide having the following physicochemical properties: Yield 98%, reddish oil 1 H-NMR (CDCl 3) d 7.01 (dd, 1 H, J = 2.2, 12.9 Hz), 6.93 (dd, 1 H, J = 2.2, 8.3
Hz), 6.75 (t, 1 H, J = 8.5 Hz), 4.10 (q, 2 H, J = 7.1 Hz), 3.62 (sa, 2 H), 1.52 (s, 6 H),
1.19 (t, 3 H, J = 7.1 Hz) Step 73-3. Preparation of ethyl 2- [3-fluoro-4- (methylsulfonylamino) phenyl] -2-methylpropionamide (7-3, CHK-654) by a procedure similar to that of example 1-3 except for the use of 2- (4 ethyl-3-fluorophenyl) -2-methylpropionamide (7-2), ethyl 2- [3-fluoro-4- (methylsulfonylamino) phenyl] -2-methylpropionamide was synthesized having the following physicochemical properties: 88%, white solid, mp = 71-72eC 1 H-NMR (CDCl 3) d 7.51 (t, 1 H, J = 8.3 Hz), 7.1-7.2 (m, 2 H), 6.56 (sa, 1 H),
4.13 (q, 2 H, J = 7.1 Hz), 3.04 (s, 1 H), 1.56 (s, 6 H), 1.20 (t, 3 H, J = 7, 1 Hz) Eíapa 73-4. Preparation of 2- [3-fluoro-4-methylsulfonylamino) phenyl] -2-methylpropionic acid (7-4, CHK-624) by a procedure similar to that of example 1-4 except for the use of 2- [3-fluoro] 4- (Methylsulfonylamino) phenyl] -2-methylpropionamide of ethyl (7-3), 2- [3-fluoro-4- (methylsulfonylamino) phenyl] -2-methylpropionic acid having the following physicochemical properties was synthesized: Yield 88%, white solid, mp = 152-153 ° C 1 H-NMR (CDCl 3) d 7.53 (t, 1 H, = 8.3 Hz), 7.18-7.25 (m, 2 H ), 6.59 (br s, 1 H), 3.04 (s, 1 H), 1.59 (s, 6 H) Example 74: Preparation of 2- [4- (methylsulfonylamino) phenyl] -2- acid methylpropionic (8-11, CHK-518) Step 74-1. Preparation of 4-nitrobenzonitrile (8-1) 4-Nitrobenzonitrile is commercially available (Sigma Aldrich, Ne N1, 200-7) Elapa 74-2. Preparation of methyl (4-nitrophenyl) acetate (8-3, CHK-500) To a stirred solution of 4-nitrobenzonitrile (8-1) in MeOH was added about 3-4 drops of HCl. After refluxing for 10 h, the mixture was concentrated in vacuo. The residue was purified by flash column chromatography on silica gel using EtOAc: hexanes (1:10) as eluent to give methyl (4-nitrophenyl) acetate (8-3, CHK-500). Yield of 82%, yellow solid, mp = 49-50 ° C 1 H-NMR (CDCl 3) d 8.15 (day, 2 H), 7.43 (day, 2 H), 3.71 (s, 2 H) ), 3.69 (s, 3 H) Eyelid 74-3. Preparation of methyl 2- (4-nitrophenyl) -2-methylpropionamide (8-5, CHK-508) By a procedure similar to that of Example 38-1 except for the use of ethylmethyl (4-nitrophenyl) acetate (8- 3), methyl 2- (4-nitrophenyl) -2-methylpropionamide (8-5, CHK-508) was synthesized having the following physicochemical properties: 95% yield, 1H-NMR yellow oil (CDCI3) d 8, 18 (day, 2 H), 7.50 (day, 2 H), 3.72 (s, 3 H), 1.63 (s, 6 H)
Stage 74-4. Preparation of methyl 2- (4-aminophenyl) -2-methylpropionamide (8-7, CHK-509) by a procedure similar to that of example 1-2 except for the use of 2- (4-nitrophenyl) -2-met Methylpropionamide (8-5), methyl 2- (4-aminophenyl) -2-methylpropionamide (8-7, CHK-509) having the following physicochemical properties was synthesized: Yield 80%, yellow oil 1 H -NRM (CDCI3) d 7.12 (day, 2 H), 6.66 (day, 2 H), 3.62 (s, 3 H), 1.52 (s, 6 H) Stage 74-5. Preparation of methyl 2- (4-methylsulfonylamino) phenyl] -2-methylpropionamide (8-9, CHK-516) by a procedure similar to that of example 1-3 except for the use of 2- (4-aminophenyl) -2 methyl-methylpropionamide (8-7), methyl 2- (4- (methylsulfonylamino) phenyl] -2-methylpropionamide (8-9, CHK-516) was synthesized having the following physicochemical properties: Yield of 96%, yellow solid, mp = 123-125 ° C 1 H-NMR (CDCl 3) d 7.33 (da, 2 H), 7.18 (da, 2 H), 6.67 (sa, 1 H), 3.66 (s, 3 H), 3.02 (s, 3 H), 1, 57 (s, 6 H) Stage 74-6. Preparation of 2- [4- (methylsulfonylamino) phenyl] -2-methylpropionic acid (8-11, CHK-518) by a procedure similar to that of Example 1-4 except for the use of 2- [4- (methylsulfonylamino) phenyl] Methyl] -2-methylpropionamide (8-9), 2- [4- (methylsulfonylamino) phenyl] -2-methylpropionic acid (8-11, CHK-518) having the following physicochemical properties was synthesized: Yield 92% , yellow solid, mp = 148-151 ° C 1 H-NMR (CDCl 3) d 7.39 (da, 2 H), 7.19 (da, 2 H), 6.44 (sa, 1 H), 3, 02 (s, 3 H),
1.60 (s, 6 H) Example 75: Preparation of 2- (3-methoxy-4- (mlsylsulfonylamino) phenyl) -2-methylpropionic acid (8-12, CHK-491) EIApa 75-1. Preparation of 3-methoxy-4-nitrobenzonitrile (8-2, CHK-78) 3-methoxy-4-nitrobenzonitrile (8-2) on the market was prepared from 3-methoxybenzonitrile by the prior literature procedure ( Gallacher et al., Biogenic Amines, pp. 49-62, 1995) 44% yield, yellow solid, mp = 87-89 ° C 1 H-NMR (CDCl 3) d 7.88 (d, 1 H, J = 8.3 Hz), 7.07 (d, 1 H, J = 1.7 Hz), 7.00 (dd, 1 H, J = 1, 7, 8.3 Hz), 4.00 (S, 3 H), 3.84 (s, 2 H) Step 75-2. Preparation of methyl (3-methoxy-4-nitrophenyl) acetate (8-4, CHK-143) by a procedure similar to that of example 74-2 except for the use of 3-methoxy-4-nitrobenzonitrile (8-2) , methyl (3-methoxy-4-nitrophenyl) acetate (8-4, CHK-143) was synthesized which has the following physicochemical properties: Yield of 79%, 1 H-NMR yellow oil (CDCI3) d 7.83 ( d, 1 H, J = 8.3 Hz), 7.03 (d, 1 H, J = 1.7 H), 6.94 (dd, 1 H, J = 1.7, 8.3 Hz) , 3.97 (s, 3 H), 3.73 (s, 3 H), 3.69 (s, 2 H) Step 75-3. Preparation of methyl 2- (3-methoxy-4-nitrophenol) -2-methylpropionamide (8-6, CHK-469) By a procedure similar to that of Example 73-1 except for the use of (3-methoxy-4-) nitrophenyl) methyl acetate (8-4), methyl 2- (3-methoxy-4-nitrophenyl) -2-methylpropionamide (8-6, CHK-469) was synthesized having the following physicochemical properties: Yield 82% , yellow oil 1 H-NMR (CDCl 3) d 7.80 (d, 1 H, J = 8.5 Hz), 7.00 (d, 1 H, J = 2 Hz), 6.96 (dd, 1 H, J = 2, 8.5 Hz), 3.93 (s, 3 H), 3.65 (s, 3 H), 1.58 (s, 6 H) Step 75-4. Preparation of methyl 2- (3-methoxy-4-aminophenyl) -2-methylpropionamide (8-8, CHK-481) By a procedure similar to that of Example 1-2 except for the use of 2- (3-methoxy) 4-nitrophenyl) -2-methylpropionamide (8-6), methyl 2- (3-methoxy-4-aminophenyl) -2-methylpropionamide (8-8, CHK-481) having the following physicochemical properties was synthesized: Yield 82%, yellow oil 1 H-NMR (CDCl 3) d 6.75-6.80 (m, 2 H), 6.66 (d, 1 H, J = 8.4 Hz), 3.84 (s) , 3 H),
3.63 (S, 3 H), 1.54 (s, 6 H) Step 75-5. Preparation of methyl 2- (3-methoxy-4- (methylsulfonylamino) phenyl) -2-methylpropionamide (8-10, CHK-489) by a procedure similar to that of example 1-3 except for the use of 2- (3 methyl-methoxy-4-aminophenyl) -2-methylpropionamide (8-8), synthesized methyl 2- (3-methoxy-4- (methylsulfonylamino) phenyl) -2-methylpropionamide (8-10, CHK-489) which has the following physicochemical properties: Yield of 90%, yellow oil 1 H-NMR (CDCl 3) d 7,46 (d, 1 H, J = 8,4 Hz), 6,95 (dd, 1 H, J = 2 , 8.4 Hz), 6.88 (d, 1 H, J = 2 Hz), 6.75 (sa, 1 H), 3.88 (s, 3 H), 3.67 (s, 3 H) ), 2.96 (s, 3 H), 1.57 (s, 6 H) Step 75-6. Preparation of 2- (3-methoxy-4- (methylsulfonylamino) phenyl) -2-methylpropionic acid (8-12, CHK-491) by a procedure similar to that of Example 1-4 except for the use of 2- (2-NaOH Methyl 3-methoxy-4- (methylsulfonylamino) phenyl) -2-methylpropionamide (8-10) as a metal salt, 2- (3-methoxy-4- (methylsulfonyamino) phenyl) -2-methylpropionic acid (8-) was synthesized 12, CHK-491) having the following physicochemical properties: Yield of 89%, white solid, mp = 122-124 ° C 1 H-NMR (CDCl 3) d 7.47 (d, 1 H, J = 8.3 Hz), 7.00 (dd, 1 H, J = 1.8, 8.3 Hz), 6.94 (d, 1 H, J = 1.8 Hz), 6.78 (sa, 1 H) , 3.88 (s, 3 H), 2.96 (s, 3 H), 1.60 (s, 6 H) Example 76: Preparation of? / - [2- (3,4-dimethylbenzyl) -3 -pivaloyloxypropyl] -2- [4- (methylsulfonylamino) phenyl] -2-methylpropionamide (9-1, CHK-520) By a procedure similar to that of Example 1-5 except for the use of 2- [4 (methylsulfonicamino) phenyl] -2-methylpropionic acid (8-11), was synthesized / - [2- (3,4-dimethylbenzyl) -3-pivaloyloxypropyl] - 2- [4- (Methylsulfonylamino) phenyl] -2-methylopropionamide (9-1, CHK-520) having the following physicochemical properties: 89% yield, yellow solid, mp = 126-130 ° C 1 H-NMR (CDCl 3 ) d 7.34 (dd, 2 H, J = 8.3, 1 Hz), 7.18 (d, 2 H, J = 8.3, 1 Hz), 6.8-7.05 (m, 3 H), 6.44 (sa, 1 H), 5.60 (t, 1 H), 3, 95 (dt, 1 H), 3.76 (ddd, 1 H), 3.27 (m, 1 H), 3.08 (m, 1 H), 3.00 (d, 3 H), 2, 45-2.65 (m, 2 H), 2.15-2.3 (m, 6 H), 2.05 (m, 1 H), 1.53 (s, 6 H), 1.19 ( d, 9 H) MS (FAB) m / z 517 (MH +) Example 77: Preparation of? / - [2- (3,4-dimethylbenzyl) -3-pivaloyloxypropyl] -2- [3-fluoro-4- ( methylsulfonyl) phenyl] -2-methylpropionamide (9-2, CHK-543) by a procedure similar to that of Example 1-5 except for the use of 2- [3-fluoro-4 (methylsulfonylamino) phenyl] -2 -methylpropionic acid (7-4), was synthesized? / - [2- (3,4-dimethylbenzyl) -3-pivaloxylopropyl] -2- [3-fluoro-4- (methylisulfonyl amino) phenyl] -2- meilypropionamide (9-2, CHK-543) having the following physicochemical properties: Yield of 82%, white solid, mp = 53-55 ° C 1 H-NMR (CDCl 3) d 7.52 (dt, 1 H), 6 , 8-7.2 (m, 5 H), 5.74 (t, 1 H), 4.01 (dt, 1 H),
3.77 (ddd, 1 H), 3.28 (m, 1 H), 2.95-3.15 (m, 4 H), 2.45-2.65 (m, 2 H), 2, 15-2.3 (m, 6 H), 2.05 (m, 1 H), 1.52 (s, 6 H), 1.20 (d, 9 H) MS (FAB) m / z 535 ( MH +) Example 78: Preparation of? / - [2- (3,4-dimethylbenzyl) -3-pivaloyloxypropyl] -2- [3-methoxy-4- (methylsulfonylamino) phenyl] -2-methylpropionamide (9-3, CHK -493) Using a procedure similar to that of Example 1-5 except for the use of 2- [3-methoxy-4- (methylsulfonylamino) phenyI] -2-methylpropionic acid (8-12), V- [2- (3,4-dimethylbenzyl) -3-pivaloyloxypropyl] -2- [3-methoxy-4- (methylsulfonylamino) phenyl] -2-methylpropionamide (9-3, CHK-493) having the following physicochemical properties: Yield 84 %, white solid, mp = 100-103 ° C 1 H-NMR (CDCl 3) d 7.48 (dd, 1 H, J = 8.3, 2 Hz), 6.8-7.05 (m, 5 H), 6.74 (sa, 1 H), 5.61 (t, 1 H), 3.95 (ddd, 1 H), 3.86 (s, 3 H), 3.75 (ddd, 1 H), 3.26 (m, 1 H), 3.06 (m, 1 H), 2.96 (d, 3 H), 2.45-2.65 (m, 2 H), 2.15 -2.3 (m, 6 H), 2.05 (m, 1 H), 1.54 (s, 6 H), 1.19 (d, 9 H) MS (FAB) m / z 547 (MH +) Example 79: Preparation of? / - [3- (3,4-dimethylphenyl) propyl] -2- [4- (methylisulfonylamino) phenyl] -2-methylpropionamide (9-4, CHK-591) By a procedure similar to that of Example 1-5 except for the use of 2- [4- (methylsulfonylamino) phenyl] -2-methylpropionic acid (8-11), N- [3- (3,4-dimethylphenyl) propyl was synthesized] -2- [4- (Methylsulfonylamino) phenyl] -2-methyl-propionamide (9-4, CHK-591) having the following physicochemical properties: Yield 83%, white solid, mp = 138-139 ° C H-NMR ( CDCl 3) d 7.33 (d, 2 H), 7.19 (d, 2 H), 7.01 (d, 1.H, J = 7.5 Hz), 6.8-6.88 (m , 2 H), 5.17 (ta, 1 H), 3.20 (dd, 2 H), 3.01 (s, 3 H), 2.47 (t, 2 H, J = 7.3 Hz ), 2.21 (s, 6 H), 1.71 (m, 2 H), 1.51 (s, 6 H) MS (FAB) m / z 403 (MH +) Example 80: Preparation of? / - [3- (3,4-Dimethylphenyl) propyl] -2- [3-fluoro-4- (methylsulfonylamino) phenyl] -2-methylpropionamide (9-5, CHK-656) By a procedure similar to that of Example 1-5 except for the use of 2- [3-fluoro-4- (methylsulfonylamino) phenyl] -2-me acid tylpropionic (7-4), N- [3- (3,4-dimethylphenyl) propyl] -2- [3-fluoro-4- (methylsulfonylamino) phenyl] -2-methylopropionamide (9-5, CHK-656) was synthesized ) which has the following physicochemical properties: Yield 89%, white solid, mp = 145-146 ° C 1 H-NMR (CDCIa) d 7.53 (t, 1 H, J = 8.3 Hz), 7.1 -7.17 (m, 2 H), 7.02 (d, 1 H), 6.8-6.9 (m, 2 H), 6.46 (sa, 1 H), 5.18 (t , 1 H), 3.23 (dd, 2 H), 3.03 (s, 3 H), 2.49 (t, 2 H, J = 7.5 Hz), 2.22 (s, 6 H) ), 1.74 (m, 2 H), 1.49 (s, 6 H) MS (FAB) m / z 421 (MH +) Example 81: Preparation of V- [3- (3,4-dimethy-phenyl) propyl ] -2- [3-meioxy-4- (methylisuphonyl-amino) phenyl] -2-methylpropionamide (9-6, CHK-600) By a procedure similar to that of Example 1-5 except for the use of 2- (3-) acid methoxy-4- (methylsulfonylamino) phenyl) -2-methylpropionic (8-12), N- [3- (3,4-dimethylphenyl) propyl] -2- [3-methoxy-4- (methylsulfonylamino) phenyl] was synthesized] -2-methylpropionamide (9-6, CHK-600) which has the following physicochemical properties: Yield of 86%, solid or white, mp = 93-95 ° C 1 H-NMR (CDCl 3) d 7.48 (d, 1 H), 6.75-7.05 (m, 6 H), 5.18 (rt, 1 H ), 3.85 (s, 3)
H), 3.20 (dd, 2 H), 2.96 (s, 3 H), 2.46 (t, 2 H, J = 7.3 Hz), 2.21 (s, 6 H), 1.71 (m, 2 H), 1.52 (s, 6 H) MS (El) m / z 432 (M +) Example 82: Preparation of α / - (4-ér-butylbenzyl) -2- [4 - (Methylsulfonylamino) phenyl] -2-methylpropionamide (9-7, CHK-715) By a procedure similar to that of Example 1-5 except for the use of 2- (3-methoxy-4- (methylsulfonylamino) phenyl) - 2-methylpropionic (8-12), N- [3- (3,4-dimethylphenyl) propyI] -2- [3-methoxy-4- (melylsulfonylamino) phenyI] -2-methylpropionamide (9-6, CHK) was synthesized -600) having the following physicochemical properties: Yield of 92%, white solid, mp = 141-143 ° C 1 H-NMR (CDCIa) d 7.36 (d, 2 H, J = 8.5 Hz), 7.31 (d, 2 H, J = 7.9 Hz), 7.18 (d, 2 H, J = 8.5 Hz), 7.07 (d, 1 H, J = 7.9 Hz) , 6.40 (sa, 1 H), 5.46 (ta, 1 H), 4.36 (d, 1 H, J = 5.7 Hz), 3.00 (S, 3 H), 1, 59 (s, 3 H), 1.55 (s, 3 H), 1, 30 (s, 9 H) MS (FAB) m / z 403 (MH +) Example 83: Preparation of? / - (4-tert. -buyylbenzyl) -2- [3-fluoro-4- (methylsulfonylamino) phenyl] -2-methylpropionamide (9-8), CHK-655) Using a procedure similar to that of Example 1-5 except for the use of 2- [4- (methylisulfonamino) phenyl] -2-methylpropionic acid (8-11), N- (4-tert- butynebenzyl) -2- [3-fIuoro-4- (methylsulfonylamino) phenyl] -2-methylpropionamide (9-8, CHK-655) having the following physicochemical properties: Yield of 74%, white solid, mp = 48-51 ° C 1 H-NMR (CDCl 3) d 7.53 (t, 1 H, J = 8.2 Hz), 7.33 (d, 2 H), 7.17 (d, 1 H), 7.09 ( d, 1 H), 6.45 (sa, 1 H), 5.50 (ta, 1 H), 4.37 (d, 1 H, J = 5.5 Hz), 3.03 (s, 3 H), 1.58 (s, 3 H), 1.55 (s, 3 H), 1.30 (s, 9 H) MS (FAB) m / z 421 (MH +) Example 84: Preparation of? - (4-ferc-butylbenzyl) -2- [3-methoxy-4- (methylsulfonylamino) phenyl] -2-methylpropionamide (9-9, CHK-1001) By a procedure similar to that of Example 1-5 except for the use 2- (3-methoxy-4- (methylsulfonylamino) phenyl) -2-methylpropionic acid (8-12), N- (4-ert-butylbenzyl) -2- [3-methoxy-4- (methylsulfonyl amino) was synthesized phenyl] -2-methylpropionamide (9-9, CHK-1 001) having the following physicochemical properties: Yield of 76%, white solid, mp = 56-58 ° C 1 H-NMR (CDCl 3) d 7.46 (d, 1 H), 7.30 (d, 2 H ), 7.09 (d, 2H), 6.98 (dd, 1 H), 6.83 (d, 1 H), 6.83 (d, 1 H), 6.77 (sa, 1 H) , 5.55 (ta, 1 H), 4.36 (d, 1 H), 3.80 (s, 3 H), 2.94 (s, 3 H), 1, 59 (s, 6 H) , 1.29 (s, 9 H) Example 85: Preparation of 1- [3-fluoro-4- (methylsulfonyl amino) phenyl] cyclopropanecarboxylic acid (10-5, CHK-996) Step 85-1. Preparation of 2- (3-fluoro-4-nitrophenyl methyl acetate (10-1 CHK-947) To a slowly stirred solution of nitric acid (11.48 mM, 0.49 ml) was added a mixture of ethyl acetate 3-Fluorophenyl (11.48 mM, 1930 mg) which is commercially available and H2SO4 (3 mmol) at 0 ° C. dropwise After stirring for 2 h, the mixture was diluted with ice water and extracted with ethyl acetate The combined organic phases were washed with water, The residue was purified by flash column chromatography on silica gel using EtOAc: hexanes (1: 4) as eluent to give 2- (3-f luoro-4-nitrofenil) Methyl acetate (10-1, CHK-947) Yield 76%, 321 mg 1 H-NMR (CDCl 3) d 8.02 (t, 1 H), 7.15-7.30 (m, 2 H) ), 3.73 (s, 3 H), 3.70 (s, 2 H) Step 85-2 Preparation of methyl 1- (3-fluoro-4-ylorophenyl) cyclopropanecarboxylate (10-2, CHK-987) ) To a stirred solution of methyl 2- (3-fluoro-4-nitrophenyl) acetate (10-1, 300 mg, 1.41 mmol) in anhydrous THF (6 mL) was added. and added NaH (14.1 mM, 338 mg) slowly. The mixture was stirred for 10 min and then dibromoethane (7.05 mM, 0.6 ml) was added. The reaction mixture was allowed to warm to room temperature for 30 min and was quenched by a saturated solution of NH 4 Cl. After the final aqueous work-up, the residue was purified by flash column chromatography with EtOAc: hexanes (1: 5) as eluent to give meifyl 1- (3-fluoro-4-ylorophenyl) cyclopropanecarboxylate (10-2, CHK-987) . Yield 76%, white solid, mp = 56-58 ° C 1 H-NMR (CDCl 3) d 7.47 (dt, 1 H), 7.15-7.30 (m, 2 H), 3.66 ( s, 3 H), 1.68 (dd, 2 H), 1.19 (dd, 2 H) Step 85-3. Preparation of methyl 1- (4-amino-3-fluorophenyl) cyclopropanecarboxylate (10-3, CHK-993) by a procedure similar to that of example 1-2 except for the use of 1- (3-fluoro-4-nitrophenyl) ) methyl cyclopropanecarboxylate (10-2) with the corresponding 4-chlorobenzylamine compound as the starting material, methyl 1- (4-amino-3-fluorophenyl) cyclopropanecarboxylate (10-3, CHIC-993) having the following was synthesized Physicochemical properties: 1 H-NMR (CDCl 3) d 6,9-7,0 (m, 2 H), 6,64 (m, 1 H), 3,89 (sa, 2 H), 3,65 (s) , 3 H), 1.68 (dd, 2 H), 1.18 (dd, 2 H) Step 85-4. Preparation of methyl 1- (4-amino-3-fluorophenyl) -cyclopropanecarboxylate
(10-4) By a procedure similar to that of Example 1-3 except for the use of methyl 1- (4-amino-3-f luorofenyl) cyclopropanecarboxylate (10-3) with the corresponding 4-chlorobenzylamine compound as the material Initially, methyl 1- (4-amino-3-fluorofenyl) cyclopropanecarboxylate (10-4) was synthesized having the following physicochemical properties: 1 H-NMR (CDCl 3) d 7,05-7,23 (m , 3 H), 6.51 (sa, 1 H), 3.68 (s, 3 H), 3.31 (s, 3 H), 1.77 (dd, 2 H), 1, 34 (dd) , 2 H) Stage 85-5. Preparation of 1- [3-fluoro-4- (methylsulfonyl) aminoethylcyclopropanecarboxylate (10-5) By a procedure similar to that of Example 1-5 except for the use of 1- (4-amino-3-fluorophenyl) cyclopropanecarboxylate methyl (10-4) with the corresponding 4-chlorobenzylamine compound as the starting material, methyl 1- [3-fluoro-4- (methylsulfonylamino) phenyl] cyclopropanecarboxylase (10-5) was synthesized having the following physicochemical properties: 1H -NMR (CDCl 3) d 7.05-7.25 (m, 3 H), 6.50 (sa, 1 H), 3.30 (s, 3 H), 1.76 (dd, 2 H), 1.33 (dd, 2 H) MS (FAB) m / z 421 (MH +) Example 86: Preparation of 1- [4- (methylsulfonylamino) phenyl] cyclopropanecarboxylic acid (11-7, CHK-530) Step 86-1. Preparation of methyl 1- (4-nitrophenyl) cyclopropanecarboxylate (11-1, CHK-521) By a procedure similar to that of example 85-2 except for the use of methyl (4-nitrophenyl) acetate (8-3) as Starting material, methyl 1- (4-nitrophenyl) cyclopropanecarboxylate (11-1, CHK-521) was synthesized having the following physicochemical properties: Yield of 71%, yellow solid, mp = 89-91 ° C 1 H- NMR (CDCl 3) d 8.18 (day, 2 H), 7.51 (day, 2 H), 3.65 (s, 3 H), 1.71 (dd, 2 H), 1.24 (dd) , 2 H) Stage 86-2. Preparation of methyl 1- (4-aminophenyl) cyclopropanecarboxylate (11-3 CHK-525) By a procedure similar to that of example 1-2 except for the use of methyl 1- (4-nitrophenyl) cyclopropanecarboxylate (11-1) As the starting material, methyl 1- (4-aminophenyl) cyclopropanecarboxylate (11-3, CHK-525) was synthesized having the following physicochemical properties: 93% yield, yellow solid, mp = 62-65 ° C 1H- NMR (CDCl 3) d 7.12 (da, 2 H), 6.63 (da, 2 H), 3.65 (sa, 2 H), 3.61 (s, 3 H), 1.54 (dd) , 2 H), 1, 13 (dd, 2 H) Stage 86-3. Preparation of methyl 1- [4- (methylsuphonyl amino) phenyl] cyclopropanecarboxylate (11-5, CHK-527) Using a procedure similar to that of Example 1-3 except for the use of methyl 1- (4-aminophenyl) cyclopropanecarboxylate ( -3) as the starting material, methyl 1- [4- (methylisu-phonyl amino) phenyl] cyclopropanecarboxylate (11-5, CHK-527) having the following physicochemical properties was synthesized:. Yield of 88% yield, white solid, mp = 118-120 ° C 1 H-NMR (CDCl 3) d 7.33 (da, 2 H), 7.15 (da, 2 H), 6.36 (sa, 1 H), 3.63 (s, 2 H), 3.03 (S, 3 H), 1.62 (dd, 2 H), 1.17 (dd, 2 H) Step 86-4. Preparation of methyl-1 - [4- (methylsulfonylamino) phenyl] cyclopropanecarboxylic acid (11-7, CHK-530) by a procedure similar to that of example 1-4 except for the use of 1- [4- (methylisulfonyl) phenyl] Methyl cyclopropanecarboxylate (11-5) as starting material, methyl-1 - [4- (methylsulfonylamino) phenyl] cyclopropanecarboxylic acid (11 -7, CHK-530) having the following physicochemical properties was synthesized: Yield of 98 %, yellow solid, mp = 220-224 ° C H-NMR (DMSO-d6) d 9.69 (sa, 1 H, CO2H), 7.26 (day, 2 H), 7.10 (day, 2) H), 2.96 (s, 3 H), 1.41 (dd, 2 H), 1.08 (dd, 2 H) Example 87: Preparation of 1- [3-methoxy-4- (methylsulfonylamino ) phenyl] cyclopropanecarboxylic acid (11 -8, CHK-539) Step 87-1. Preparation of methyl 1- (3-methoxy-4-nitrophenyl) cyclopropanecarboxylate (11-2, CHK-528) By a procedure similar to that of example 85-2 except for the use of (3-methoxy-4-nitrophenyl) acetate of methyl (8-4) as starting material, 1- (3-methoxy-4-ylorophenyl) cyclopropanecarboxylane meylyl (11-2, CHK-528) having the following physicochemical properties was synthesized: Yield 70%, yellow oil 1 H-NMR (CDCl 3) d 7.81 (d, 1 H, J = 8.3 Hz), 7.07 (d, 1 H, J = 1.5 Hz), 7.00 (dd, 1 H, J = 8.3, 1.5 Hz), 3.97 (s, 3 H), 3.65 (s, 3 H), 1.68 (dd, 2 H), 1, 23 (dd , 2 H) Eíapa 87-2. Preparation of methyl 1- (4-amino-3-methoxyphenyl) cyclopropanecarboxylate (11-4, CHK-531) By a procedure similar to that of Example 1-2 except for the use of 1- (3-methoxy-4-nitrophenyl) Methyl cyclopropanecarboxylate (11-2) as a starting material, methyl 1- (4-amino-3-methoxyphenyl) cyclopropanecarboxylate (11-4, CHK-531) having the following physicochemical properties was synthesized:
Yield 92%, reddish oil 1 H-NMR (CDCl 3) d 6,6-6,8 (m, 3 H), 3,85 (s, 3 H), 3,77 (sa, 2 H), 3 , 62 (s, 3 H), 1.55 (dd, 2 H), 1, 15 (dd, 2 H) Stage 87-3. Preparation of methyl 1- (3-methoxy-4- (methylsulfonyl) amino) phenyl] cyclopropanecarboxylate (11 -6, CHK-534) by a procedure similar to that of example 1-3 except for the use of 1- (4-amino) Methyl-3-methoxyphenyl) cyclopropanecarboxylate (11-4) as starting material, methyl 1- [3-methoxy-4- (methylsulfonylamino) phenyl] cyclopropanecarboxylate (11-6, CHK-534) having the following was synthesized Physicochemical properties: Yield of 92%, reddish oil 1H-NMR (CDCI3) d6.6-6.8 (m, 3 H), 3.85 (s, 3 H), 3.77 (sa, 2 H) , 3.62 (s, 3 H),
1.55 (dd, 2 H), 1.15 (dd, 2 H) Step 87-4. Preparation of 1- [3-methoxy-4- (methylsulfonylamino) phenyl] cyclopropanecarboxylic acid (11-8, CHK-539) By a procedure similar to that of Example 1-3 except for the use of 1- [3-methoxy] 4- (Methylsulfonylamino) phenyl] cyclopropanecarboxylic acid methyl ester (11-6) as the starting material, 1- [3-methoxy-4- (methylsulfonylamino) phenyl] cyclopropanecarboxylic acid (11-8, CHK-539) was synthesized having the following physicochemical properties: Yield of 92%, reddish oil 1 H-NMR (CDCl 3) d, 6,6-6,8 (m, 3 H), 3,85 (s, 3 H), 3,77 (sa, 2 H), 3.62 (s, 3 H), 1.55 (dd, 2 H), 1.15 (dd, 2 H) Example 88: Preparation of? / - [2- (3,4-dimethylbenzyl ) -3-pivaloyloxypropyl] -1- [4- (methylsulfoniamino) phenyl] cyclopropanecarboxamide (12-1, CHK-533) by a procedure similar to that of example 1-5 except for the use of 1- [4- (methylsulfonylamino ) phenyl] cyclopropanecarboxylic (11-7) as a starting material, was synthesized? / - [2- (3,4-dimethylbenzyl) -3-pivaloyloxypropyl] -1- [4- (methylsulfonic acid lamino) phenyl] cyclopropanecarboxamide (12-1, CHK-533) having the following physicochemical properties: Yield 80%, white solid, mp = 54-56 ° C 1 H-NMR (CDCl 3) d 7.38 (d, 2 H, J = 8.3 Hz), 7.21 (d, 2 H, J = 8.3 Hz), 6.75-7.05 (m, 3 H), 6.37 (sa, 1 H) ), 5.56 (sa, 1 H), 3.93 (m, 1 H), 3.76 (m, 1 H), 3.27 (m, 1 H), 2.95-3.1 ( m, 4 H), 2.4-2.6 (m, 2 H), 2.15-2.3 (m, 6 H), 2.05 (m, 1 H), 1.58 (m, 2 H), 1.17 (s, 9 H), 1.00 (m, 2 H) MS (FAB) m / z 515 (MH +) Example 89: Preparation of N- [2- (3,4-dimethylbenzyl ) -3-pivaloyloxypropyl] -1- [3-fluoro-4- (methylsulfonylamino) phenyl] cyclopropanecarboxamide (12-2, CHK-538) By a procedure similar to that of example 1-5 except for the use of l- [ 3-Fluoro-4- (methylsulfonylamino) pheny1] cyclopropanecarboxylic acid (10-6) as starting material, was synthesized? / - [2- (3,4-dimethylbenzyl) -3-pivaloyloxypropyl] -1 - [3-f luoro -4- (Methylsulfonylamino) phenyl] cyclopropanecarboxamide (12-2, CHK-538) having the following physicochemical properties : white solid, mp = 55-56 ° C 1 H-NMR (CDCl 3) d 7.48 (t, 1 H), 7.1-7.2 (m, 2 H), 6.75-7.05 ( m, 3 H), 6.39 (sa, 1 H), 5.58 (sa, 1 H), 3.92 (m, 1 H), 3.77 (m, 1 H), 3.25 ( m, 1 H), 2.9-3.1 (m, 4 H), 2.4- 2.6 (m, 2 H), 2.15-2.3 (m, 6 H), 2, 07 (m, 1 H), 1.58 (m, 2 H), 1, 18 (s, 9 H), 1, 02 (m, 2 H)
MS (FAB) m / z 533 (MH +) Example 90: Preparation of? / - [2- (3,4-dimethylbenzyl) -3-pivaloyloxypropyl) -1- [3-methoxy-4- (methylsulfonyl) phenyl] cyclopropanecarboxamide (12-3, CHK-541) By a procedure similar to that of Example 1-5 except for the use of 1- [3-fluoro-4- (methylsulfonylamino) phenyl] cyclopropanecarboxylic acid (10-6) as starting material, was synthesized? / - [2- (3,4-dimethylbenzyl) -3-pivaloyloxypropyl] -1- [3-methoxy-4- (methylsulfonylamino) phenyl] cyclopropanecarboxamide (12-3, CHK-541) having the following properties physicochemical: Yield of 82%, white solid, mp = 66-68 ° C 1 H-NMR (CDCl 3) d 7.50 (dd, 1 H, J = 8.3, 1, 3 Hz), 6.75-7 , 05 (m, 6 H), 5.65 (ta, 1 H), 3.94 (m, 1 H), 3.90 (s, 3 H), 3.76 (m, 1 H), 3 , 29 (m, 1 H), 2.9-3.1 (m, 4 H), 2.4-2.6 (m, 2 H), 2.15-2.3 (m, 6 H) , 2.05 (m, 1 H), 1.58 (m, 2 H), 1.16 (d, 9 H), 1.02 (m, 2 H) MS (FAB) m / z 545 (MH + Example 91: Preparation of? / - [3- (3,4-dimethyphenyl) propyl] -1- [4- (methylsulfonylamino) phenyl] cyclopropanecar boxamide (12-4, CHK-590) Using a procedure similar to that of Example 1-5 except for the use of 1- [4- (methylsulfonylamino) phenyl] cyclopropanecarboxylic acid (11-7) as starting material, was synthesized? / - [3- (3,4-dimethylphenyl) propiI] -1- [4- (methylisulfonyl) phenyl] cyclopropanecarboxamide (12-4, CHK-590) having the following physicochemical properties: Yield of 81%, white solid, mp = 127-128 ° C H-NMR (CDCl 3) d 7.37 (m, 2 H, J = 8.3 Hz), 7.19 (m, 2 H, J = 8.3 Hz), 6.75-7.05 (m, 3 H), 6.40 (sa, 1 H), 5.25 (sa, 1 H), 3.17 (dd, 2 H), 3.06 (s, 3 H), 2.46 (t, 2 H, J = 7.3 Hz), 2.21 (s, 6 H), 1, 68 (m, 2 H), 1, 59 (dd, 2 H), 0.99 (dd, 2 H) MS (FAB) m / z 401 (MH +) Example 92: Preparation of? / - [3- (3,4-dimethylphenyl) propyl] -1- [3-f luoro-4- (methylsulfonylamino) f enylcyclopropanecarboxamide (12-5) By a procedure similar to that of Example 1-5 except for the use of 1- [3-fluoro-4- (methylsulfonylamino) phenyl] cyclopropanecarboxylic acid (10-6) as the starting material, Did you intetize? / - [3- (3,4-dimethylphenyl) propyl] -1- [3-fluoro-4- (methylsulfonylamino) phenyl] cyclopropanecarboxamide (12-5) which has the following physicochemical properties: 81% yield, solid white, mp = 127-128 ° C 1 H-NMR (CDCl 3) d 7.50 (1, 1 H), 7.1-7.2 (m, 2 H), 6.8-7.1 (m, 3 H), 6.40 (sa, 1
H), 5.30 (sa, 1 H), 3.16 (dd, 2 H), 3.05 (s, 3 H), 2.48 (t, 2 H), 2.25 (s, 6) H), 1.69 (m, 2 H), 1.60 (m, 2 H), 1.00 (dd, 2 H) MS (FAB) m / z419 (MH +) Example 93: Preparation of? - [ 3- (3,4-Dimethylphenyl) propyl] -1- [3-methoxy-4- (methylsulfonylamino) phenyl] cyclopropanecarboxamide (12-6, CHK-632) By a procedure similar to that of Example 1-5 except for the use of 1- [3-methoxy-4- (methylsulfonyllamino) phenyI] cyclopropanecarboxylic acid (11-8) as starting material, was synthesized? / - [3- (3,4-dimethylphenyl) propyl] -1- [ 3-methoxy-4- (methylsulfonylamino) phenyl] cyclopropanecarboxamide (12-6, CHK-632) having the following physicochemical properties: Yield 87%, white solid, mp = 88-89 ° C 1 H-NMR (CDCl 3) d 7.50 (d, 1 H, J = 8.1 Hz), 6.75-7.05 (m, 6 H), 5.34 (t, 1 H), 3.88 (s, 3 H) ), 3.18 (dd, 2 H), 3.00 (s, 3 H), 2.47 (t, 2 H, J = 7.5 Hz), 2.21 (s, 6 H), 1 , 69 (m, 2 H), 1.59 (dd, 2 H), 1, 01 (dd, 2 H) MS (FAB) m / z 431 (MH +) Example 94: Preparation of / V- (4- ferobutilbencil) -1- [ 4- (mephilsulfonylamino) phenyl] cyclopropanecarboxamide (12-7, CHK-719) By a procedure similar to that of Example 1-5 except for the use of 1- [4- (methylsulfonylamino) pheny1] cyclopropanecarboxylic acid (11-7) as Starting material, was synthesized? / - (4-ér-buty-benzyl) -1- [4- (meilylsulfonylamino) phenyl] cyclopropanecarboxamide (12-7, CHK-719) which has the following physicochemical properties: Yield of 90%, solid white, mp = 200-203 ° C 1 H-NMR (DMSO-de) d 9.75 (br s, 1 H), 4.15 (d, 2 H, J = 6 Hz), 2.98 (s, 3 H), 1.32 (dd, 2 H), 1.25 (s, 9 H), 0.94 (dd, 2 H) MS (FAB) m / z401 (MH +) Example 95: Preparation of. ? / - (4-t-butylbenzyl) -1- [3-fluoro-4- (methylsulfonyl amino) f enylcyclopropanecarboxamide (12-8, CHK-998) By a procedure similar to that of Example 1-5 except for the use of 1- [3-Fluoro-4- (methylsulfonylamino) phenyl] cyclopropanecarboxylic acid methyl ester (10-5) as a starting material, was synthesized? / - (4-fer-butylbenzyl) -1- [3-fluoro-4- ( methylsulfonylamino) phenyl] cyclopropanecarboxamide (12-8, CHK-998) having the following physicochemical properties: Yield 90%, white solid, mp = 200-203 ° C 1 H-NMR (CDCl 3) d 9.75 (sa, 1 H), 4.15 (d, 2 H, J = 6 Hz), 2.98 (s, 3 H), 1.32
(dd, 2 H), 1.25 (s, 9 H), 0.94 (dd, 2 H) MS (FAB) m / z 401 (MH +) Example 96: Preparation of / V- (4-fer butylbenzyl) -1- [3-methoxy-4- (methylsulfonylamino) phenyl] cyclopropanecarboxamide (12-9, CHK-718) by a procedure similar to that of Example 1-5 except for the use of 1- [3-methoxy] 4- (Methylsulfonylamino) phenyl] cyclopropanecarboxylic acid (11-8) as a starting material, was synthesized / V- (4-ert-butylbenzyl) -1- [3-methoxy-4- (methylsulfonylamino) phenyl] cyclopropanecarboxamide (12- 9, CHK-718) having the following physicochemical properties: Yield 90%, white solid, mp = 200-203 ° C 1 H-NMR (CDCl 3) d 7.48 (d, 1 H), 7.31 ( da, 2 H), 7.09 (day, 2 H), 7.03 (dd, 1 H), 6.94 (sa, 1 H), 6.80 (sa, 1 H), 5.67 ( ta, 1 H), 4.36 (d, 2 H), 3.86 (s, 3 H), 2.97 (s, 3 H), 1, 65 (dd, 2 H), 1.29 ( s, 9 H), 1.06 (dd, 2 H) MS (FAB) m / z 431 (MH +) Example 97: Preparation of 1- [4- (methylsulfonylamino) phenyl] ethylamine (13-11, LJO-302 ) Stage 97-1. Preparation of 4 '- (methylsulfonylamino) acetophenone (13-5, LJO-298) A cold solution of 4'-aminoacetophenone (10 mmol) in pyridine (10 ml) at 0 ° C was treated with methanesulfonyl chloride (15 mmol) and was stirred at room temperature for 2 h. The reaction mixture was diluted with H2O and extracted with EtOAc several times. The combined organic phases were washed with H2O and brine, dried over MgSO4, filtered, and the filtrate was concentrated in vacuo. The residue was purified by flash column chromatography on silica gel using EtOAc: hexanes to give 4 '- (methylsulfonylamino) acetophenone (13-5, LJO-298). 95% yield, mp = 161 QC 1 H-NMR (CDCl 3) d 7.97 (dd, 2 H, J = 2, 6.8 Hz,), 7.26 (dd, 2 H, J = 2, 6 , 8 Hz), 6.87 (sa, 1 H), 3.10 (s, 3 H), 2.59 (s, 3 H) Stage 97-2. Preparation of 4 '- (methylsulfonylamino) acetophenone oxime (13-8, LJO-299) A mixture of 4' - (methylsulfonylamino) acetophenone (13-5.5 mmol) and hydroxylamine hydrochloride (0.695 g, 10 mmol) in pyridine (5 ml) was heated at 70 ° C for 3 h.The reaction mixture was cooled to room temperature, diluted with H2O, and extracted with EtOAc several times. The combined organic phases were washed with H2O and brine, dried over MgSO4, filtered, and the filtrate was concentrated in vacuo. The residue was purified by flash column chromatography on silica gel using EtOAc: hexanes (1: 1) as eluent to give 4'- (methylsulfonylamino) acetophenone oxime (13-8, LJO-299). Yield 91%, white solid, mp = 1809C 1 H-NMR (CDCl 3) d 7.65 (dd, 2 H, J = 2, 6.6 Hz), 7.29 (s, 1 H), 7, 20 (dd, 2 H, J = 2, 6.8 Hz), 6.43 (s, 1 H), 3.03 (s, 3 H), 2.26 (s, 3 H) Step 97-3 . Preparation of 1 [4- (methylsulfonylamino) phenyI] ethylamine (13-11, LJO-302) A suspension of 4 '- (methylsulfonylamino) acetophenone oxime (13-8.5 mmol) and 10% palladium on carbon ( 150 mg) in MeOH (25 ml) was treated with concentrated hydrochloric acid (10 drops) and hydrogenated with a hydrogen balloon for 6 h. The reaction mixture was neutralized with solid NaHCO3, filtered and the filtrate was concentrated in vacuo. The residue was purified by flash column chromatography on silica gel using CH2Cl2: MeOH as eluent to give 1- [4- (methylsulfonamino) phenyl] ethylamine (13-11, LJO-302). Yield of 99%, white solid, mp = 2119C 1 H-NMR (CDCl 3) d 7.35 (d, 2 H, J = 8.6 Hz), 7.18 (d, 2 H, J = 8.6 Hz), 4.13 (q, 1
H, J = 7 Hz), 3.00 (s, 3 H), 1.37 (d, 3 H, J = 7 Hz) Example 98: Preparation of 1- [3-fluoro-4- (methylsulfonylamino) phenyl ] ethylamine (13-12,
MK-232) Step 98-1 Preparation of / V- (2-fluoro-4-iodophenyl) methanesulfonamide (13-3 SH-14) Using a procedure similar to that of Example 97-1 except for the use of 2-fluoro- 4-iodoaniline (13-1) as starting material, was synthesized? - (2-fluoro-4-iodophenyl) methane sulfonamide (13-3, SH-14) having the following physicochemical properties: Yield of 96%, white solid , mp = 123 ° C 1 H-NMR (CDCl 3) d 7.43 (da, 2 H), 7.26 (t, 1 H, J = 8.3 Hz), 6.58 (sa, 1 H) , 2.97
(s, 3 H) Stage 98-2. Preparation of 3'-fIuoro-4 '- (methylsulfonylamino) acetophenone (13-6, LJO- 363) A mixture of? / - (2-fluoro-4-iodophenyl) methanesulfonamide (13-3.5 mmol) and acetate of palladium (ll) (0.15 mM, 0.034 g), 1,3-bisdiphenylphosphinopropane (0.3 mM, 0.124 g), thallium (II) acetate (5.5 mM, 1.450 g) and butyl vinyl ether ( 10 mM, 1.3 ml) in DMF (10 ml) was heated at 95 ° C for 19 h. The reaction mixture was cooled to room temperature, diluted with THF, treated with 10% HCl (10 mL) and ambient temperature was stirred. A mixture was diluted with EOAc, washed three times with an ammonium chloride solution and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel using EtOAc: hexanes as eluent to give 3'-fluoro-4 '- (methylsulfonylamino) acetophenone (13-6, LJO-363). Yield 78%, yellow solid, mp = 141 ° C 1 H-NMR (CDCl 3) d 7.65-7.80 (m, 3 H), 6.89 (sa, 1 H), 3.12 (s, 3 H), 2.59 (s, 3
H) Stage 98-3. Preparation of 3'-fluoro-4 '- (methylsulfonylamino) acetophenone oxime (13-9, LJO-327) By a procedure similar to that of example 97-2 except for the use of 3'-fluoro-4' - ( methylsulfonylamino) acetophenone (13-6) as the starting material, 3'-fluoro-4 '(methylsulfonylamino) acetophenone oxime (13-9, LJO-327) having the following physicochemical properties was synthesized: Yield 87%, solid white, mp = 173 ° C 1 H-NMR (CDCl 3) d 7.59 (t, 1 H, J = 8.3 Hz), 7.4-7.52 (m, 2 H), 6.60 ( sa, 1 H), 3.05 (s, 3 H), 2.25 (s, 3 H) Stage 98-4. Preparation of 1- [3-fluoro-4- (methylsulfonylamino) phenyl] ethylamine (13-12, MK-232) by a procedure similar to that of example 97-3 except for the use of 3'-fluoro-4 'oxime - (meilylsulfonylamino) acetophenone (13-9) as starting material, 3'-fluoro-4- (methylsulfonylamino) phenyl] eylamine (13-12, MK-232) having the following physicochemical properties was synthesized: Yield of 98% , white solid, mp = 160-1679C 1 H-NMR (CD3OD) d 7.45 (t, 2 H, J = 8.2 Hz), 7.24 (dd, 1 H, J = 11.5, 2 Hz), 7.18 (dd, 1 H, J = 8.3, 2 Hz), 4.15 (q, 1 H, J = 7 Hz), 2.97 (s, 3 H), 1.43 (d, 3 H, J = 7 Hz) Example 99: Preparation of 1- [3- (methoxycarbonyl) -4- (methylsulfonylamino) phenyl] eylamine
(13-13, YHS-181) Stage 99-1. Preparation of? / - (2-fIuoro-4-iodophenyl) methanesulfonamide (13-3 SH-14) To a solution of 2-amino-4-iodobenzoic acid (11 mM) in MeOH (50 mL) was added HCl ( 20 mmoi) and H2SO4 (2 mmol). The reaction mixture was refluxed and concentrated overnight, diluted with NaHCO3 and filtered with MgSO4 several times. The combined organic phases were washed with water, dried over MgSO 4, filtered, and the filtrate was concentrated in vacuo. The residue was purified by flash column chromatography on silica gel using EtOAc: hexanes to give? / - (2-fluoro-4-iodophenyl) methanesulfonamide (13-3, SH-14). Yield of 50% (13-2) 1 H-NMR (CDCIs) d 8.34 (d, 1 H, J = 2.2 Hz), 7.80 (dd, 1 H, J = 2.2, 8 , 8 Hz), 7.50 (d, 1 H, J = 8.8 Hz), 3.93 (s, 3 H), 3.04 (s, 3 H) (13-4) 1 H-NMR ( CDCIs) d 8.34 (d, 1 H, J = 2.2 Hz), 7.80 (dd, 1 H, J = 2.2, 8.8 Hz), 7.50 (d, 1 H, J = 8.8 Hz), 3.93 (s, 3 H), 3.04 (s, 3 H) Step 99-2. Preparation of 3- (methoxycarbonyl) -4 '- (methylsulfonylamino) accelofenone (13-7. YHS-176) By a procedure similar to that of example 98-2 except for the use of N- [4-iodo-2- ( meioxycarbonyl (I) phenylene) methane sulfonamide (13-4, YHS-27) as the starting material, 3- (mexoxycarbonyl) -4 '- (methylsulfonylamino) acetophenone (13-7, YHS-176) having the following physicochemical properties was synthesized: Yield 60%, pale yellow solid, mp = 112-115 ° C 1 H-NMR (CDCl 3) d 8.67 (d, 1 H, J = 2 Hz), 8.14 (dd, 1 H, J = 2 , 8.6 Hz), 7.82 (d, 1 H, J = 8.6 Hz), 3.99 (s, 3 H), 3.15 (s, 3 H), 2.61 (s, 3 H) Stage 99-3. Preparation of 3 '- (methoxycarbonyl) -4' - (methylsulfonylamino) acetophenone oxime (13-10, YHS-180) By a procedure similar to that of example 97-2 except for the use of 3- (methoxycarbonyl) -4 ' - (methylsulfonylamino) acetophenone (13-7) as starting material, 3 '- (methoxycarbonyl) -4' - (methylsulfonyl amine) acetophenone oxime (13-10, YHS-180) having the following physicochemical properties was synthesized: Yield 82%, white solid, mp = 136-137 ° C 1 H NMR (CDCl 3) d 10.54 (br s, 1 H), 8.32 (d, 1 H, J = 2.2 Hz), 7.85 (dd, 1 H, J =
2.2, 8.8 Hz), 7.76 (d, 1 H, J = 8.8 Hz), 3.96 (s, 3 H), 3.09 (s, 3 H), 2.29 (s, 3 H) Stage 99-4. Preparation of 1- [3- (methoxycarbonyl) -4- (methylsulfoniamino) phenyl] ethylamine (13-13, YHS-181) by a procedure similar to that of example 97-3 except for the use of 3-methoxycarbonyl oxime) -44met L-sulfonylamino) acetophenone (13-10) as a starting material, l- [3- (methoxycarbonyl) -4- (methylsulfonylamino) phenyl] ethylamine (13-13, YHS-181) having the following physicochemical properties was synthesized: Yield 65%, colorless oil 1 H-NMR (CDCl 3) d 8.07 (d, 1 H, J = 2.2 Hz), 7.70 (d, 1 H, J = 8.6 Hz), 7.58 (dd, 1 H, J = 2.2, 8.6 Hz), 4.18 (q, 1 H, J = 6.6 Hz), 3.94 (s, 3 H), 3.05 (s) , 3 H), 1.41 (d, 3 H, J = 6.6 Hz) Example 100: Preparation of 1- [3-methoxy-4- (methylsulfonylamino) phenyl] ethylamine (14-3, CHK-570) Stage 100-1. Preparation of ?/-. { 1- [3-methoxy-4 (methylsulfonylamino) phenyl] ethyl} Benzyl carbamate (14-1, CHK-567) To a 2- (3-methoxy-4-methylsulfonylamino) propionic acid (260 mg) in toluene (4 ml) was added diphenylphosphoryl azide (0.25 ml), triethylamine ( 0.33 mmol), refluxed for 30 min, treated with benzyl alcohol (1.5 ml). The reaction mixture was refluxed for 5 h. The combined organic phases were concentrated in vacuo. The residue was purified by flash column chromatography on silica gel using EtOAC: hexanes giving? / -. { 1- [3-methoxy-4- (methylsulfonylamino) phenyl] ethyl} Benzyl carbamate (14-1, CHIC-567). Yield 72%, yellow oil 1 H-NMR (CDCl 3) d 7.47 (d, 1 H, J = 8.3), 7.34 (sa, 5 H), 6.90 (da, 1 H, J = 8.3),
6. 85 (s a, 1 H), 6.73 (s a, 1 H), 5.08 (dd of AB, 2 H), 5.02 (s a, 1 H), 4.81 (m, 1 H),
3. 86 (S, 3 H), 2.94 (s, 3 H), 1.47 (d, 3 H, J = 6.8 Hz) Step 100-2 Preparation of 1- [3-methoxy-4- ( methylsulfonylamino) phenyl] ethylamine (14-3, CHK-570) by a procedure similar to that of example 1-2 except for the use of N-. { l- [3-methoxy-4- (methylsulfonylamino) phenyl] ethyl} Benzyl carbamate (14-1) as a starting material, 1- [3-methoxy-4- (methylsulfonylamino) phenyl] ethylamine (14-3, CHK-570) having the following physicochemical properties was synthesized: Yield of 97% yield, colorless oil H-NMR (CDCl 3) d 7.45 (d, 1 H, J = 8.3), 6.97 (d, 1 H, J = 1.7 Hz), 6.90 (dd, 1 HOUR,
J = 1, 7, 8.3 Hz), 4.13 (q, 1 H, J = 6.8 Hz), 3.90 (s, 3 H), 2.94 (s, 3 H), 1 , 38 (d, 3 H, J =
6.8 Hz) Example 101: Preparation of 1- [3-chloro-4- (methylsulfonylamino) phenyl] ethylamine (14-4) Step 101-1. Preparation of ?/-. { 1- [3-chloro-4- (methylsulfonylamino) phenyl] ethyl} benzyl carbamate (14-2) The? / -. { l- [3-C ioro-4- (methylsulfonylamino) phenyl] ethyl} Benzyl carbamate (14-2) was prepared by a procedure similar to that described in the previous example 100-1. 1 H-NMR (CDCl 3) d 7.47 (d, 1 H), 7.34 (s a, 5 H), 6.90 (d a, 1 H), 6.85 (s a, 1 H),
6.73 (sa, 1 H), 5.08 (dd of AB, 2 H), 5.02 (sa, 1 H), 4.81 (m, 1 H), 3.86 (s, 3 H) ), 2.94 (s, 3 H), 1, 47 (d, 3 H) Step 101-2. Preparation of 1- [3-chloro-4- (methylsulfonylamino) phenyl] ethylamine (14-4) by a procedure similar to that of example 1-2 except for the use of N-. { 1- [3-chloro-4- (methylsulfonylamino) phenyl] ethyl} Benzyl carbamate (14-2) as a starting material, 1- [3-chloro-4- (methylsulfonylamino) phenyl] ethylamine (14-4) was synthesized having the following physicochemical properties: 1 H-NMR (CDCl 3) d 7.53 (d, 1 H), 7.00 (d, 1 H), 6.92 (dd, 1 H), 4.15 (q, 1 H), 2.96 (s, 3 H), 1.40 (d, 3 H) Example 102: Preparation of? / - (4-y-butylbenzyl) -? / -. { 1- [4- (Methylsulfonylamino) phenyl] efil} thiourea (15-1, LJO-328) A mixture of 1- [4- (methylsulfonylamino) phenyl] ethylamine (13-11, 1 mmol) and isothiocyanate (1 mmol) in DMF (2 mL) was stirred at room temperature for 2 h. The reaction mixture was diluted with H2O and extracted with EtOAc several times. The combined organic phases were washed with H2O and brine, dried over MgSO4, filtered, and the filtrate was concentrated in vacuo. The residue was purified by flash column chromatography on silica gel with EtOAc: hexanes (1: 1) as eluent to give / V- (4-y-butylbenzyl) -? / '-. { 1- [4- (Methylsulfonylamino) phenyl] ethyl} thiourea (15-1, LJO-328) Yield 93%, white solid, mp = 1759C 1 H-NMR (CDCl 3) d 7.50 (t, 1 H, J = 8.04 Hz), 7.36 (d. , 2 H), 7.14 (d, 2 H), 7.0-7.05 (m, 2 H), 6.48 (s, 1 H), 5.95 (sa, 2 H), 5 , 17 (sa, 1 H), 4.56 (d, 2 H, J = 5.1 Hz), 3.02 (s, 3 H), 1.46 (d, 3 H, J = 6.8 Hz), 1.31 (s, 9 H) MS (FAB) m / z 438 (MH +) Example 103: Preparation of? / - (4-f-butylbenzyl) -? / -. { 1- [3-fluoro-4- (methylsulfonylamino) phenyl] ethyl} iourea (15-2, CHK-992) By a procedure similar to that of Example 102 except for the use of methyl 2-amino-5-iodobenzoate (13-2) as starting material, was synthesized? - (4-f -butylbenzyl) -? /, -. { 1- [3-fluoro-4- (methylsulfonylamino) phenyl] ethyl} thiourea (15-2, CHK-992) which has the following physicochemical properties:
Yield 92%, white solid, mp = 165SC 1 H-NMR (CDCl 3) d 7.59 (d, 1 H), 7.36 (d, 2 H), 7.32 (d, 1 H), 7, 1-7.18 (m, 3 H), 6.75 (s, 1 H), 5.93 (sa, 1 H), 5.16 (sa, 1 H), 4.57 (sa, 1 H) ), 3.00 (s, 3 H), 1, 46 (d, 3 H), 1.31 (s, 9 H) MS (FAB) m / z 455 (MH +) Example 104: Preparation of? Í- (4-y-butylbenzyl) -? / '-. { 1- [3-methoxy-4- (methylsulfonylamino) phenyl] ethyl} thiourea (15-3, CHK-575) By a procedure similar to that of Example 67 except for the use of 1- [3-methoxy-4- (methylisuphonyl-amino) phenyl] ethylamine (14-3) as the starting material, it was synthesized V- (4-y-butylbenzyl) -? / '-. { 1- [3-methoxy-4- (methylsulfonylamino) phenyl] ethyl} thiourea (15-3, CHK-575) which has the following physicochemical properties: Yield 91%, white solid, mp = 80-82 ° C 1 H-NMR (CDCl 3) d 7.46 (d, 1 H, J = 8.04 Hz), 7.31 (d, 2 H), 7.03 (d, 2 H), 6.75-6.85 (m, 3 H), 6.14 (sa, 2 H) , 5.80 (sa, 2 H), 4.93 (sa, 1 H), 4.58 (ddd of AB, 2 H), 3.83 (s, 3 H), 2.94 (s, 3 H), 1.49 (d, 3 H, J = 6.6 Hz), 1.30 (s, 9 H) MS (FAB) m / z 450 (MH +) Example 105: Preparation of? / - (4 -í-butilbenciI) -? f-. { 1- [3- (methoxycarbonyl) -4- (methylsulfonyl) phenyl] ethyl} thiourea (15-4, YHS-187) By a procedure similar to that of Example 102 except for the use of N- (2-f luoro-4-iodophenyl) methanesulfonamide (13-3) as starting material, it was synthesized
? / - (4-f-butiIbenzyl) -? / '-. { 1 - [3- (methoxycarbonyl) -4- (methylsulfonylammonyl) ethyl] ethyl} thiourea (15-4,
YHS-187) which has the following physicochemical properties: Yield of 70%, white solid, mp = 132-135 ° C 1 H-NMR (CDCl 3) d 7.99 (d, 1 H, J = 2.2 Hz) , 7.31 (d, 1 H, J = 8.6 Hz), 7.41 (dd, 1 H, J = 8.6, 2.2 Hz), 7.33 (d, 2 H), 7 , 11 (d, 2 H), 6,04 (sa, 1 H), 5,90 (sa, 1 H), 5,15 (sa, 1 H),
4.58 (s, 2 H), 3.94 (s, 3 H), 3.05 (s, 3 H), 1.48 (d, 3 H, J = 6.8 Hz), 1.30 (s, 9 H) MS (FAB) m / z 478 (MH +) Example 106: Preparation of? / - (4-y-butylbenzyl) -? / '-. { 1- [3-carboxy-4- (methylsulfonylamino) phenyl] ethyl} thiourea (15-5.YHS-209) By a procedure similar to that of example 1-4 except for the use of? - (4-f-butylbenzyl) -N'-. { 1- [3- (methoxycarbonyl) -4- (methylsulfonylamino) phenyl] eiyl} thiourea (15-4) as a starting material, was synthesized? - (4-f-butylbenzyl) -? / -. { 1- [3-carboxy-4- (methylsulfonylamino) phenyl] efil} thiourea (15-5, YHS-209) having the following physicochemical properties: Yield of 72%, white solid, mp = 189-192 ° C 1 H NMR (CD3OD) d 8.00 (d, 1 H, J = 2 , 2 Hz), 7.49 (d, 1 H, J = 8.6 Hz), 7.35 (dd, 1 H, J = 8.6, 2.2 Hz), 7.22 (d, 2 H), 7.04 (d, 2 H), 6.78 (sa, 1 H), 5.34 (sa, 1 H), 4.64 (d, 1 H, J = 14 Hz), 4, 47 (d, 1 H, J = 15 Hz), 2.88 (s, 3 H), 1, 38 (d, 3 H, J = 7 Hz), 1, 19 (s, 9 H) EM (FAB) ) m / z464 (MH +) Example 107: Preparation of / V- (4-y-butylbenzyl) -? / '-. { (1R) -1- [4- (Methylsulfonylamino) phenyl] ethyl} thiourea (16-5, SU-388) Stage 107-1. Preparation of? / - (4-í-butylbenzyl) -? R - [(1R) -1- (4-nitrophenyl) ethyl] thiourea (16-1,
SU-354) To a stirred solution of (R or S) -a-methyl-4-nitrobenzylamine hydrochloride
(203 mg, 1 mmol) in anhydrous CH 2 Cl 2 (10 mL) was added triethylamine (0.28 mL, 2 mmol) at room temperature. When the reaction mixture became clear, isothiocyanate (1 mmol) was added and stirred overnight at room temperature. The mixture was evaporated by rotary evaporator and the residue was purified by flash column chromatography on silica gel with EtOAc: hexanes as eluent to give? / - (4-f-butylbenzyl) -? / -. { (1R) -1- [4- (Methylsulfonylamino) phenyl] ethyl} Thiourea (16-5, SU-388). Yield 98%, colorless sticky oil 1 H-NMR (CDCl 3) d 8.12 (d, 2 H, J = 8.76 Hz), 7.34 (da, 4 H), 7.14 (d, 2 H, J =
8.0 Hz), 6.21 (sa, 2 H), 5.37 (sa, 1 H), 4.54 (m, 2 H), 1.47 (d, 3 H, J = 7.05 Hz), 1.30 (s, 9 H) Step 107-2. Preparation of? / - (4-f-butylbenzyl) -? - / (1R) -1- (4-aminophenyl) eiÍI] thiourea (16-3, SU-358) Aluminum paper (0.05 mm thickness, 406 mg, 15 mmol) was sanded with sandpaper, cut into 0.5 cm squares, and weighed in the reaction flask. The aluminum was etched with a 5% KOH hydroxide solution until a vigorous H2 detachment took place and then the basic solution was removed by means of decanation. The Al was rinsed with H2 and covered with 0.5% HgCl2 solution for 2 min. The HgCl2 solution was removed by pouring and the Al was washed with H2O. The HgCl2 solution was reintroduced for 2 min and the solution was decanted. The Al was washed with H2O followed by ethanol and diethyl ether several times. A solution of nitro (0.5 mmol) in diethyl ether (5 ml) was added to the freshly prepared amalgam and then a drop of H2O was introduced and the mixture was refluxed for 10 minutes. After completion of the reaction by TLC, the mixture was concentrated in vacuo. The residue was purified by flash column chromatography on silica gel with E? OAc: hexanes as eluent to give / V- (4-y-butylbenzyl) -? / '- [(1R) -1- (4-aminophenyl) ethyl ] thiourea (16-3, SU-358). Yield 67%, dim yellow oil 1 H-NMR (CDCl 3) d 7.29 (d, 2 H, J = 8.3 Hz), 7.04 (d, 2 H, J = 8.3 Hz), 6.99 (d, 2 H, J = 8.04 Hz), 6.63 (d, 2 H, J = 8.3 Hz), 6.16 (sa, 1 H), 5.73 (sa, 1 H), 4.69 (S a, 1 H), 4.60 (d, 2 H, J = 4.86 Hz), 3.69 (sa, 2 H), 1.45 (d, 3 H) , J = 6.84 Hz), 1.30 (s, 9 H) Step 107-3. Preparation of? / - (4-f-butylbenzyl) -? '-. { (1R) -1- [4- (Methylsulfonylamino) phenyl] ethyl} thiourea (16-5 SU-388) A cold solution of / - (4-í-butylbenzyl) -? / - [(1R) -1- (4-aminophenyl) ethyl] thiourea (16-3, 0.25 mmol ) in pyridine (2 ml) at 0 ° C was treated with methanesulfonyl chloride (0.3 mmol) and stirred for 10 min at 0 ° C. After the aqueous work-up, the residue was purified by flash column chromatography with EtOAc: hexanes as eluent 75% yield, white solid, mp = 1019C The spectral data of compound 16-5 are identical to those of the compound
-1. [a] = -13.34 (CHCk, C = 1.075) Example 108: Preparation of? / - (4-f-butylbenzyl) -? / -. { (1S) -1- [4- (Methylsulfonylamino) phenyl] ethyl} thiourea (16-6, SU-400) Eypa 108-1. Preparation of? / - (4-y-butylbenzyl) -? F - [(1S) -1- (4-nitrophenyl) eyl] thiourea (16-2, SU-366) The? / - (4-I) was prepared -butilbencil) -? - [(1S) -1- (4-nitrophenyl) ethyl] thiourea (16-2, SU-366) by a procedure similar to that described in example 107-1 above. A sticky white oil The spectral data of compound 16-2 are identical to those of the compound
16-1. Stage 108-2. Preparation of ? - (4-f-butylbenzyl) -? F - [(1S) -1- (4-aminophenyl) ethyl] thiourea (16-4, SU-394) The? / - (4-butylbenzyl) - ? / - [(1S) -1- (4-aminophenyl) ethyl] thiourea (16-4, SU-394) by a procedure similar to that described in example 107-1 above. A faint yellow oil The spectral data for compound 16-4 are identical to those for compound 16-3. Stage 108-3. Preparation of α- (4-f-butylbenzyl) -? / '-. { (1S) -1- [4- (Methylsulfonyl amino) phenyl] ethyl} iourea (16-6, SU-400)? / - (4-f-butylbenzyl) -? / '- was prepared. { (1S) -1- [4- (Methylsulfonylamino) phenyl] ethyl} thiourea (16-6, SU-400) by a procedure similar to that described in example 107-1 above. Yield of 75%, white solid, mp = 1019C The spectral data of compound 16-6 are identical to those of the compound
-1. [a] = + 10.60 (CHCl3, c = 1, 075) Example 109: Preparation of (R) -? / - (4-y-butylbenzyl) -? / -. { 1- [3-fluoro-4- (methylsulfonylamino) phenyl] ethyl} thiourea (17-3, CJU-032) Stage 109-1. Preparation of (R) -sulfonamide (17-1) To a solution of 0.5 M Ti (OEt) (0.3 ml, 1.44 mmol) and? / - (4-acetyl-2-fluorophenyl) -methanesulfonamide (0.2 g, 0.87 mmol) in THF (5 mL) under an atmosphere of N2 was added (R) - (+) - 2-methyl-2-propanesulfinamide (0.087 g, 0.72 mmol) and the mixture was heated (70 ° C). At the end, as determined by TLC, the mixture was cooled to room temperature and then to -40 ° C before cannulation dropwise in a solution at -40 ° C of NaBH 4 (0.109 g 2.88 mmol). The mixture was stirred at -40 ° C for 12 h, and then MeOH was added dropwise until no more gas was evolved. The resulting suspension was filtered through a plug of Celite and filter cake was washed with EtOAc. The filtrate was washed with brine, and the brine phase was extracted with EtOAc. The combined organics were dried (Na2SO), filtered, and concentrated. After silica gel column chromatography (n-hexane / EtOAc), (R) sulfonamide (0.105 g, 0.31 mmol, 36%) was isolated. 1 H-NMR (CDCl 3) d 7.53 (t, 1 H, J = 8.4 Hz), 7.19 (m, 1 H), 7.15 (m, 1 H), 6.97 (sa, 1 H), 4.53 (m, 1 H), 3.50 (d, 1 H, J = 3.8 Hz), 3.04 (s, 3 H), 1.75 (sa, 1 H) , 1.51 (d, 3 H, J = 6.5 Hz), 1.25 (s, 9 H). Stage 109-2. Preparation of (R) -1- [3-fluoro-4- (methylsulfonylamino) phenyl] ethylamine hydrochloride (17-2) To a (R) -sulfonamide (0.105 g, 0.31 mmol) was added a solution of dioxane 1: 1 (v / v) MeOH and HCl (4.0 M, 0.22 ml). The mixture was stirred at room temperature for 30 minutes and then concentrated to near dryness. Diethyl ether was added to precipitate the amine hydrochloride. He then removed the precipitate by filtration and washed with diethyl ether to give (R) -1- [3-fluoro-4- (methylsulfonylamino) phenyl] -yrylamine hydrochloride (17-2, 0.059 g, 0.22 mmol, 70% , 96.11% ee) analytically pure.
1 H-NMR (DMSO-d 6) d 9.71 (s a, 1 H), 8.60 (s a, 3 H), 7.52 (dd, 1 H, J = 1.9,
11.8 Hz), 7.42 (t, 1 H, J = 8.4 Hz), 7.33 (dd, 1 H, J = 1.8, 8.4 Hz), 4.39 (m, 1 H), 3.62 (m, 1 H), 3.05 (s, 3 H), 1.49 (d, 3 H, J = 6.5 Hz). Stage 109-3. Preparation of ?/-. { 4-. { 1- [3- (4-fer-butyl-benzyl) -thioreido] ethyl} -2-f luoro-f enil} -methanesulfonamide (17-3, CJU-032) To anhydrous solution of 4- [4- (1-amino-etiI) -2-fluoro-phenyl] -methanesulfonamide hydrochloride (0.020 g, 0.075 mmol) in DMF (1 ml), Et3N (13 μL, 0.09 mmol), 1-ert-butyl-4-isothiocyanatomethylbenzene (15 mg, 0.075 mmol) was added in written order. The reaction mixture was stirred for 3 hours at room temperature. And then the reaction solution was extracted by EtOAc and the organic phase was washed with H2O, dried (Na2SO4), filtered and concentrated. It was isolated after silica gel column chromatography (n-hexane / EtOAc),? / -. { 4-. { 1- [3- (4-tert-buffyl-benzyl) -thioreido] -ethyl} -2-fluoro-phenyl} methanesulfonamide (26 mg, 0.06 mmol, 85%) [a] -19.24 (c 0.7, CHCl3),% e.e. 98.41% H-NMR (CDCl 3) d 7.42 (t, 1 H, J = 9.0 Hz), 7.35 (m, 1 H), 7.33 (m, 1 H), 7 , 12
(m, 2 H), 7.00 (m, 2 H), 6.90 (sa, 1 H), 6.45-6.10 (sa, 2 H), 5.18 (sa, 1 H) , 4.54 (m, 2 H), 2.98 (s, 3 H), 1.43 (d, 3 H, J = 3.0 Hz), 1.29 (s, 9 H). Example 110: Preparation of (S) - / V- (4-f-butylbenzyl) -? '-. { 1- [3-fluoro-4- (methylsulfonicamino) phenyl] ethyl} thiourea (17-6, CJU-039) Stage 110-1. Preparation of (S) -sulfonamide (17-4) Compound 17-4 was prepared from (S) - (-) - 2-methyl-2-propanesuIfinamide following a procedure similar to that described in example 109-1 . Yield of 31% 1 H-NMR (CDCl 3) d 7.47 (m, 1 H), 7.26 (sa, 1 H), 7.17-7.08 (m, 2 H), 4.48 (m , 1 H), 3.54 (d, 1 H, J = 3.8 Hz), 2.99 (s, 3 H), 1, 47 (d, 3 H, J = 6.5 Hz), 1 , 21 (s, 9 H). Stage 110-2. Preparation of (S) -1- [3-fluoro-4- (methylsulfonylamino) phenyl] ethylamine hydrochloride (17-5) Compound 17-5 was prepared from (S) -sulfonamide (17-4) following a procedure similar to that described in example 109-2. Yield of 88%, 97.9% of e.e. The spectral data are identical to those of 17-2. Stage 110-3. Preparation of (S) -? / - (4-y-butylbenzyl) - / V-. { 1- [3-fluoro-4- (methylsulfonyl) phenyl] etl} thiourea (17-6, CJU-039) Compound 17-6 was prepared from (S) -1- [3-fluoro-4- (methylsulfonylamino) phenyl] ethylamine hydrochloride (17-5) following a similar procedure to that described in example 1-5. Yield of 80%, [a] = 16.04 (c 0.7, CHCI3), 97.76% e.e. The spectral data are identical to those in 17-3. Example 111: Preparation of? / - [(2R) -2-benzyl-3- (pivaloyloxy) propiI] -? / -. { (R) -1 [4- (methylisulfonyl) phenyl] etl} thiourea (18-1, MK 229)? / - [(2R) -2-benzyl-3- (pivaloyloxy) propyl] -N'- was prepared. { (1R) -1- [4- (Methylsulfonylamino) phenyl] ethyl} thiourea (18-1) by the procedure similar to that described in example 1-5 above. Yield 84%, white solid, mp = 62-649C [a] = -10.8 (CHCl3, c 1.0) 1H-NMR (CDCl3) d 7.1-7.35 (m, 9 H), 6.61 (sa, 1 H), 6.26 (sa, 1 H), 6.15 (ta, 1 H), 4.82 (sa, 11-1), 4.10 (dd, 1 H, J = 11.7, 3.3 Hz), 3.6-3.75 (m, 2 H), 3.24 (m, 1 H), 2.96 (s, 3 H), 2.55 ( dd, 1 H), 2.54 (dd, 1 H), 2.36 (dd, 1 H), 2.29 (sa, 1 H), 1.49 (d, 3 H, J = 6.6 Hz), 1.21 (m, 9 H) MS (El) m / z 505 (M +) Example 112: Preparation of / V - [(2S) -2-benzyl-3- (pivaloyloxy) propyl] -? / -. { (1R) -1- [4- (Methylsulfonylamino) phenyl] efil} thiourea (18-2, MK-202)? - [(2S) -2-benzyl-3- (pivaloyloxy) propyl] -? / '- was prepared. { (1) -1- [4- (Methylsulfonylamino) phenyl] ethyl} thiourea (18-2) by the procedure similar to that described in example 1-5 above. Yield 76%, white solid, mp = 58-62sC [a] = +2.04 (CHCl3, c 1.0) 1 H-NMR (CDCl3) d 7.1-7.35 (m, 9 H) , 6.37 (sa, 1 H), 6.11 (sa, 1 H), 4.80 (sa, 1
H), 3.7-3-9 (m, 2 H), 3.58 (m, 1 H), 3.12 (m, 1 H), 2.94 (s, 3 H), 2.54 (ddd, 2 H), 2.17 (sa, 1 H), 1.47 (d, 3 H, J = 6.6 Hz), 1, 21 (m, 9 H) EM (FAB) m / z 506 (MH +) Example 113: Preparation of? / - [(2R) -2-benzyl-3- (pivaloyloxy) propyl] -? -. { (1S) -1- [4- (Methylsulfonylamino) phenyl] ethyl} thiourea (18-3, MK-230)? / - [(2R) -2-benzyl-3- (pivaloyloxy) propyl] -? / '- was prepared. { (1S) -1- [4- (Methylsulfonylamino) phenyl] efil} thiourea (18-3) by the procedure similar to that described in example 1-5 above. Yield of 81%, white solid, mp = 58-62 C [a] = -2.48 (CHCl3, c 1.0) The spectral data of compound 18-3 are identical to those of the compound
18-2. Example 114: Preparation of - [(2S) -2-benzyl-3- (pivaloyloxy) propyl] -? '-. { (1S) -1 [4- (methylsulfonylamino) phenyl] ethyl} thiourea (18-4, MK-228)? / - [(2S) -2-benzyl-3- (pivaloyloxy) propyl] - '- was prepared. { (1S) -1- [4- (Methylsulfonylamino) phenyl] ethyl} thiourea (18-4) by the procedure similar to that described in example 1-5 above. Yield of 88%, white solid, mp = 62-649C [] = +11.61 (CHCl3, c 1.0) The spectral data of compound 18-3 are identical to those of the compound
18-1. MS (FAB) m / z 506 (MH +) Example 115: Preparation of? / - [2- (3,4-dimethylbenzyl) -3- (pivaloyloxy) propyl] -? / '-. { 1- [4- (Methylsulfonylamino) phenyl] ethyl} thiourea (18-5, LJO-388)? / - [2- (3,4-Dimethylbenzyl) -3- (pivaloyloxy) propyl] -? / - was prepared. { 1- [4- (Methylsulfonylamino) phenyl] ethyl} thiourea (18-5) by a procedure similar to that described in example 1-5 above. 87% yield, white solid, mp = 779C 1 H-NMR (CDCIs) d 7.15-7.35 (m, 4 H), 6.8-7.05 (m, 4 H), 6.36 (sa, 1 H ), 6.18 (sa, 1 H), 4.79 (sa, 1 H), 3.55-3.75 (sa, 3 H), 3.12 (m, 1 H), 2.95- 3.0 (s, 3 H), 2.4-2.6 (m, 2 H), 2.1-2.3 (m, 7 H), 1.4-1.5 (m, 3 H) ), 1.20 (m, 9 H) MS (FAB) m / z 534 (MH +) Example 116: Preparation of? / - [2- (3,4-dimethylbenzyl) -3- (pivaloyloxy) propyl] -? / '-. { (1R) -1- [4- (Methylsulfonylamino) phenyl] ethyl} thiourea (18-6, SU-472)? / - [2- (3,4-Dimethylbenzyl) -3- (pivaloyloxy) propyl] -? / '- was prepared. { (1R) -1- [4- (Methylsulfonylamino) phenyl] ethyl} thiourea (18-6) by a procedure similar to that described in example 1-5 above. White solid, The spectral data of compound 18-6 were identical to those of compound 18-5. Example 117: Preparation of? / - [(2R) -2- (3,4-dimethylbenzyl) -3 (pivaloyloxy) propyl] -? / -. { (1 R) -1- [4- (Methylsulfonylamino) phenyl] ethylthiourea (18-7, SU-512) The? / - [(2R) -2- (3,4-dimethylbenzyl) -3- (pivaloyloxy) was prepared ) propil] -? / '-. { (1R) -1- [4- (Methylsulfonylamino) phenyl] ethyl} thiourea (18-7) by a procedure similar to that described in example 1-5 above.
1 H-NMR (CDCl 3) d 7.34 (da, 2 H), 7.19 (da, 2 H), 6.7-7.05 (m, 3 H), 6.29 (sa, 1 H) , 6.15 (sa, 1 H), 4.81 (sa, 1 H), 4.12 (m, 1 H), 3.5-3.75 (m, 2 H), 3.18 (m , 1 H), 2.96 (s, 3 H), 2.4-2.6 (m, 2 H), 2.1-2.3 (m, 7 H), 1, 4-1.5 (d, 3 H), 1.21 (m, 9 H) Example 118: Preparation of? - [(2S) -2- (3,4-dimethylbenzyl) -3 (pivaloyloxy) propyl] -? / '-. { (1R) -1- [4- (Methylsulfonylamino) phenyl] ethyl} thiourea (18-8) The? / - [(2S) -2- (3,4-dimethylbenzyl) -3- (pivaloyloxy) propyl] -? / - was prepared. { (1R) -1- [4- (Methylsulfonylamino) phenyl] ethyl} thiourea (18-8) by a procedure similar to that described in example 1-5 above. 1 H-NMR (CDCl 3) d 7.33 (da, 2 H), 7.18 (da, 2 H), 6.72-7.05 (m, 3 H), 6.28 (sa, 1 H) , 6.12 (sa, 11-1), 4.80 (sa, 1 H), 4.11 (m, 1 H), 3.5-3.75 (m, 2 H), 3.19 ( m, 1 H), 2.98 (s, 3 H), 2.4-2.6 (m, 2 H), 2.1-2.3 (m, 7 H), 1.4-1, 5 (d, 3 H), 1.22 (m, 9 H) MS (FAB) m / z 534 (MH +) Example 119: Preparation of? / - [2- (4-te / 'c-butylbenzyl) - 3- (pivaloyloxy) propyl] -? / -. { 1- [4- (Methylsulfonylamino) phenyl] ethyl} thiourea (18-9, LJO-401)? / - [2- (4-t-butylbenzyl) -3- (pivaloyloxy) propyl] -? - was prepared. { 1- [4- (Methylsulfonylamino) phenyl] ethyl} thiourea (18-9) by a procedure similar to that described in example 1-5 above. Yield 84%, white solid, mp = 879C 1 H-NMR (CDCl 3) d 7.0-7.35 (m, 8 H), 6.43 (sa, 1 H), 6.19 (sa, 1 H ), 4.83 (sa, 1 H), 3.55-3.75 (sa, 3 H), 3.1-3.3 (m, 1 H), 2.93 (s, 3 H), 2.4-2.6 (m, 2 H), 2.25 (m, 1 H), 1.4-1.5 (m, 3 H), 1.28 (s, 9 H), 1, 20 (s, 9 H) MS (FAB) m / z 562 (MH +) Example 120: Preparation of? - [2- (4-Ierc-buti-benzyl) -3- (pivaloyloxy) propyl] -? / '-. { (1R) -1- [4- (Methylsulfonylamino) phenyl] ethyl} thiourea (18-10, MK-296) The / V- [2- (4-ferc-butylbenzyl) -3- (pivaloyloxy) propyl] -? / - was prepared. { (1R) -1- [4- (Methysulfonylamino) phenyl] ethyl} thiourea (18-10) by a procedure similar to that described in example 1-5 above. Yield 88%, white solid, mp = 88-909C 1 H-NMR (CDCl 3) d 7.25-7.35 (m, 4 H), 7.15-7.23 (m, 2 H), 7, 0-7.1 (m, 2 H), 6.36 (sa, 1 H), 6.15 (sa, 1 H), 4.84 (sa, 1 H), 3.5-3.9 ( m, 3 H), 3.1-3.3 (m, 1 H), 2.94 (s, 3 H), 2.3-2.55 (m, 2 H), 2.15 (m, 1 H), 1.48 (m, 3 H, J = 6.8 Hz), 1.29 (s, 9 H), 1.21 (s, 9 H) MS (FAB) m / z 562 (MH + Example 121: Preparation of? / - [(2R) -2- (4-ert-butylbenzyl) -3 (pivaloyloxy) propyl] -? Í-. { (1 R) -1- [4- (Methylsulfonylamino) phenyl] ethyl} thiourea (18-11, MK-334)? / - [(2R) -2- (4-Ierc-butylbenzyl) -3- (pivaloyloxy) propyl] -? / - was prepared. { (1 R) -1- [4- (Methylsulfonylamino) phenyl] ethyl} thiourea (18-11) by a procedure similar to that described in example 1-5 above. Yield of 88%, white solid, mp = 85-879C [a] = -17.3 (c 1, 00, CHCl 3) 1 H-NMR (CDCl 3) d 7.28-7.36 (dd, 4 H) , 7.19 (d, 2 H), 7.03 (d, 2 H), 6.80 (sa, 1 H), 6.34 (sa, 1 H), 6.15 (ta, 1 H) , 4.84 (sa, 1 H), 4.08 (dd, 1 H, J = 3.8, 11.7 Hz), 3.55-3.7 (m, 2 H), 3.24 ( ddd, 1 H), 2.95 (s, 3 H), 2.50 (dd, 1 H), 2.34 (dd, 1 H), 2.26 (m, 1 H), 1, 48 ( d, 3 H, J = 6.8 Hz), 1.29 (s, 9 H), 1.21 (s, 9 H) MS (FAB) m / z 562 (MH +) Example 122: Preparation of? - [(2S) -2- (4-Ierc-butylbenzyl) -3- (pivaloyloxy) propyl] -? / -. { (1 R) -1- [4- (Methylsulfonyl) phenyl] ethyl} thiourea (18-12, MK-298)? / - [(2S) -2- (4-Ierc-butylbenzyl) -3- (pivaloyloxy) propyl] -? / '- was prepared. { (1 R) -1- [4- (Methylsulfonylamino) phenyl] ethyl} thiourea (18-12) by a procedure similar to that described in example 1-5 above. Yield 86%, white solid, mp = 88-90 gC [a] = -3.77 (c 1.00, CHCl 3) 1 H-NMR (CDCl 3) d 7.25-7.35 (dd, 4 H) , 7.18 (d, 2 H), 7.05 (d, 2 H), 6.47 (br s, 1 H), 6.15 (br s, 1 H); 4.84 (sa, 1 H), 3.55-3.9 (m, 3 H), 3.14 (ddd, 1 H), 2.94 (s, 3 H), 2.52 (ddd of AB, 2 H), 2.16 (m, 1 H), 1.47 (d, 3 H, J = 6.8 Hz), 1.29 (s, 9 H), 1.21 (s, 9 H) MS (FAB) m / z 562 (MH +) Example 123: Preparation of? / - [2- (3,4-dimethylbenzyl) -3- (pivaloyloxy) propyl] -? / -. { 1- [3-fluoro-4- (methylsulfonylamino) phenyl) ethyl} thiourea (18-13, LJO-344)? / - [2- (3,4-Dimeti-benzyl) -3- (pivaloyloxy) propylj-? / - was prepared. { 1- [3-fluoro-4- (methylsulfonylamino) phenyl] ethyl} thiourea (18-13) by a procedure similar to that described in example 1-5 above. Yield 76%, white solid, mp = 73 ° C 1 H-NMR (CDCl 3) d 7.50 (m, 1 H), 6.8-7.2 (m, 5 H), 6.75 (s) , 1 H), 6.30 (sa, 1 H), 6.22 (sa, 1 H), 4.89 (sa, 1 H), 4.16 (m, 1 H), 3.6-3 , 9 (m, 2 H), 3.10 (m, 1 H), 3.0
(m, 3 H), 2.45-2.65 (m, 2 H), 2.15-2.3 (m, 7 H), 1.4-1.5 (m, 3 H), 1 , 22 (m, 9 H) MS (FAB) m / z 552 (MH +) Example 124: Preparation of? / - [2- (4-Ierc-butylbenzyl) -3- (pivaloyloxy) propyl] -? / '. { 1- [3-fluoro-4- (methylsulfonylamino) phenyl] ethyl} Thiourea (18-14, LJO-366) The? / - [2- (4-to? C-butylbenzyl) -3- (pivaloyloxy) propy] -? '- was prepared. { 1- [3-fluoro-4- (methylsulfonylamino) phenyl] ethyl} thiourea (18-14) by a procedure similar to that described in example 1-5 above. Yield 73%, white solid, mp = 78eC 1 H-NMR (cDCIa) d 7.53 (m, 1 H), 7.0-7.35 (m, 6 H), 6.53 (sa, 1 H), 6.24 (ta, 1
H), 6.17 (sa, 1 H), 4.92 (sa, 1 H), 4.15 (m, 1 H), 3.6-3.9 (m, 2 H), 3.10 (m, 1
H), 3.0 (m, 3 H), 2.4-2.6 (m, 2 H), 2.24 (m, 1 H), 1.4-1.5 (m, 3 H) , 1.29 (m, 9 H),
1.22 (m, 9 H) MS (FAB) m / z 580 (MH.). Example 125: Preparation of? / - [(2R) -3-phenyl-1-pivaloyloxy-2-propyl] -? / '- [(R) -a-methyl-4- (methylsulfonylamino) benzyl] thiourea (19-13, SU-692) Step 125-1. Preparation of (2R) -3-phenyl-1-pivaloyloxy-2-propyl amine (19-1, YHS-43) To a solution of (2R) -? / - (tert-butoxycarbonyl) phenylalaniol (3.323g) which is found in the market in methylene chloride (50 ml) was added triethylamine (7.4 ml) and pivaloyl chloride (2.4 ml). The mixture was stirred for 4 h at room temperature, 50 ° C and then for 10 min. at room temperature. The mixture was purified directly by column chromatography using EtOAc: hexanes (1: 4) as eluent to give ester compound. And then the reaction compound was diluted in methylene chloride (10 ml) and trifluoroacetic acid (2.5 ml) was stirred. The mixture was stirred at room temperature for 2 hours and concentrated in vacuo to give (2R) -3-phenyl-1-pivaloyloxy-2-propyl amine (19-1, YHS-43). 1 H-NMR (CDCl 3) d 7.15-7.38 (m, 5 H), 4.22 (dd of AB, 2 H), 3.73 (sa, 1 H), 3.03 (ddd of AB , 2 H), 1, 22 (s, 9 H) Step 125-2 Preparation of (2R) -3-phenyl-1-pivaloyloxy-2-propyl isothiocyanate (19-3, SU-684) A solution of (2R) -3-phenyl-1-pivaloyloxy-2-propylamine (19-1, immol) and Et 3 N (1 mmol) in DMF (1 ml) dropwise in a previously dissolved 1,1-thiocarbonyldiimidazole solution (1, 2 mmol) in DMF (2 ml) at 50 ° C for 1 min. The mixture was stirred for 1 min. at 50 ° C and then for 10 min. to. room temperature. The mixture was directly purified by column chromatography using EtOAc: hexanes (1: 5) as eluent to give (2R) -3-phenyl-1-pivaloyloxy-2-propylisothiocyanate (19-3, SU-684). 89% yield, colorless oil. 1 H-NMR (CDCl 3) d 7.15-7.35 (m, 5 H), 4.22 (dd, 1 H, J = 2.7, 10 Hz), 4.02-4.12 (m, 2 H), 2.94 (d, 2 H, J = 6.3 Hz), 1.25 (s, 9 H) Step 125-3. Preparation of? / - [(2R) -3-phenyl-1-pivaloyloxy-2-propyl] -? / - [(R) -a-methyl-4-niirobenzyl] iiourea (19-5, SU-688) A a stirring solution of (R or S) -a-methyl-4-nitrobenzylamine hydrochloride (1.1 mmol) in CH2Cl2 (8 mL) was added Et3N (1.1 mmol) at room temperature. The mixture was stirred for 10 minutes. When the reaction mixture became clear, isoliocyanate (1 mmol) in CH2Cl2 (2 mL) was added. The mixture was stirred overnight at room temperature and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel with EOAc: hexanes (1: 2 to 1: 1). Yield 81%, yellow oil 1 H-NMR (CDCl 3) d 8.15 (d, 2 H, J = 8.5 Hz), 7.45 (d, 2 H, J = 8.5 Hz), 7, 15-7.35 (m, 5 H), 6.60 (sa, 1 H), 6.08 (sa, 1 H), 5.22 (sa, 1 H), 4.47 (sa, 1 H) ), 4.13 (dd, 1 H, J = 3, 11.8 Hz), 3.86 (dd, 2 H, J = 5.6, 11.8 Hz), 2.96 (dd, 1 H , J = 5.85, 13.5 Hz), 2.80 (dd, 1 H, J = 7.3, 13.5 Hz), 1.49 (d, 3 H, J = 7.1 Hz) , 1.16 (s, 9 H) Step 125-4. Preparation of? / - [(2R) -3-phenyl-1-pivaloyloxy-2-propyl-V - [(R) -a-methyl-4-aminobenzyl thiourea (19-9, SU-690) Aluminum foil was sanded (0.05 mm thick, 328 mg, 12.174 mmol) with sand bar, cut into 0.5 cm squares and etched with a 5% KOH hydroxide solution until a vigorous evolution of H2 occurred . The basic solution was removed by decanting and the Al was rinsed with H2O twice and covered with a 0.5% HgCl2 solution for 2 minutes. The mercuric chloride was poured out, the Al was washed with H20 twice and the solution was reintroduced.
HgCI2 for 2 minutes. Once again the HgCl2 solution was decanted, the Al was washed with H2O several times followed by ethanol diethyl ether several times. A solution of? / - [(2R) -3-phenyl-1-pivaloyloxy-2-propyl] -? / - [(R) -a-methyl-4-nitrobenzyl] thiourea (19-5, 180 mg) was added , 0.406 mmol) in diethyl ether (10 ml) was added to the freshly prepared amalgam then H2O (3 drops) was introduced, the mixture was refluxed for 30 minutes. After the reaction was completed by TLC, the mixture was cooled to room temperature and filtered through a glass funnel with dispersed MgSO4 (0.7 cm) on Celite 545 (0.7 cm). The filtrate was evaporated by a rotary evaporator to dry it by a vacuum pump. Yield 96%, colorless oil 1 H-NMR (CDCl 3) d 7.15-7.35 (m, 5 H), 7.00 (d, 2 H, J = 8.3 Hz), 6; 63 (d , 2 H, J = 8.3 Hz), 6.30 (sa, 1 H), 5.70 (sa, 1 H), 4.75 (sa, 1 H), 4.52 (sa, 1 H ), 3.96 (dd, 1 H, J = 3, 11.2 Hz), 3.79 (dd, 2 H, J = 4.6, 11.2 Hz), 2.97 (dd, 1 H , J = 5.85, 13.9 Hz), 2.77 (dd, 1 H, J = 8, 13.9 Hz), 1.41 (d, 3 H, J = 7.1 Hz), 1 , 16 (s, 9 H) Stage 125-5. Preparation of? / - [(2R) -3-phenyl-1-pivaloyloxy-2-propyl] - '- [(R) -a-methyl-4- (methylsulfonylamino) benzyl] thiourea (19-13, SU-692 ) A solution of? / - [(2R) -3-phenyl-1-pivaloyloxy-2-propyl] -? / - [(R) -a-methyl-4-aminobenzyl] thiourea (19-9.0) was treated , 5 mmol) in pyridine (2 ml) at 0 ° C dropwise with methanesulfonyl chloride (0.75 mmol) and stirred for 10 minutes at 0 ° C. The mixture was purified directly by flash column chromatography on silica gel with EtOAc: hexanes (1: 1) as eluent to? / - [(2R) -3-phenyl-1-pivaloyloxy-2-propyI] -? / ' - [(R) - - methyl - 4- (methylsulfonylamino) benzyl] thiourea (19-13, SU-692). Yield 92%, pale yellow solid, mp = 59-61 ° C, [a] = +18.1 (c 1, 00, CHCl3) 1 H-NMR (CDCl 3) d 7.1-7.35 (m , 9 H), 6,62 (sa, 1 H), 5,88 (sa, 1 H), 4,84 (sa, 1 H), 4,65 (sa, 1 H), 4,00 (da , 1 H), 3.76 (dd, 2 H, J = 4.6, 11.2 Hz), 2.9-3.05 (m, 4 H), 2.80 (dd, 1 H, J = 7.1, 13.4 Hz), 1.46 (d, 3 H, J = 7.1 Hz), 1.18 (s, 9 H) MS (FAB) m / z 492 (MH +) Example 126 : Preparation of N - [(2S) -3-phenyl-1-pivaloyloxy-2-propyl] -? / - [(R) -a-methyl-4- (methylsulfonylamino) benzylthiourea (19-14, SU-704) Stage 126-1. Preparation of? / - [(2S) -3-phenyl-1-pivaloyloxy-2-propyl] -? / - (R) - -methyl-4-nitrobenzyl thiourea (19-6, SU-698) The? - [(2S) -3-phenyl-1-pivaloyloxy-2-propyl] -? / - [(R) - -methyl-4-nitrobenzyl thiourea (19-6) by a procedure similar to that described in examples 125-1 , 125-2 and 125-3 above. Yield 94%, pale yellow solid, mp = 99-100 ° C The spectral data of this compound were identical to those of the compound
19-5. Stage 126-2. Preparation of / V - [(2S) -3-phenyl-1-? Ivaloyloxy-2-propyl] -? '- (R) -a-methyl-4-aminobenzyloxyurea (19-10, SU-702) By a procedure similar to that of example 125-4 except for the use of? / - [(2S) -3-phenyl-1-pivaloyloxy-2-propyl] -? / '- [(R) -a-methyl-4-nitrobenzyl] thiourea (19-6) as a starting material, was synthesized? / - [(2S) -3-phenyl-1-pivaloyloxy-2-propyl] -? / - [(R) -a-methyl-4-aminobenzylthiourea ( 19-10, SU-702) having the following physicochemical properties: Yield of 97%, yellow oil The spectral data of this compound were identical to those of compound 19-9. Stage 126-3. Preparation of? - [(2S) -3-phenyl-1-pivaloyloxy-2-propyl] -? / '- [(R) -a-methyl-4- (methylsulfonylamino) benzylthiourea (19-14, SU-704) By a procedure similar to that of example 125-5 except for the use of 3 '- (methoxycarbonyl) -4, - (methylsulfonylamino) acetophenone oxime (13-10) as starting material,? / - [(2S) was synthesized -3-phenyl-1-pivaloyloxy-2-propyl] -N '- [(R) - - methyl - 4- (methylsulfonylamino) benzyl] thiourea (19-14, SU-704) having the following physicochemical properties : Yield of 51%, yellow solid, mp = 61-64 ° C, [a] = -10.9 (c 1, 00, CHCl3)
The spectral data of this compound were identical to those of compound 19-13. MS (FAB) m / z492 (MH +) Example 127: Preparation of? / - [(2R) -3-phenyl-1-pivaloyloxy-2-propii] -? / - [(S) - -methyl-4- ( methylsulfonylamino) benzyl] thiourea (19-15, SU-720) Step 127-1. Preparation of (2S) -3-phenyl-1-ivaloyloxy-2-propylamine (19-2, YES-45) (2S) -3-phenyl-1-pivaloyloxy-2-propylamine (19-2, YHS-45) by a procedure similar to that described in example 125-1 above. Yield 94%, pale yellow oil 1 H-NMR (CDCl 3) d 7.15-7.38 (m, 5 H), 4.22 (dd AB, 2 H), 3.73 (sa, 1 H) ,
3.03 (ddd of AB, 2 H), 1.22 (s, 9 H) Stage 127-2. Preparation of (2S) -3-phenyl-1-ilaryloyloxy-2-propyl isothiocyanate (19-4, SU-686) By a procedure similar to that of example 92-2 except for the use of (2S) -3- phenyl-1-piva! oyloxy-2-propylamine (19-2) as a starting material, (2S) -3-phenyl-1-pivaloyloxy-2-propyl isothiocyanate (19-4, SU-686) having the following physicochemical properties: 89% yield, colorless oil The spectral data for this compound 19-4 were identical to those for 19-3. Stage 127-3. Preparation of? / - [(2R) -3-phenyl-1-pivaloyloxy-2-propyl] - / V - [(S) - -methyl-4-nitrobenzyl thiourea (19-7, SU-714) By a similar procedure to that of example 125-3 except for the use of (2S) -3-phenyl-1-pivaloyloxy-2-ylamylamine (19-2) as starting material, was synthesized? / - [(2R) -3-phenyl -1-pivaloyloxy-2-propyl] -? / '- [(S) - -methyl-4-nitrobenzyl] thiourea (19-7, SU-714) having the following physicochemical properties:
Yield 78%, white solid, mp = 100-101 ° C 1 H-NMR (CDCIa) d 8.18 (d, 2 H, J = 8.5 Hz), 7.46 (d, 2 H, J = 8.5 Hz), 7.05-7.3 (m, 5 H), 6.64 (sa, 1 H), 6.12 (sa, 1 H), 5.12 (sa, 1 H), 4.62 (sa, 1 H), 4.19 (dd, 1 H, J = 4.9, 11.6 Hz), 4.00 (dd, 2 H, J = 4.1, 11.6 Hz ), 2.94 (dd, 1 H, J = 5.34, 13.4 Hz), 2.64 (sa, 1 H), 1.55 (d, 3 H, J = 7.1 Hz), 1.19 (s, 9 H) Stage 127-4. Preparation of? / - [(2R) -3-phenyI-1-pivaloyloxy-2-propyl] -? / - [Sa-methyl-4-aminobenzyl thiourea (19-11, SU-716) By a procedure similar to that of the example 92-4 except for the use of? / - [(2R) -3-f-enyl-1-pivaloyloxy-2-propyl] -? / '- [(S) - -methyl-4-nitrobenzyl] thiourea (19-) 7) as a starting material, was synthesized? / - [(2R) -3-phenyl-1-pivaloyloxy-2-propyl] -? / '- [(S) -a-methyl-4-aminobenzylthiourea (19-11) , SU-716) having the following physicochemical properties: Yield 86%, pale yellow oil 1 H-NMR (CDCl 3) d 6.95-7.25 (m, 7 H), 6.67 (d, 2 H , J = 8.3 Hz), 6.42 (d, 1 H, J = 5.1 Hz), 5.80 (d, 1 H, J = 8.3 Hz), 4.83 (sa, 1 H), 4.53 (sa, 1 H), 4.07 (dd, 1 H, J =
.1, 11.7 Hz), 3.94 (dd, 2 H, J = 3.9, 11.7 Hz), 3.60 (sa, 2 H), 2.84 (dd, 1 H, J = 5.4,
13.7 Hz), 2.49 (dd, 1 H, J = 8.3, 13.7 Hz), 1.44 (d, 3 H, J = 7.1 Hz), 1.20 (s, 9 H)
Stage. 127-5. Preparation of V - [(2R) -3-phenyI-1-pivaloyloxy-2-propyl] -? / - [(S) -a-methyl-4- (mephsulfonylamino) benzyl] thiourea 19-15 SU-720) a procedure similar to that of Example 125-5 except for the use of
? - [(2R) -3-phenyl-1-pivaloyloxy-2-propyl] -? / '- [(S) -a-methyl-4-aminobenzyl] thiourea (19-11) as starting material, was synthesized? / - [(2R) -3-phenyl-1-pivaloyloxy-2-propyl] -? /, - [(S) -a -methyl-4- (methylsulfonylamino) benzylthiourea (19-15, SU-720) having the following physicochemical properties: Yield of 93%; Pale yellow solid, mp = 61-64 ° C, [a] = +11.5 (c 1.00,
1 H-NMR (CDCl 3) d 7.45 (br s, 1 H), 7.15-7.3 (m, 7 H), 7.05 (d, 2 H, J = 6.3 Hz),
6.78 (sa, 1 H), 6.02 (sa, 1 H), 4.76 (sa, 2 H), 4.14 (dd, 1 H, J = 5.1, 11.7 Hz) , 3.97
(dd, 2 H, J = 4.1, 11.7 Hz), 3.01 (s, 3 H), 2.89 (dd, 1 H, J = 5.4, 13.6 Hz), 2 , 55 (br s, 1 H), 1.50 (d, 3 H, J = 7.1 Hz), 1.19 (s, 9 H) MS (FAB) m / z 492 (MH +) Example 128: Preparation from ? - [(2S) -3-phenyl-1-pivaloyloxy-2-propyl] -? '- [(S) -a-methyl-4- (methylsulfonylamino) benzyl] thiourea (19-16, SU-710) Step 128-1 Preparation of / V - [(2S) -3-phenyl-1-pivaloyloxy- 2-propyl] -? / '- [(S) - -meti-4-nitrobenzyl thiourea (19-8, SU-700) The / V - [(2S) -3-phenyl-1-pivaloyloxy- 2-propyl] - / V, - [(S) -a-methyl-4-nitrobenzyl thiourea (19-8, SU-700) by a method similar to that described in example 127-1, 127-2 and 127-3 previous. Yield of 82%, yellow oil The spectral data of this compound were specific to those of compound 19-7. Stage 128-2. Preparation of N - [(S) -3-phenyl-1-pivaloyloxy-2-propyl] -N '- [(S) -a-methyl-4-aminobenzylthiourea (19-12, SU-706) By a similar procedure to that of example 125-4 except for the use of
? / - [(2S) -3-phenyl-1-pivaloyloxy-2-propyl] -? /, - [(S) - -methyl-4-nitrobenzyl] thiourea (19-8) as starting material, was synthesized - [(2S) -3-phenyl-1-pivaloyloxy-2-propyl] -? / - [(S) -a-methyl-4-aminobenzyl thiourea (19-12, SU-706) having the following physicochemical properties: Yield 93%, yellow oil The spectral data of this compound were identical to those of compound 19-11. Stage 128-3. Preparation of? - [(2S) -3-phenyl-1-pivaloyloxy-2-propyl] -? '- [(S) - -methyl-4- (methylsulphonylamino) benzyl] thiourea (19-16, SU-710) By a procedure similar to that of example 125-5 except for the use of
? / - [(2S) -3-f-enyl-1-pivaloyloxy-2-propyl] -? - [(S) -a-mef-l-4-aminobenzyl] -iourea (19-12) as starting material, was synthesized? - [(2S) -3-phenyl-1-pivaloyloxy-2-propyl] -? / '- [(S) -a-methyl-4- (methylsulfonylamino) benzyl] thiourea (19-16, SU-710) having the following physicochemical properties: Yield of 85%, white solid, mp = 59-61 ° C, [a] = -18.2 (c 1.00, CHCl3) The spectral data for this compound were identical to those for compound 19-15. MS (FAB) m / z 492 (MH +) Example 129: Preparation of α / - (4-β-γ-γ-ylbenzyl) -? / -. { 1- [4- (Methylsulfonylamino) -3-fluorophenyl] propyl} thiourea (20-12, LJO-399) Stage 129-1. Preparation of 2-fluoro-4-vinylaniline (20-1 LJO-324) A solution of 2-fluoro-4-iodoaniline (2.37 g, 10 mmol) in toluene was treated.
(50 ml) with tetrakis (triphenylphosphine) palladium (0.578 g, 0.5 mmol), tributyl vinyl tin (3.5 ml, 12 mmol) and a catalytic amount of 2,6-d, -er-butyl-4 -methylphenol. After being heated at 100 ° C for 1 h, the reaction mixture was filtered through Celite and the filtrate was concentrated in vacuo. The residue was purified by flash column chromatography on silica gel using EOAc: hexanes (1: 5) as eluted to give 2-fluoro-4-vinylaniline (20-1, LJO-324, 1, 275 g, 93%) as a yellow oil 1 H-NMR (CDCl 3) d 7.08 (dd, 1 H, J = 1.95, 12.4 Hz), 6.98 (dd, 1 H, J = 1.47 Hz, 8.04 Hz), 6.71 (t, 1 H, J = 9 Hz), 6.57 (dd, 1 H, J = 10.8, 17.5 Hz), 5.55 (d, 1 H, J = 17.5 Hz), 5.09 (dd, 1 H, J = 10.8 Hz), 3.75 (sa, 2 H) Stage 129-2. Preparation of? / - (2-fluoro-4-viniIfeniI) methanesulfonamide (20-2 LJO-325) A cold solution of 2-fluoro-4-vinylaniline (20-1, 0.96 g, 7 mmol) was treated in pyridine (10 ml) at 09 ° C with methanesulfonyl chloride (0.644 ml, 8.4 mmol) and stirred at room temperature for 30 min. The reaction mixture was diluted in water and extracted with EtOAc several times. The combined organic phases were washed with water and brine, dried over MgSO 4, filtered, and the filtrate was concentrated in vacuo. The residue was purified by flash column chromatography on silica gel using EtOAc: hexanes (1: 3) as eluent to give? Í- (2-fluoro-4-vinylphenyl) methanesulfonamide (20-2, LJO-325, 1.372 g, 91%) as a white solid. mp = 829C 1 H-NMR (CDCl 3) d 7.53 (t, 1 H, J = 8 Hz), 7.15-7.25 (m, 2 H), 6.64 (dd, 1 H, J =
.7, 17.5 Hz), 6.50 (sa, 1 H), 5.72 (d, 1 H, J = 17.5 Hz), 5.32 (dd, 1 H, J = 10, 7 Hz), 3.03 (s, 3 H) Step 129-3. Preparation of? / - (2-fluoro-4-formylphenyl) methanesulfonamide (20-3 LJO-326) A solution of? / - (2-fluoro-4-vinylphenyl) methanesulfonamide (20-2,
1.076 g, 5 mmol) in acetone and water (1: 1, 20 ml) with a catalytic amount of osmium tetraoxide (4% by weight solution in hydroxy peroxide) and sodium periodate (2.139 g, 10 mmol). After being stirred at room temperature for 1 h, the mixture was concentrated to a small volume in vacuo. The residue was treated with aqueous sodium trisulfate solution and then extracted with EtOAc several times. The combined organic layers were washed with water and brine, dried over MgSO 4, filtered, and the filtrate was concentrated in vacuo. The residue was purified by flash column chromatography on silica gel using EtOAc: hexanes (1: 2) as eluent to give? / - (2-fluoro-4-formylphenyl) methanesulfonamide (20-3, LJO-326, 0.521 g, 48%) as a white solid.
mp = 1512C 1 H-NMR (CDCl 3) d 9.92 (d, 1 H, J = 2.2 Hz), 7.78 (t, 1 H, J = 8.6 Hz), 7.65-7, 74 (m, 2 H), 6.92 (s at, 1 H), 3.15 (s, 3 H) Stage 129-4. Preparation of? / - [2-fluoro-4- (1-hydroxypropyl) phenyl] methanesulfonamide (20-4, LJO-337) A cold solution of? / - (2-fluoro-4-formylphenyl) methanesulfonamide (20 -3, 0.424 g, 2 mmol) in THF (20 ml) at 09C with a Grignard reagent (4 mmol) and stirred at 09C for 30 min. The reaction mixture was quenched with a saturated solution of ammonium chloride, diluted with water and exfoliated with EtOAc several times. The combined organic layers were washed with water and brine, dried over MgSO 4, filtered, and the filtrate was concentrated in vacuo. The residue was purified by flash column chromatography on silica gel using EtOAc: hexanes (1: 1) as eluent to? / - [2-fluoro-4- (1-hydroxypropyl) phenyl] methanesulfonamide (20-4, LJO- 337). Yield 92% yield, colorless oil 1 H-NMR (CDCl 3) d 7.53 (t, 1 H, J = 8.22 Hz), 7.19 (dd, 1 H, J = 1.8, 11.2 Hz), 7.12 (dd, 1 H, J = 1.8 Hz, 8 Hz), 6.45 (sa, 1 H), 4.61 (m, 1 H), 3.02 (s, 3 H), 1.87 (m, 1 H), 1.7-1.8 (m, 2 H), 0.93 (t, 3 H, J = 7.3 Hz) Step 129-5. Preparation of ? - [2-fluoro-4- (1-azidopropyl) phenyl] methanesulfonamide (20-8, LJO-397) A cold solution of the alcohol (1 mmol) in toluene (10 ml) at 09C was treated with diphenylphosphorylazide (0.26) ml, 1.2 mmol) followed by 1,8-diazabicyclo [5.4.0] undec-7-ene (0.18 ml, 1.2 mmol) and stirred for 2 h at 09C. After being stirred for a further 20 h at room temperature, the reaction mixture was diluted in EtOAc. The organic phase was washed with 5% HCl (10 ml), water and brine, dried over MgSO 4, filtered, and the filtrate was concentrated in vacuo. The residue was purified by flash column chromatography on silica gel using EtOAc: hexanes (1: 3) as eluent to give? / - [2-fIuoro-4- (1-azidopropyl) phenyl] methanesulfonamide (20-8, LJO397) . Yield 91%, colorless oil 1 H-NMR (CDCl 3) d 7.56 (i, 1 H, J = 8.04 Hz), 7.0-7.1 (m, 2 H), 6.70 ( sa, 1 H),
4.34 (t, 1 H, J = 7.32 Hz), 3.03 (s, 3 H), 1.7-1.8 (m, 2 H), 0.93 (t, 3 H, J = 7.3 Hz) Step 129-6. Preparation of - (4-f-butylbenzyl) -N-. { 1- [4- (methylsulfonamino) -3-f luorofenyl] propyl} thiourea (20-12, LJO-399) A suspension of the azide (1 mmol) and 10% palladium on carbon (50 mg) in MeOH (10 ml) was hydrogenated with a hydrogen balloon for 1 h. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was dissolved in DMF (3 ml) and then 4-urea-butylbenzyl isothiocyanate (0.205 g, 1 mmol) was added. After being stirred at room temperature for 3 h, the reaction mixture was diluted in water and extracted with EtOAc several times. The combined organic phases were washed with water and brine, dried over MgSO, filtered, and the filtrate was concentrated in vacuo. The residue was purified by flash column chromatography on silica gel with EOAc: hexanes (1: 1) as eluent to give N- (4-t-buylbenzyl) -? / '-. { 1 - [4 (Methylsulfonylamino) -3-fluorophenyl] propyl} thourea (20-12, LJO-399) Yield 82%, white solid, mp = 859C 1 H-NMR (CDCl 3) d 7.45 (t, 1 H, J = 8.04 Hz), 7.34 (d, 2 H, J = 8.04 Hz), 7.12 (d,
2 H, J = 8.04 Hz), 6.9-7.0 (m, 2 H), 6.76 (sa, 1 H), 6.24 (sa, 2 H), 4.88 (sa , 1 H), 4.55 (sa, 2 H), 3.00 (s, 3 H), 1.7-1.8 (m, 2 H), 1.30 (s, 9 H), 0 , 82 (i, 3 H, J = 7.05 Hz) MS (FAB) m / z 452 (MH +) Example 130: Preparation of W- (4-f-butylbenzyl) -? / -. { 1- [4- (Methylsulfonylamino) -3-fluorophenyl] -2-methylpropi !} thiourea (20-13, LJO-402) Stage 130-1. Preparation of? / - [2-fluoro-4- (1-hydroxy-2-methylpropyl) phenyI] methanesulfonamide (20-5 LJO-396) By a procedure similar to that of Example 129-5 except for the use of? / - (2-fluoro-4-formylphenyl) methanesulfonamide (20-3) as starting material, N- [2-fluoro-4- (l-hydroxy-2-methylpropyl) phenyl] methanesulfonamide was synthesized (20-5, LJO- 396) having the following physicochemical properties: Yield 90%, colorless oil 1 H-NMR (CDCl 3) d 7.50 (t, 1 H, J = 8.28 Hz), 7.15 (dd, 1 H, J = 1.95, 11.2 Hz), 7.07 (dd, 1 H, J = 1.8 Hz, 8 Hz), 6.62 (sa, 1 H), 4.38 (d, 1 H, J = 6.36 Hz), 3.01 (s, 3 H), 1.80 (m, 2 H), 0.95 (d, 3 H, J = 6.8 Hz), 0.83 (d , 3 H, J = 6.8 Hz) Step 130-2. Preparation of? / - [2-fluoro-4- (1-azido-2-methylpropi!) PhenyI] methanesulfonamide (20-9 LJO-398) By a procedure similar to that of Example 129-5 except for the use of N- [2-fluoro-4- (1-hydroxy-2-methylpropyl) phenyl] -mefanosulfonamide (20-5) as a starting material, was synthesized? / - [2-fIuoro-4- (1-azido-2-methylpropyl) phenyl] methanesulfonamide (20-9, LJO-398) having the following physicochemical properties: Yield 85%, colorless oil 1 H-NMR (CDCl 3) d 7.57 (t, 1 H, J = 8.07 Hz), 7.05-7.15 (m, 2 H), 6.64 (sa, 1 H), 4.15 (d, 1 H, J = 7.56 Hz), 3.05 (s, 3 H) , 1.93 (m, 1 H), 0.99 (d, 3 H, J = 6.8 Hz), 0.81 (d, 3 H, J = 6.8 Hz) Step 130-3. Preparation of? / M4 ^ butylbenzyl) -N-. { 1- [4- (Methylsulfonylamino) -3-fluorophenyl] -2-methylpropyl} thiourea (20-13, LJO-402) By a procedure similar to that of example 129-6 except for the use of
N- [2-fluoro-4- (1-azido-2-methylpropyl) phenyl] methanesulfonamide (20-9) as starting material,? / '- (4-f-butylbenzyl) -? / - was synthesized. { 1 - [4- (Methylsulfonylamino) -3-f luorof enirj-2-methyl? Ropil} thiourea (20-13, LJO-402) having the following physicochemical properties: Yield of 87%, white solid, mp = 84 ° C 1 H-NMR (CDCIs) d 7.45 (t, 1 H, J = 8, 04 Hz), 7.36 (d, 2 H, J = 8.04 Hz), 7.14 (d, 2 H, J = 8.04 Hz), 6.85-6.95 (m, 2 H) ), 6.78 (sa, 1 H), 6.25 (sa, 2 H), 4.81 (sa, 1 H), 4.53 (sa, 2 H), 3.01 (s, 3 H) ), 1.92 (m, 1 H), 1.30 (s, 9 H), 0.77 (m, 6 H) MS (FAB) m / z 466 (MH +) Example 131: Preparation of V- ( 4-y-butylbenzyl) -? / -. { [4- (meilylsulfonylamino) -3-f luorofenyl] (phenyl) methyl} thiourea (20-14, LJO-403) Stage 131-1. Preparation of ?/-. { 2-fluoro-4- [hydroxy (phenyl) methyl] phenyl} methanesulfonamide (20-6 LJO-330) Using a procedure similar to that of Example 129-4 except for the use of Grignard reagent (R = Ph) of? / - (2-fluoro-4-formylphenyl) methanesulfonamide (20-6) 3) as starting material, was synthesized? / -. { 2-fluoro-4- [hydroxy (phenyl) methyl] phenyl} methanesulfonamide (20-6, LJO-330) having the following physicochemical properties: Yield of 100%, white solid, mp = 919C 1 H-NMR (CDCl 3) d 7.52 (t, 1 H, J = 8.25 Hz), 7.3-7.38 (m, 5 H), 7.22 (dd, 1 H, J = 1.6, 11.2 Hz), 7.17 (dd, 1 H, J = 1 , 6 Hz, 8 Hz), 6.46 (sa, 1 H), 5.81 (s, 1 H), 3.00 (s, 3 H), 1.99 (sa, 1 H) Stage 131- 2. Preparation of V-. { 2-fluoro-4- [azido (phenyl) methyl] phenyl} methanesulfonamide (20-10, LJO-335) By a procedure similar to that of Example 129-5 except for the use of? / -. { 2-fluoro-4- [hydroxy (phenyl) methyl] phenyl} methanesulfonamide (20-6) as starting material, was synthesized? / -. { 2-fluoro-4- [azido (phenyl) methyl] phenyl} methanesulfonamide (20-10, LJO-335) having the following physicochemical properties: Yield 84%, white solid, mp = 609C 1 H-NMR (CDCl 3) d 7.56 (t, 1 H, J = 8.25 Hz ), 7.25-7.45 (m, 5 H), 7.1-7.15 (m, 2
H), 6.48 (s a, 1 H), 5.68 (s, 1 H), 3.03 (s, 3 H) Stage 131-3. Preparation of / / - (4-í-buylbenzyl) - / V- [4- (methylsulfonylamino) -3-fluorophenyl] (phenyl) methyl} thiourea (20-14, LJO-403) by a procedure similar to that of example 129-6 except for the use of
? / -. { 2-fluoro-4 [hydroxy (phenyl) methyl] phenyl} methanesulfonamide (20-6) as starting material,? / - (4---butylbenzyl) -? / - was synthesized. { [4- (methylsulfonylamino) -3-f luorofenyl] (feniI) methyl} thiourea (20-14, LJO-403) having the following physicochemical properties: Yield 92%, white solid, mp = 1919C 1 H-NMR (CDCl 3) d 7.50 (t, 1 H, J = 8.55 Hz ), 7.25-7.4 (m, 7 H), 7.13 (d, 2 H, J = 8.04 Hz), 6.9-7.0 (m, 2 H), 6.51 (sa, 1 H), 6.30 (sa, 1 H), 6.23 (sa, 1 H), 4.58 (sa, 2 H), 3.02 (s, 3 H), 1.31 (s, 9 H) MS (FAB) m / z 500 (MH +) Example 132: Preparation of? / - (4-y-butylbenzyl) - / V'-. { 1- [4- (Methylsulfonylamino) -3-fluorophenyl] -2-phenylethyl} thiourea (20-15, LJO-395) Stage 132-1. Preparation of N- [2-fluoro-4- (1-hydroxy-2-phenylethyl) phenyl] methanesulfonamide (20-7, LJO-336) by a procedure similar to that of example 129-4 except for the use of Grignard reagent (R = Ph) of? / - (2-fluoro-4-formylphenyl) methanesulfonamide (20-3) as starting material, was synthesized? / - [2-fIuoro-4- (1-hydroxy-2-phenylethyl) phenyl] methanesulfonamide (20-7, LJO-336) having the following physicochemical properties: Yield 94%, yellow solid, mp = 1239C 1 H-NMR (CDCl 3) d 7.54 (t, 1 H, J = 8, 22 Hz), 7.1-7.35 (m, 7 H), 6.44 (sa, 1 H), 4.89 (m, 1 H), 3.02 (s, 3 H), 2, 98 (ddd of AB, 2 H), 1.98 (d, 1 H, J = 2.9 Hz) Step 132-2. Preparation of? / - [2-fluoro-4- (1-azido-2-phenylethyl) phenyl] methanesulfonamide (20-11 LJO-394) By a procedure similar to that of Example 129-5 except for the use of? / - [2-fluoro-4- (1-hydroxy-2-phenylethyl) phenyl] methanesulfonamide (20-7) as a starting material, was synthesized? / - [2-fluoro-4- (1-azido-2-phenylethyl) ) phenyl] methanesulfonamide (20-11, LJO-394) which has the following physicochemical properties: Yield 94%, white solid, mp = 74 ° C 1 H-NMR (CDCl 3) d 7.55 (t, 1 H, J = 8.04 Hz), 7.0-7.3 (m, 7 H), 6.62 (sa, 1 H), 4.66 (t, 1 H, J = 6.84 Hz), 3, 04 (s, 3 H), 3.00 (ddd of AB, 2 H) Stage 132-3. Preparation of / V- (4-y-butylbenzyl) -? -. { 1- [4- (Methylsulfonylamino) -3-f luorofenyl] -2-phenylethyl} thiourea (20-15, LJO-395) by a procedure similar to that of example 129-6 except for the use of? / - [2-fluoro-4- (1-azido-2-phenylethyl) phenyl] methanesulfonamide (20 -11) as starting material, was synthesized? / - (4-f-butylbenzyl) -? / -. { 1- [4- (Methylsulfonylamino) -3-fluorophenyl] -2-phenylenyl} iourea (20-15, LJO-395) which has the following physicochemical properties: Yield 93%, white solid, mp = 1169C 1 H-NMR (CDCl 3) d 7.43 (t, 1 H, J = 8.04 Hz ), 7.33 (d, 2 H, J = 8.04 Hz), 7.2-7.3 (m, 5 H), 7.06 (d, 2 H, J = 8.04 Hz), 6.9-7.0 (m, 2 H), 6.63 (sa, 1 H), 6.11 (sa, 1 H), 5.45 (sa, 1 H), 4.43 (sa, 2 H), 3.06 (d, 2 H, J = 5.6 Hz), 3.00 (s, 3 H), 1.31 (s, 9 H) EM (FAB) m / z 514 (MH + Example 133: Preparation of? / - (4-y-butylbenzyl) -? / '-. { 1-methyl-1- [4- (methylsulfoniamino) phenyl] ethyl} thiourea (21-7, CHK 593) Step 133-1. Preparation of N ~. { \ -methyl-1 - [4- (methylsulfonylamino) phenyl] ethyl} Benzyl carbamate (21-1, CHK-582) A solution of 2- [4- (methylsulfonylamino) phenyl] -2-methylpropionic acid (8-11, 1 mmol) in toluene (6 mL) was treated with a molecular sieve of 4A (200 mg), Et 3 N (1.3 mmol) and diphenylphosphorylazide (1.3 mmol) and heated at 110 ° C for 1 h. The mixture was cooled to room temperature and BnOH (20 mmol) was added. The mixture was then heated to 110 ° C for 12 hours and concentrated in vacuo. The residue was purified by column chromatography on silica gel with EtOAc: hexanes as eluent to give N- \ -methyl-1 - [4- (methylsulfonylamino) phenyl] etiI} Benzyl carbamate (21-1, CHK-582) 1 H-NMR (CDCl 3) d 7.25-7.4 (m, 7 H), 7.12 (da, 2 H), 6.60 (sa, 1 H), 5.22 (s, 1 H), 5.02 (S, 2 H), 2.98 (s, 3 H), 1.65 (s, 6 H) Step 133-2. Preparation of / V- (4-f-butylbenzyl) -? / -. { 1-methyl-1 - [4- (methylsulfonylamino) f-ethyl] ethyl} thiourea (21 -7), CHIC-593) A suspension of? / - was hydrogenated. { 1-methyl-1 - [4- (methylsulfonylamino) phenyl] ethyl} Benzyl carbamate (21-1, 0.5 mmol) and 5% palladium on carbon (100 mg) in MeOH (10 mL) with a hydrogen balloon for 1 h. After the solvent was evaporated by a rotary evaporator, the residue was dissolved in DMF (5 ml) and treated with 4-f-butylbenzyl isothiocyanate (0.5 mmol). After stirring overnight, a final aqueous treatment was made to the mixture and the residue was purified by column chromatography on silica gel with EtOAc: hexanes as eluent to give? / - (4-y-buylbenzyl) -? '-. { 1-methyl-1 - [4 (methylsuphonyl amino) phenyl] ethyl} thiourea (21-7, CHIC-593) Yield 94%, white solid, mp = 161-164 ° C 1 H-NMR (CDCl 3) d 7.42 (d, 2 H), 7.22 (dd, 4 H ), 6.83 (sa, 1 H), 6.80 (d, 2 H), 6.63 (sa, 1 H), 5.23 (ta, 1 H), 4.58 (d, 2 H) , J = 4.9 Hz), 2.97 (s, 3 H), 1.65 (s, 6 H), 1.28 (s, 9 H) MS (FÁB) m / z 434 (MH +) Example 134: Preparation of? / - (4-y-butiibenzyl) -? / -. { 1-methyl-1 - [3-f luoro-4- (methylsulfonylamino) phenyl] ethyl} thiourea (21-8, CHK-660) Stage 134-1. Preparation of ?/-. { 1-methyl-1 - [3-f luoro-4 (methylsulfonylamino) phenyl] ethyl} Benzyl carbamate (21-2, CHK-657) By a procedure similar to that of Example 133-1 except for the use of 2- [3-fluoro-4 (methylsulfonylamino) phenyl] -2-methylpropionic acid (7-4) As a starting material, was it synthesized? -methyl-1 - [3-f luoro-4- (methylisulfonicamino) phenyl] ethyl} Benzyl carbamate (212, CHK-657) having the following physicochemical properties: 1 H-NMR (CDCl 3) d 7.50 (t, 1 H, J = 8.3 Hz), 7.34 (sa, 5 H) , 7.15-7.2 (m, 2 H), 6.45 (sa, 1 H), 5.18 (sa, 1 H), 5.02 (s, 2 H), 3.02 (s) , 3 H), 1.63 (s, 6 H) Step 134-2. Preparation of ?/-. { 1-methyl-1 - [3-f luoro-4- (methylsulfonylamino) phenyl] ethyl} Benzyl carbamate (21-2, CHK-657) By a procedure similar to that of Example 133-2 except for the use of? / -. { 1-methyl-l- [3-fluoro-4- (methylsulfonylamino) phenyl] ethyl} Benzyl carbamate (21-2) as starting material, N- was synthesized. { 1-methyl-1 - [3-f Iuoro-4- (methylsulfonylamino) phenyl] ethyl} Benzyl carbamate (21-2, CHK-657) having the following physicochemical properties: Yield 80%, white solid, mp = 83-85 ° C 1 H-NMR (CDCl 3) d 7.52 (t, 1 H, J = 8.2 Hz), 7.18-7.3 (m, 4 H), 6.86 (d, 2 H, J = 7.9 Hz), 6.50 (sa, 1 H), 5 , 20 (sa, 1 H), 4.59 (d, 2 H, J = 4.8 Hz), 2.98 (s, 3 H), 1.65 (s, 6 H), 1.29 ( S, 9 H) MS m / z 486 (MNa +) Example 135: Preparation of? / - (4-y-butylbenzyl) -? / -. { 1-methyl-1 - [3-methoxy-4- (methylsulfonylamino) phenyl} ethyl} thiourea (21-9, CHK 629) Stage 135-1. Preparation of ?/-. { 1-methyl-1 - [3-methoxy-4- (methylsulphonylamino) phenyl] ethyl} benzyl carbamate (21-3, CHK-646), by a procedure similar to that of example 133-1 except for the use of 2- (3-methoxy 4- (methylsulfonylamino) phenyl) -2-methylpropionic acid (8-12) ) as starting material, was synthesized? { 1-methyl-1 - [3-methoxy-4- (methylsulfonylamino) phenyl] ethyl} Benzyl carbamate (21-3, CHK-646) having the following physicochemical properties: 1 H-NMR (CDCl 3) d 7,44 (d, 1 H, J = 8.3 Hz), 7.34 (sa, 5 H), 6.98 (dd, 1 H, J = 2, 8.3 Hz), 6.91 (d, 1 H, J = 2 Hz), 6.74 (sa, 1 H), 5.21 (sa, 1 H), 5.02 (s, 2 H), 3.79 (s, 3 H), 2.93 (8, 3 H), 1.65 (s, 6 H) Stage 135-2 . Preparation of? / - (4-y-butylbenzyl) -? -. { 1-methyI-1- [3-methoxy-4- (methylsulfonylamino) phenyl] ethyl} thiourea (21 -9 CHK-629) By a procedure similar to that of example 135-1 except for the use of
? -methyl-1 - [3-methoxy-4- (methylsulfonylamino) phenyl] ethyl} Benzyl carbamate (21-3) as starting material, N- (4---butylbenzyl) -? -. { 1-methyl-1 - [3-methoxy-4- (methylsulfonylamino) phenyl] ethyl} thiourea (21-9, CHK-629) having the following physicochemical properties: Yield of 69%, white solid, mp = 148-150 ° C 1 H-NMR (CDCl 3) d 7.47 (d, 1 H, J = 8.2 Hz), 7.23 (d, 1 H), 6.94-7.0 (m, 2 H), 6.80 (d, 3 H), 6.50 (sa, 1 H), 5.31 (t, 1 H), 4.57 (d, 2 H, J = 5.1 Hz), 3.77 (s, 3 H), 2.89 (s, 3 H), 1.65 (S, 6 H), 1.29 (s, 9 H) Example 136: Preparation of? / - (4-f-butylbenzyl) - / V-. { 1- [4- (Methylsulfonylamino) phenyl] cyclopropyl} thiourea (22-7, CHK 579) Stage 136-1. Preparation of ?/-. { 1- [4 (methylsulfonylamino) phenyl] cyclopropyl} benzyl carbamate (22-1 CHK-577) By a procedure similar to that of Example 135-1 except for the use of 1- [4- (methylsulfonylamino) phenyl] cyclopropanecarboxylic acid (11-7, CHK-530) as a Starting, it was synthesized? / - (4-í-butylbenzyl) -? / -. { 1-methyl-1 - [3-methoxy-4- (methylsulfonylamino) phenyl] ethyl} thiourea (21-9, CHK-629) having the following physicochemical properties: Yield of 77%, white solid, mp = 142-143eC 1 H-NMR (CDCl 3) d 7.35 (sa, 5 H), 7, 24 (day, 2 H), 7.13 (day, 2 H), 6.32 (day, 1)
H), 5.46 (sa, 1 H), 5.09 (s, 2 H), 2.98 (s, 3 H), 1.2-1, 35 (m, 4 H) Stage 136-2 . Preparation of ? - (4-f-butylbenzyl) -? '-. { 1- [4 (methylsulfonylamino) phenyl] cyclopropyl} thiourea (22-7 CHK-579) By a procedure similar to that of example 133-2 except for the use of 1- [4- (methylsulfonylamino) phenyl] cyclopropanecarboxylic acid (11-7) as a starting material, it was synthesized / V- (4-f-butylbenzyl) - / V'-. { 1- [4- (Methylsulfonylamino) phenyl] cyclopropyl} thiourea (22-7, CHK-579) having the following physicochemical properties: Yield 78%, white solid, mp = 110-113 ° C 1 H-NMR (CDCl 3) d 7.33 (d, 2 H), 7.17 (m, 4 H), 7.05 (d, 2 H), 4.58 (m, 2 H), 3.01 (s, 3 H), 1.7-1, 9 (m, 2 H), 0.85 (t, 2 H, J = 7.5 Hz) MS (FAB) m / z 433 (M ++ 2) Example 137: Preparation of N- (4-y-butylbenzyl) - / -11- [3-Fluoro-4- (methylsulfonylamino) phenyl] cyclopropyl} Thiourea (22-8) Stage 137-1. Preparation of ?/-. { 1- [3-Fluoro-4- (methylsulfonylamino) phenyl-3-cyclopropyl) benzyl carbamate (22-2) By a procedure similar to that of Example 133-2 except for the use of 1- [3-fluoro-4- (methylsulfonyl amino) phenyl] cyclopropanecarboxylic (10-6) as starting material, was synthesized? / -. { 1- [3-fluoro-4- (methylsulfonylamino) phenyl] cyclopropyl} Benzyl carbamate (22-2) having the following physicochemical properties: 1 H-NMR (CDCl 3) d 7.50 (t, 1 H), 7.35 (sa, 5 H), 6.90 (d, 1 H), 6.84 (dd, 1 H),
6.68 (br s, 1 H, NHSO2), 5.48 (br s, 1 H), 5.12 (s, 2 H), 2.93 (s, 3 H), 1.2-1.3 (s) m, 4 H) Step 137-2. Preparation of? / - (4-y-butylbenzyl) -? / '-. { 1- [3-fluoro-4- (methylsuphonyl amino) phenyl] cyclopropyl} thiourea (22-8) Using a procedure similar to that of Example 133-2 except for the use of
? / -. { 1- [3-fluoro-4- (methylsulfonylamino) phenyl] cyclopropyl} Benzyl carbamate (22-2) as starting material, was synthesized? / - (4-y-butylbenzyl) - / V-. { 1- [3-fluoro-4- (methylisulfonic acid) phenyl] cyclopropyl} thiourea (22-8) which has the following physicochemical properties: 1 H-NMR (CDCl 3) d 7,53 (t, 1 H), 7,34 (d, 1 H), 7,05 (d, 2 H) 6.75-6.90 (m, 3 H),
6.23 (sa, 1 H), 5.80 (sa, 1 H), 4.58 (ddd, 2 H), 2.95 (s, 3 H), 1, 7-1.9 (m, 2 H), 1.30 (s,
9 H), 0.88 (t, 2 H) MS (FAB) m / z 450 (MH +) Example 138: Preparation of? / - (4-y-butylbenzyl) -? / -. { 1- [3-methoxy-4- (methylisuphonyl amino) phenyl] cyclopropyl} thiourea (22-9, CHK-631) Stage 138-1. Preparation of ?/-. { 1- [3-methoxy-4- (methylsulfonylamino) phenyl] cyclopropyl} benzyl carbamazo (22-3 CHK-627) By a procedure similar to that of Example 133-1 except for the use of 1- [3-methoxy-4- (methylsulfonylamino) phenyl] cyclopropanecarboxylic acid (11-8) as a game, was synthesized? / -. { 1- [3-methoxy-4- (methylsulfonylamino) phenyl] cyclopropyl} Benzyl carbamate (22-3, CHK-627) which has the following physicochemical properties: Yield of 86%, white solid, mp = 100-103SC 1 H-NMR (CDCIg) d 7.42 (d, 1 H, J = 8.3 Hz), 7.35 (sa, 5 H), 6.88 (d, 1 H, J = 1.8 Hz), 6.82 (dd, 1 H, J = 1.8, 8.3 Hz), 6.68 (sa, 1 H), 5.46 (sa, 1 H) ), 5.09 (s, 2 H), 3.79 (s, 3 H), 2.91 (s, 3 H), 1.2-1, 3 (m, 4 H) Step 138-2. Preparation of? / - (4-y-butylbenzyl) -? / -. { 1- [3-methoxy-4- (methylsulfonylamino) phenyl] cyclopropyl} thiourea (22-9, CHK-631) by a procedure similar to that of example 133-2 except for the use of acid? / -. { 1- [3-methoxy-4- (methylsulfonylamino) phenyl] cyclopropyl} Benzyl carbamate (22-3) as a starting material, was synthesized? / - (4-y-butylbenzyl) -? / -. { 1 - [3-methoxy-4- (methylsulfonylamino) phenyl] cyclopropyl} thiourea (22-9, CHK-631) having the following physicochemical properties: Yield 86%, white solid, mp = 100-1039C 1 H-NMR (CDCl 3) d 7.46 (d, 1 H), 7, 31 (d, 1 H), 7.02 (d, 2 H), 6.7-6.85 (m, 3 H), 6.20 (sa, 1 H), 5.78 (sa, 1 H) ), 4.58 (ddd, 2 H), 3.83 (s, 3 H), 2.94 (s, 3 H), 1.7-1, 9 (m, 2 H), 1, 30 ( s, 9 H), 0.88 (t, 2 H, J = 7.5 Hz) MS (FAB) m / z 463 (MH ++ 2) Example 139: Preparation of α- (4-γ-butylbenzyl) ) - / -. { 1- [4- (Methylsulfonylamino) phenyl] ethyl} urea (23-1, MK-82) Using a procedure similar to that of Example 133-2 except for the use of 1- [4- (methylsulfonylamino) phenyl] ethylamine (13-11) as a starting material, N- was synthesized (4-y-butylbenzyl) -? / -. { 1- [4- (Methylsulfonylamino) phenyl] ethyl} urea (23-1, MK-82) having the following physicochemical properties: Yield 83%, white solid, mp = 95-989C 1 H-NMR (CDCl 3) d 7.34 (d, 2 H, J = 8, 3 Hz), 7.23 (d, 2 H, J = 8.5 Hz), 7.16 (d, 2 H, J = 8.3 Hz), 7.11 (d, 2 H, J = 8 , 5 Hz), 6.86 (s, 1 H), 4.82 (m, 1 H), 4.63 (m, 2 H), 4.31 (d, 2 H, J = 4.4 Hz ), 2.97 (s, 3 H), 1, 40 (d, 3 H, J = 6.8 Hz), 1, 30 (s, 9 H) MS (IE) m / z 403 (MH +) Example 140: Preparation of α- (4-γ-butylbenzyl) -? -. { 1- [4- (Methylsulfonylamino) phenyl] ethyl} urea (23-1, MK-82) By a procedure similar to that of Example 102 except for the use of 1- [3-fluoro-4- (methylsulfonylamino) phenyl] ethylamine (13-12) as a starting material, it was synthesized N- (4-f-buylbenzyl) -? / -. { 1- [4- (Methylsulfonylamino) phenyl] ethyl} urea (23-1, MK-82) having the following physicochemical properties: Yield 70%, white solid, mp = 152-1549C 1 H-NMR (CDCl 3) d 7.44 (t, 1 H, J = 8, 2 Hz), 7.34 (day, 2 H, J = 8.5 Hz), 7.18 (day, 2 H, J = 8.3 Hz), 7.0-7.08 (m, 2 H) ), 6.66 (s, 1 H), 4.84 (m, 1 H), 4.75 (m, 2 H), 4.30 (ddd, 2 H), 2.99 (s, 3 H) ), 1.38 (d, 3 H, J = 6.8 Hz), 1.30 (s, 9 H) MS (FAB) m / z 422 (MH +) Example 141: Preparation of? / -. { 1- [3-fIuoro-4- (methylsulfonylamino) phenyl] eyl} -3- (4-ert-Butylphenyl) acetamide (24-1, KMJ-586) The? - was prepared. { 1- [3-fluoro-4- (methylsulfonylamino) phenyl] ethyl} -3- (4-ferc-butylphenyl) acetamide (24-1) by a procedure similar to that described in example 1-5 above. Yield 36%, white solid, mp = 134-1369C H-NMR (CDCl 3) d 7.48 (t, 1 H, J = 8.8 Hz), 7.39 (da, 2 H, J = 8, 3 Hz), 7.18 (day, 2 H, J = 8.3 Hz), 6.92-7.02 (m, 2 H), 6.44 (sa, 1 H), 5.58 (d , 1 H, J = 7.8 Hz), 5.06 (m, 1 H), 3.56 (s, 2 H), 3.00 (s, 3 H), 1.37 (d, 3 H) , J = 7 Hz), 1.33 (s, 9H) MS (FAB) m / z 407 (MH +) Example 142: Preparation of / v-. { 1- [3-fluoro-4- (methylsulfonylamino) phenyl] ethyl} -3- (4-ferc-buil-phenyl) I) propionamide (24-2, KMJ-552) The? - was prepared. { 1- [3-fluoro-4- (methylsulfonylamino) phenyl] ethyl} -3- (4-ert-butylphenyl) propionamide (24-2) by a procedure similar to that described in example 1-5 above. Yield 29%, white solid, mp = 152-1549C 1 H-NMR (CDCIg) d 7.44 (t, 1 H, J = 8 Hz), 7.31 (da, 2 H, J = 8.3 Hz ), 7.11 (day, 2 H, J = 8.3 Hz), 6.95-7.02 (m, 2 H), 6.82 (sa, 1 H), 5.72 (d, 1) H, J = 7.1 Hz), 5.02 (m, 1 H), 3.00 (s, 3 H), 2.93 (t, 2 H, J = 7.1 Hz), 2.50 (m, 2 H), 1.34 (d, 3 H, J = 7 Hz), 1.30 (s, 9 H) MS (FAB) m / z 421 (MH +) Example 143: Preparation of? / - . { 1- [3-fluoro-4- (methylsulfonylamino) phenyl] ethyl} -3- (4-tert-butyl! Phenyl) -2-propenamide (24-3, KMJ-570) The? / - was prepared. { 1- [3-fluoro-4- (methylsulfonylamino) phenyl] ethyl} -3- (4-ye / -c-butylphenyl) -2-propenamide (24-3) by a procedure similar to that described in example 1-5 above. 67% yield, white solid, mp = 154-1569C 1 H-NMR (CDCIa) d 7.62 (d, 1 H, J = 15.5 Hz), 7.52 (t, 1 H, J = 8 Hz), 7, 41 (dd, 4 H), 7.12-7.18 (m, 2 H), 6.54 (sa, 1 H), 6.37 (d, 1 H, J = 15.5 Hz), 5 , 88 (d, 1 H, J = 7.1 Hz), 5.21 (m, 1 H), 3.02 (s, 3 H), 1.53 (d, 3 H, J = 7 Hz) , 1.32 (s, 9 H) MS (FAB) m / z 419 (MH +) Example 144: Preparation of? / -. { 1- [3-fluoro-4- (methylsulfonylamino) phenyl] ethyl} -3- (3,4-dimethy-phenyl) propanamide (24-4, CHK-602)? - was prepared. { 1- [3-fluoro-4- (methylisulfonyl) phenyl] ethyl} -3- (3,4-dimethylphenyl) propanamide (24-4) by a procedure similar to that described in example 1-5 above. Yield 70%, white solid, mp = 176-1779C 1 H-NMR (CDCl 3) d 7.47 (t, 1 H, J = 8 Hz), 6.9-7.1 (m, 5 H), 6 , 43 (sa, 1 H), 5.46 (d, 1 H), 5.03 (m, 1 H), 3.01 (s, 3 H), 2.90 (t, 2 H, J = 7.3 Hz), 2.49 (dt, 2 H), 2.23 (d, 6 H, J = 3.8 Hz), 1.37 (d, 3 H, J = 7 Hz) EM (FAB ) m / z 393 (MH +) Example 145: Preparation of? / -. { 1- [3-fluoro-4- (methylsulfonylamino) phenyl] ethyl} -3- (3,4-dimethy-phenyl) -2-propenamide (24-5, CHK-651) The? / - was prepared. { 1- [3-fluoro-4- (methylsulfonylamino) phenyl] ethyl} -3- (3,4-dimethylphenyl) -2-propenamide (24-5) by a procedure similar to that described in Example 1-5 above. Yield 74%, white solid, mp = 212-2139C 1 H-NMR (CDCl 3) d 7.59 (d, 1 H, J = 15.6 Hz), 7.54 (t, 1 H, J = 8 Hz ), 7.1-7.26 (m, 5 H), 6.46 (sa, 1 H), 6.35 (d, 1 H, J = 15.6 Hz), 5.77 (d, 1) H, J = 7.7 Hz), 5.22 (m, 1 H), 3.02 (s, 3 H), 2.27 (sa, 6 H), 1.53 (d, 3 H, J = 7 Hz). MS (FAB) m / z 391 (MH +) Example 146: Preparation of? / -. { 1- [3-fluoro-4- (methylsulfonylamino) phenyl] etiI} -3- (4-chlorophenyl) propanamide (24-6, KMJ-534) The / V- was prepared. { 1- [3-fluoro-4- (methylsulfonylamino) phenyl] ethyl} -3- (4-chlorophenyl) propanamide (24-6) by a procedure similar to that described in example 1-5 above. Yield 65%, white solid, mp = 170-1729C 1 H-NMR (CDCl 3) d 7.48 (t, 1 H, J = 8 Hz), 7.23 (d, 2 H, J = 8.3 Hz ), 7.10 (d, 2 H, J = 8.3 Hz), 6.92-7.0 (m, 2 H), 6.44 (sa, 1 H), 5.47 (d, 1 H), 5.03 (m, 1 H), 3.03 (s, 3 H), 2.94 (t, 2 H, J = 7.3 Hz), 2.48 (m, 2H), 1 , 38 (d, 3 H, J = 7 Hz) MS (FAB) m / z 399 (MH +) Example 147: Preparation of / V-. { 1- [3-fluoro-4- (meilylsu-phenylamino) phenyl] ethyl} -3- (4-chlorophenyl) -2-propenamide (24-7, KMJ-558) The? / - was prepared. { 1- [3-fluoro-4- (methylsulfonylamino) phenyl] ethyl} -3- (4-chlorophenyl) -2-propenamide (24-7) by a procedure similar to that described in example 1-5 above.
Yield 57%, white solid, mp = 219-2219C 1 H-NMR (CDCl 3) d 7.59 (d, 1 H, J = 15.7 Hz), 7.56 (1, 1 H, J = 8 Hz), 7.42 (d, 2 H, J = 8.3 Hz), 7.34 (d, 2 H, J = 8.3 Hz), 7.12-7.18 (m, 2 H) , 6.44 (sa, 1 H), 6.37 (d, 1 H, J = 15.7 Hz), 5.77 (d, 1 H), 5.22 (m, 1 H), 3, 02 (s, 3 H), 1.54 (d, 3 H, J = 7 Hz) MS (FAB) m / z 397 (MH +) Example 148: Preparation of? / -. { 1- [3-fIuoro-4- (methylsulfonylamino) phenyl] etiI} -3- (3,4-dimethylphenyl) butanamide (24-8, CHK-647) The? / - was prepared. { 1- [3-fluoro-4- (methylsulfonylamino) phenyl] ethyl} -3- (3,4-dimethylphenyl) butanamide (24-8) by a procedure similar to that described in example 1-5 above. Yield 81%, mp = 152-1549C 1 H-NMR (CDCl 3) d 7.52 (1, 1 H, J = 8 Hz), 6.85-7.1 (m, 5 H), 6.46 ( sa, 1 H), 5.56 (d, 1 H, J = 7 Hz), 5.08 (m, 1 H), 3.01 (s, 3 H), 2.58 (t, 2 H, J = 7.3 Hz), 2.23 (s, 6 H), 2.19 (i, 2 H, J = 7.9 Hz), 1.94 (m, 2 H), 1.44 (d , 3 H, J = 7 Hz) MS (FAB) m / z 407 (MH +)
Experimental example 1: Assay affinity receptor binding. Vanilloid receptor 1 binding assay Cell culture Plasmid pUHG102 VR1 was transfected into the CHO cells containing the regulatory plasmid pTet Off (Clontech). In these cells, the expression of VR1 in the presence of tetracycline is suppressed but is induced with the withdrawal of the anttic. Stable clones were isolated in a culture medium containing puromycin (10 μg / ml) and maintained in a medium of HAM F12 supplemented with tetracycline (1 μg / ml), geneticin 5 μg / ml, HEPES 25 mM, 10% FBS. The cells used for the assays were grown in a culture medium without anttics for 48 h before use. Cells were seeded in T75 cell culture flasks in medium without anttics and grown to approximately 90% confluency. The flasks were then washed with PBS and collected in 0.25% trypsin, 1 mM EDTA. The cells were pelleted by gentle centrifugation and stored at -20 ° C until assay.
Competitive binding assay Binding studies with [3H] resiniferatoxin (RTX) were carried out as described above with minor modifications (Szallasi et al., 1992).
Mixtures of binding assays were placed on ice and contained [3 H] (RTX) 50 -100 pM, various concentrations of competitive ligands, 0.25 mg / ml BSA (Cohn V fraction), and approximately 5 x 10 5 cells transfected with VR1. The final volume was adjusted to 350 μl with DPBS with Ca2 + and Mg2 + and serum albumin coil (0.25 mg / ml). Non-specific binding was determined in the presence of 100 nM non-radioactive RTX. The binding reaction was initiated by transferring the test mixtures to a 379C water bath and was determined after an incubation period of 60 min by cooling the tubes on ice. To reduce non-specific binding, α-glycoprotein (200 μg / ml) was added. Then RTX bound to the membrane of the free was separated by centrifugation of the membranes in a Beckman 12 bench top centrifuge (15 min, maximum speed), the tips of the tubes containing the pellets were cut, and the radioactivity was determined by the scintillation counter. The equilibrium binding parameters (K, and cooperativity) were determined by adjusting the Hill equation with the measured values with the help of the MicroCal Origin 6.0 program.
Preparation of the compound The initial stocks were dissolved in DMSO. For binding assays, the compounds were diluted in DPBS with Ca2 + and Mg2 + and serum albumin coil 0.25 mg / ml. For the calcium entry assays, the compounds were diluted in DMEM with 0.25 mg / ml serum albumin coil.
Experimental Example 2: Functional Characterization of Agonist / Antagonist Activity 45 Ca2 + Entry Assay The molecules were characterized to determine whether they were completely agonist, partially agonist, or antagonist. For the studies of the uptake of 45Ca2 + by CHO / VR1 cells (cells in way of preventing - "tet-off"), the cells were seeded in 24-well plates giving a cell density of 20-40% of that required to produce confluence. The next day the medium was changed to remove the tetracycline and induce the expression of VR1. The experiments were performed approximately 36-40 hours after the introduction. For the 45Ca2 + uptake assay, the cells were incubated for 5 min at 37 ° C in a total volume of 400 μl of serum free DMEM (containing 1.8 M CaCl2) in the presence of 0.25 mg / ml BSA (Sigma) , 45Ca2 + 1μCi / ml (5-30 Ci / g of ICN, CA), and increasing concentrations of the compound to be tested. Immediately after the incubation, extracellular 45Ca2 + was removed by washing the cells three times with cold DPBS (containing 1.8 mM CaCl2). Then, 400 μl of RIPA buffer (Tris pH 7.4 50 mM) was added.; 150 mM NaCl; Triton X-100 at 1%; 0.1% SDS; sodium deoxycholate ai 1%) to each well in order to lyse the cells. The plates were shaken slowly for 20 min; then 300 μl of the cell lysate was transferred from each well into a scintillation vial and the radioactivity was determined by the scintillation counter. For each data point in each experiment, four wells were tested. The data from these experiments were analyzed by computer fitting in the Hill equation. At least 3 separate experiments were carried out for each compound. In order to determine the antagonist activity, studies were conducted in exactly the same way with the exception that 50 mM capsaicin was added to the assay mixture to stimulate the entry of 45Ca2 +.
Experimental example 3: Analgesic test Twisting test induced by acetic acid. Experimental protocols including animals in this study were reviewed by the Animal Care and Use Committee of the faculty of pharmacy, National University of Seoul, according to NIH guidelines (NIH publication number 85- 23, revised in 1985) of "principles for the care of laboratory animals". Male ICR mice (Bio Genomics, Korea) were maintained, weighing -25 g, with a 12-h light-dark cycle (light switched on between 6:00 p.m. and 6:00 a.m.) and allowed free access. to food and water. The temperature and humidity of the animal room were maintained at 22 ± 29C and 50 ± 5%, respectively. The mice were allowed to become habituated for -30 min to the test room on the day of experimentation. The animals were then given an intraperitoneal injection of 0.3 ml of an acetic acid solution (1.2%, diluted in 0.9% saline), and placed in a clear acrylic cage. Five minutes later the number of writhing movements (abnormal stretches) was counted during a period of 20 min. The animals were pretreated (10 animals / dose) with compounds or test vehicle (0.2 ml, i.p.) 30 min before the acetic acid injection. The test compounds were dissolved either in a mixture of ethanol / Tween-80 / saline (10/10/80) or in a mixture of Cremophor EL / DMSO / distilled water (10/10/80). The effect of each compound was tested in 4-7 different doses. A reduction in the number of writhing movements compared to the treatment group per vehicle (the mean number of writhing movements in this group was 35) was considered as indicative of an amphinociceptive effect of a compound. The percentage of antinociceptive efficiency (eff) was calculated as follows:% eff = 100 - [(n9 of twisting movements / n9 of control of twisting movements) x 100)]. The data are expressed as ED50 values that indicate the concentration at which a given compound reduces the number of kinks by 50% compared to those in the vehicle treatment group. The ED50 values were obtained based on dose-response curves using mean data and adjusted by non-linear regression analysis (Winnonlin version 3.1, Pharsight Corp., Mountainview, CA) with a PC. Table 1 shows the potencies of vanilloid ligands to bind to rat VR1 and to induce an influx of calcium into CHO / VR1 cells.
[Table 1] N9 of compound K1 (nM) Ki (nM) Affinity of binding Antagonism
Capsazepine 1300 520 1-51 KMJ-372 58.45.47 1-52 KMJ-470 30.7 29.5 1-53 SH-173 7.41 24.9 1-54 SH-168 23.3 29, 9 1-55 SH-285 19.9 7.38 1-56 SH-219 344 467 1-57 KMJ-806 6731 NE 1-58 KMJ-788 NE NE 1-59 KMJ-838 1606 951 1-60 KMJ- 836 3712 FROM 1-61 YS-65 FROM 1-62 YS-49 FROM 1-63 YS-76 FROM 1-64 YS-79 NE NE 1-65 CHK-717 536 232 1-66 KMJ-708 358 120 1-67 KMJ-698 1423 4480 2-7 KMJ-750 105 17.5 2-8 YS-85 3500 1089 2-9 YS-97 1652 253 3-5 SU-834 43.9 6.87 3-6 SU-824 458 102 4-1 SH-291 1055 367 4-2 SH-290 729 447 4-3 SH-335 541 296 4-4 SH-94 199 115 4-5 SH-286 289 176 4-6 SH- 337 226 89.6 4-7 SH-351 4-8 KMJ-928 127 143 4-9 SH-353 DE 1350 -10 SH-93 657 274 -11 KMJ-498 1746 261 -12 SH-92 959 239 -13 SH-112 NE NE -14 KMJ-374 553 42.6 -15 SU-770 412 97.4 -16 SU-774 (R) 944 204 -17 SU-776 (S) 236 33.7 -18 KMJ-686 277 152 -19 KMJ-518 466 135 -20 KMJ-732 897 384 -21 SH-109 9417 DE -22 SH-130 5859 DE -23 SH-116 1697 2487 -24 KMJ-378 128 36.6 -25 KMJ- 724 21.5 14.2 -26 KMJ-908 3 6.0 8.03 -27 SH-135 43.3 29.3 -28 SH-199 141 121
-1 CHK-512 119 38.0
-2 CHK-514 55.2 52.0
-3 SU-542 33.1 10.78
-4 SU-564 13.6 3.24
-5 CHK-479 71.2 13.6
-6 CHK-499 24.0 NE
-7 KMJ-472 11.3 35.7
-8 KMJ-690 3.62 12.3
6-1 SU-730 12792 1468
6-2 SU-634 DE
6-3 SU-636 DE
6-4 SU-728 NE NE
6-5 SU-826 43.45.55
6-6 SU-830 20.3 10.0
6-7 SU-838 372 205
6-8 SU-818 297 98.3 -9 MK-271 4.24 0.58 -10 MK-272 6.58 10.9 -11 MK-450 63.8 142 -12 MK-452 53.0 30 , 3 -13 MK-453 1, 83 5.23 -14 MK-451 3.29 12.1 -1 CHK-520 372 103 -2 CHK-543 276 65.4 -3 CHK-493 152 133 -4 CHK -591 1696 573 -5 CHK-656 960 418 -6 CHK-600 838 366 -7 CHK71 425 2552 -8 CHK-655 1069 467 -9 CHK-1001 2-1 CHK-533 396 197 2-2 CHK-538 1577 567 2-3 CHK-541 238 117 2-4 CHK-590 1735 1103 2-5 2-6 CHK-632 1699 1242 2-7 CHK-719 608 1763 2-8 CHK-659 2-9 CHK-718 745 2252 5-1 LJO-303 59.3 14.7 5-2 LJO-328 54 9.16 5-3 CHK-575 66.5 28.6 5-4 YHS-187 163 65.8 5-5 YHS-209 2769 NE 6-5 SU-388 40.8 4.52 6-6 SU-400 3594 NE 7-7 CJU-032 32.8 39.4 7-8 CJU-039 2579 4314 8-1 MK-229 22, 7 44.5 8-2 MK-202 19.4 89 -3 MK-230 1138 3474 -4 MK-228 706 133 -5 LJO-388 37.2 25.9 -6 SU-472 6.1 6.86 -7 SU-512 15.2 7.14 -8 -9 LJO-401 42.7 28.7 -10 MK-296 9.95 23.9 -11 MK-334 15.7 53.0 -12 MK- 298 8,09 30,6 -13 LJO-344 37 7,09 -14 LJO-366 37 9,34 -13 SU-692 420 193 -14 SU-704 272 290 -15 SU-720 NE -16 SU- 710 NE D E -12 LJO-399 230 54.3 -13 LJO-402 338 223 -14 LJO-403 100 861 -15 LJO-395 1741 695 1-7 CHK-593 DE 1827 1-8 CHK-660 7741 983 1-9 CHK-629 2888 663 -7 CHK-579 171 60.3 -8 -9 CHK-631 372 .243 -1 MK-82 1193 544 -2 MK-205 447 298 -1 KMJ-586 2129 2216 -2 KMJ-552 376 103 -3 KMJ-570 104 23.9 -4 CHK-602 NE 4129 4-5 CHK-651 2525 1354 -6 KMJ-534 DE 5651 -7 KMJ-558 773 938 24-8 CHK-647 3529 988 NE: not effective, DE: weakly effective
EXPERIMENTAL EXAMPLE 4: Toxicity test Toxicity tests after a single dose in ICR mice (mean body weight of 25 ± 5 g) and Sprague-Dawley rats (235 ± 10 g) were carried out using compounds 35 and 37. At each group consisted of 3 rations or rats was administered intraperitoneally 20 mg / kg, 10 mg / kg and 1 mg / kg of test compounds or solvents (0.2 ml, ip), respectively and were observed during 24 h. There were no treatment-related effects on mortality, clinical signs, changes in body weight and general findings in either group or gender. These results suggested that the compounds prepared in the present invention are potent and safe. The formulation methods and classes of excipients will now be described in the present document, but the present invention is not limited thereto. Representative examples of preparation were described as follows.
Preparation of powder Compound 35 500 mg Corn starch 100 mg Lactose 100 mg Talc 10 mg The powder preparation was prepared by mixing the above compounds and filling a sealed package.
Preparation of tablets Compound 37 100 mg Corn starch 100 mg Lactose 100 mg Magnesium stearate 2 mg Tablet preparation was prepared by mixing the above compounds and tabletting.
Preparation of capsules Compound 35 50 mg Lactose 50 mg Magnesium stearate 1 mg Table preparation was prepared by mixing the above compounds and filling gelatin capsules by the conventional gelatin preparation method.
Preparation of invections Compound 37 100 mg Distilled water for injection Optimum quantity pH controller Optimum quantity The preparation of injections was prepared by dissolving the active principle, controlling the pH to approximately 7.5 and then filling all the components in an ampoule of 2 ml and sterilization by the conventional injection preparation method.
Preparation of liquid Compound 35 1 g Sugar 10 g Citric acid 0.05 - 0.3% Vitamin C 0.1 - 1% Lemon aroma Optimal quantity Distilled water Optimal quantity The liquid preparation was prepared by dissolving the active ingredient, adding lemon aroma and distilled water and then filling all the components in a 100 ml brown bottle and sterilizing using the conventional liquid preparation method. Having thus described the invention, it will be obvious that it can be varied in many ways. Such variations should not be considered as departing from the spirit and scope of the present invention, and it is intended that all such modifications that are obvious to one skilled in the art are included within the scope of the following claims.
INDUSTRIAL APPLICABILITY The novel 4- (methylsulfonylamino) phenyl analogues as vanilloid antagonists and the pharmaceutical composition comprising them according to the present invention act as vanilloid receptor 1 antagonists and analgesics so that the compounds of the invention are useful in the prevention , pain relief or treatment, acute pain, chronic pain, neuropathic pain, postoperative pain, migraine, arthralgia, neuropathies, nerve injury, diabetic neuropathy, neurodegeneration, neurotic skin disorder, cerebrovascular accident, hypersensitivity of the urinary bladder, irritable bowel, respiratory disorder such as asthma or chronic obstructive pulmonary disease, irritation of the skin, eyes or mucous membrane, fever, gastroduodenal ulcer, inflammatory bowel disease or urgent urinary incontinence, etc.
Claims (14)
- (D) wherein, Ri to R4 is independently at least one selected from hydrogen, halogen atom, cyano group, nitro group, lower alkylamine, lower alkoxy group having from 1 to 3 carbon atoms, carboxylic acid, hydroxamic acid , alkyl ester group having 1 to 6 carbon atoms, alkylamide group having 1 to 6 carbon atoms, benzylamide group, five or six membered heterocyclic ring; R5 and R6 are independently at least one selected from hydrogen, hydroxyl group, amino group, linear or branched alkyl group having from 1 to 6 carbon atoms, cycloalkyl group having from 1 to 6 carbon atoms and phenyl or benzyl group optionally substituted with at least one selected from halogen atom, amine group and alkyl group having from 1 to 6 carbons, provided that R5 and R6 are not simultaneously a hydrogen atom; B is a group selected from the group (1-1) to (I-6) defined in the general formula (I) as set forth in claim 1; the asterisk * mark indicates a chiral carbon atom. 3. The compound of claim 2 wherein said compound is at least one selected from the group consisting of; N- (4-Ierc-butylbenzyl) -2- [3-f luoro-4- (methylsulfonylamino) phenyl] propionamide (1-51, KMJ-372), N- (4-ert-butylbenzyl) -2- [3 -chloro-4- (methylsulfonylamino) phenyl] propionamide (1-52, KMJ-470), N- (4-ert-butylbenzyl) -2- [3-bromo-4- (methylsulfonylamino) phenyl] propionamide (1 -53, SH-173), M- (4-tert-butylbenzyl) -2- [3-iodo-4- (methylsulfonyl) phenyl] propionamide (1-54, SH-168), N- (4- ferc-butylbenzyl) -2- [3,5-difluoro-4- (methylsulfonylamino) phenyl] propionamide (1-55, SH-285), N- (4-ert-butylbenzyl) -2- [3-cyano-4 - (Methylsulfonylamino) phenyl] propionamide (1-56, SH-219), N- (4-tert-buty-benzyl) -2- [3-ert-butoxycarbonyl-4- (methylsulfonylamino) phenyl] propionamide (1-57, KMJ -806), N- (4-ene-buty-benzyl) -2- [3-carboxyl-4- (methylsulfonylamino) phenyl] propionamide (1-58, KMJ-788), N- (4-tert-butylbenzyl) -2 - [3-methoxycarbonyl-4- (methylsulfonylamino) phenyI] propionamide (1-59, KMJ-838), N- (4-ert-butylbenzyl) -2- [3- (benzylamino) carbonyl-4- (methylsulfonylamino) phenyl ] propionamide (1-60, KMJ-836), N- (4-terobuti) lbenzyl) -2- [3-piperidino-4- (methylsulfonylamino) phenyl] propionamide (1-61, YS-65), N- (4-ert-butylbenzyl) -2- [3-morpholino-4- (methylsulfonylamino) phenyl] propionamide (1-62, YS-49), N- (4-fer-butylbenzyl) -2- [3- (N-Boc) piperazino-4- (methylsulfonylamino) phenyl] propionamide (1-63, YS-76), N- (4-fer-butylbenzyl) -2- [3-piperazino- 4- (methylsulfonylamino) phenyl] propionamide (1-64, YS-79), N- (4-fer-butylbenzyl) -2- [3-methoxy-4- (methylsulfonylamino) phenyI] propionamide (1-65, CHK- 717), N- (4-tert-butylbenzyl) -2- [2-f luoro-4- (methylsulfonylamino) phenyI] propionamide (1-66, KMJ-708), N- (4-ert-buty-benzyl) -2- [2-chloro-4- (methylisuifonylamino) phenyl] propionamide (1-67,
- KMJ-698), N- (4-tert-butylbenzyl) -2- [4- (methylsulfonylamino) phenyl] propionamide (2-7, KMJ-750), N- (4-chloro) -2- [4- ( methylsuiphenylamino) pheny] propionamide (2-8, YS-85), N- (3,4-dichloro) -2- [4- (methylsulfonylamino) phenyl] propionamide (2-9, YS-97), N- (4-Yerc-buylbenzyl) - (2S) -2- [3-fluoro-4- (melylsulfonamino) phenyl] propionamide (3-5, SU-834), N- (4-phenobutylbenzyl) - (2R) -2 - [3-fluoro-4- (methylsulfonylamino) phenyl] propionamide (3-6, SU-824), N- (4-chlorobenzyl) -2- [3-fluoro-4- (methylsulfonylamino) phenyl] propionamide (4- 1, SH-291), N- (4-chlorobenzyl-2- (3-chloro-4- (methylsulfonylamino) phenyl] propionamide (4-2, SH-290), N- (4-chlorobenzyl) 2- [3 -bromo-4- (methylsulfonylamino) phenyl] propionamide (4-3, SH-335), N- (3,4-dichlorobenzyl) -2- [3-fIuoro-4- (methylsulfonylamino) phenyl] propionamide (4-4 , SH- 94), N- (3,4-dichlorobenzyl) -2- [3-chloro-4- (methylsulfonylamino) phenyl] propionamide (4-5, SH-286), N- (3,4-dic! orobenzyl) -2- [3-bromo-4- (methylsulfonamino) phenyl] propionamide (4-6, SH-337), N- (4-meilybenzyl) -2- [3-fluoro-4- (meliIsu lfonylamino) phenyl] propionamide (4-7, SH-351), N- (4-isopropylbenzyl) -2- [3-fluoro-4- (methylsulfonylamino) phenyI] propionamide (4-8, KMJ- 928), N- (4-methoxybenzyl) -2- [3-fluoro-4- (methylsulfonylamino) phenyI] propionamide (4-9, SH-353), N- (4-trifluoromethylbenzyl) -2- [3-fluoro-4- (methylisulfonyl) ) phenyl] propionamide (4-10, SH-93), N- (4-phenylbenzyl) -2- [3-fluoro-4- (methylsulfonylamino) phenyl] proponamide (4-11, KMJ-498), N - (1-naphthylmethyl) - [3-fluoro-4- (methylsulfonylamino) phenyl] propionamide (4-12, SH-92), N- (1, 2,3,4-tetrahydro-1-naphthalenyl) -2- [3-fluoro-4- (methylsulfonylamino) phenyI] propionamide (4-13, SH-112), N- [2- (4-ert-butylphenyl) ethyl] -2- [3-f luoro-4- (methylsulfonylamino ) phenyl] propionamide (4-14, KMJ-374), N- [3- (3, 4-dimethylphenyl) propyl] -2- [3-f luoro-4- (methylsulfonylamino) f enyljpropionamide (4-15, SU -770), N- [3- (3,4-dimethylphenyl) propyl] - (2R) -2- [3-fluoro-4- (methylsulfonylamino) phenyl] propionamide (4-16, SU-774), N- [3- (3,4-dimethylphenyl) propyl] - (2S) -2- [3-fluoro-4- (methylsulfonyllamine) phenyl] propi onamide (4-17, SU-776), N- [3- (3,4-dimethylphenyl) -2-propenyl] -2- [3-fluoro-4- (methylsulfonylamino) phenyl] propionamide (4-18, KMJ -686), N- [3- (4-chlorophenyl) propyIJ-2- [3-fluoro-4- (methylsulfonylamino) phenyl] propionamide (4-19, KMJ-518), N- [3- (4-chlorophenyl ) -2-propeniI] -2- [3-fluoro-4- (methylsulfonamino) phenyl] propionamide (4-20, KMJ-732), N-benzyloxy-2- [3-f luoro-4- (methylsulfonylamino) f enyljpropionamide (4-21, SH-109), N- (benzhydryl) -2- [3-f luoro-4- (methylsulfonylamino) phenyl] propionamide (4-22, SH-130), N- (2,2- diphenylethi) -2- [3-fluoro-4- (methylsulfonylamino) phenyl] propionamide (4-23, SH-116), N- (3,3-diphenylpropyl) -2- [3-fluoro-4- (methylsulfonylamino) phenyl] propionamide (4-24, KMJ-378), N- (3,3-diphenyl-2-propenyl) -2- [3-fluoro-4- (methylsulphonamino) phenyl] propionamide (4-25, KMJ -724), N- [3,3-di (4-methylphenyl) -2-propenyl] -2- [3-fluoro-4- (methylsulfonylamino) phenyl] propionamide (4-26, KMJ-908), N- [3,3-di (4-fluorophenyl) -2-propenyl] -2- [3-fluoro-4- (methylsulfonylamino) phenyl] propionamide (4-27, SH-135), N- [2- (10,11-dihydro-5 H -dibenzo [a, d] cyclohepten-5-ylidene) ethyl] -2- [3-fluoro-4- (methylsulfonamino) pheny!] Propionamide (4-28, SH-199), N- [2- (3,4-dimethyl-benzyl) -3-pivaloxypropyl] -2- [4- (methylsulfonylamino) phenyl] propionamide (5-1, CHK-512), N- [2- (4-yr -butylbenzyl) -3-pivaloxypropyl] -2- [4- (methylsulfonylamino) phenyl] propionamide (5-2, CHK-514), 2- [3-fluoro-4- (methylsuphonyl amino) phenyl] -N- [2- (3,4-dimethylbenzyl) -3-pivaloxypropyljpropionamide (5-3, SU-542), 2- [3-fluoro-4- (methylsulfonylamino) phenyl] -N- [2-4-yerc-butylbenzyl] -3- pivaloxypropyl] propionamide (5-4, SU-564), N- [2- (3,4-dimethylbenzyl) -3-pivaloxypropyl] -2- [3-methoxy-4- (methylsulfonylamino) phenyl] propionamide (5-5 , CHK-479), N- [2- (4-Ierc-butylbenzyl) -3-pivaloxypropyl] -2- [3-methoxy-4- (methylsulfonylamino) phenyl] propionamide (5-6, CHK-499), N - [2- (3,4-dimethylbenzyl) -3-pivaloxypropyl] -2- [3-chloro-4- (methylsulfonylamino) pheny] propionamide (5-7, KNJ-472), N- [2- ( 4-fer-butylbenzyl) -3-pivaloxypropyl] -2- [3-chloro-4- (methylsulfonylamino) phenyl] propionamide (5-8, KMJ-690), N - [(1 R) -1-benzyl-2- (pivaloxy) ethyl] - (2S) -2- [3-f luoro-4- (methylsulfonylamino) phenyl] propionamide (6-1, SU-730), N - [(1S) -1-benzyl-2- (pivaloxy) ethyl] - (2S) -2- [3-fluoro-4- (methylsulfonylamino) phenyl] propionamide (6-2, SU -634), N - [(1 S) -1-benzyl-2- (pivaloxy) ethyl] - (2R) -2- [3-f luoro-4- (methylsulfonylamino) phenyl] propionamide (6-3, SU -636), N - [(1R) -1-benzyl-2- (pivaloxy) ethyl] - (2R) -2- [3-fluoro-4- (methylsulfonylamino) phenyI] propionamide (6-4, SU-728 ), N - [(2R) -2-benzyl-3- (pivaloxy) propyl] - (2S) -2- [3-fluoro-4- (methylsulfonylamino) phenyl] propionamide (6-5, SU-826), N - [(2S) -2-benzyl-3- (pivaloxy) propyl] - (2S) -2- [3-fluoro-4-Cmethylsulfonylamino) phenyl] propionamide (6-6, SU-830), N- [ (2S) -2-benzyl-3- (pivaloxy) propyl] - (2R) -2- [3-fluoro-4-methylsulfonylamino) phenyl] propionamide (6-7, SU-838), N - [(2R) -2-benzyl-3- (pivaloxy) propyl] - (2R) -2- [3-fluoro-4- (methylsulfonylamino) phenyl] propionamide (6-8, SU-818), N - [(2R) -2 - (4-Ierc-butyl) benzyl-3- (pivaloxy) propyl] - (2S) -2- [3-fluoro-4-fmethylsulfonylamino) phenyl] propionamide (6-9, K-271), N - [( 2S) -2- (4-tert-butyl) benzyl-3- (pivaloxy) propyl] - (2S) -2- [3-fluoro-4- (meilylsulfonicamino) fe niI] propionamide (6-10, MK-272), N - [(2S) -2- (4-fieryl butyl) benzyl-3- (pivaloxy) propyl] - (2R) -2- [3-fluoro-4] - (methylsulfonylamino) phenyl] propionamide (6-11, MK-450), N - [(2R) -2- (4-ferc-butyl) benzyl-3- (pivaloxy) propyl] - (2R) -2- [ 3-fIuoro-4- (methylsulfonyl amino) phenyl] propionamide (6-12, MK-452), N - [(2R) -2- (4-ferc-butyl) benzyl-3- (pivaloxy) propyl] - (2S ) -2- [3-chloro-4- (methylsulfonamino) phenyI] propionamide (6-13, MK-453), N - [(2S) -2- (4-tert-butyl) benzyl-3- (pivaloxy) propyl] - (2S) -2- [3-chloro-4- (methylsulfonylamino) phenyl] propionamide (6-14, MK-451), 2- [3-fluoro-4- (methylsulfonylamino) phenyl] -2- methylpropionic acid (7-4, CHK-624), 2- [4- (methylsulfonylamine) phenyl] -2-methylpropionic acid (8-11), 2- [3-methoxy-4- (methylsulfonylamino) phenyl] -2- methylpropionic (8-12), N- [2- (3,4-dimethylbenzyl) -3-pivaloxypropyl] -2- [4- (methylsulfonylamino) phenyl] -2-methylpropionamide (9-1, CHK, 520), N- [2- (3,4-dimethylbenzyl) -3-pivaloxypropyl] -2- [3-fluoro-4- (methylsulfonylamino) phenyl] -2-methylpropionamide (9-2, CHK-543), N -[2- (3,4-dimethylbenzyl) -3-pivayloxypropyl] -2- [3-methoxy-4- (methylsulfonylamino) phenyl] -2-methylpropionamide (9-3, CHK-493), N- [3- (3,4 -dimethylphenyl) propyl] -2- [4- (methylsulfonylamino) phenyl] -2-methylpropionamide (9-4, CHK-591), N- [3- (3,4-dimethylphenyl) propyl] -2- [3- fluoro-4- (methylsulfonylamino) phenyl] -2-methylpropypnamide (9-5, CHK-656), N- [3- (3,4-dimethylphenyl) propyl] -2- [3-methoxy-4- (methylsulfonylamino) phenyl] -2-methypropionamide (9-6, CHK-600), N- (4-fer-butylbenzyl) -2- [4- (methylsulfonylamino) phenyl] -2-methylpropionamide (9-7, CHK-715), N- (4-Ierc-butylbenzyl) -2- [3-fluoro-4- (meilylsulfonicamino) phenyl] -2-methylpropionamide (9-8, CHK-655), N- (4-ert-butylbenzyl) - 2- [3-methoxy-4- (methylsulfonylamino) phenyl] -2-methylpropionamide (9-9), 1- [3-fluoro-4- (methylisulfonylamino) phenyl] cyclopropanecarboxylic acid (10-5), acid 1- [ 4- (methylsulfonylamino) phenyl] cyclopropanecarboxylic acid (11-7, CHK-530), 1- [3-meioxy-4- (methylsulfonylamino) pheny1] cyclopropanecarboxylic acid (11-8), N- [2- (3,4- dimethylbenzyl) -3-pivaloxipropi l] -1- [4- (meilylsulfonylamino) phenyl] cyclopropanecarboxyamide (12-1, CHK-533), N- [2- (3,4-dimethylbenzyl) -3-pivaloxypropyl] -1- [3-fluoro-4] - (Methylsulfonylamino) phenyl] cyclopropanecarboxyamide (12-2, CHK-538), N- [2- (3,4-dimethylbenzyl) -3-pivaloxypropyl] -1- [3-methoxy-4- (methylsulfonylamino) phenyl] cyclopropanecarboxyamide (12-3, CHK-541), N- [3- (3,4-dimethylphenyl) propyI] -1- [4- (methylisuphonyl amino) phenyl] cyclopropanecarboxyamide (12-4, CHK-590), N- [3 - (3,4-dimethylphenyl) propyl] -1 - [3-fluoro-4- (methylisulfonyl) phenyl] cyclopropanecarboxamide (12-5), N- [3- (3,4-dimethylphenyl) propyl] -1- [ 3-methoxy-4- (methylsulfonylamino) phenyl] cyclopropanecarboxyamide (12-6, CHK-632), N- (4-fer-butylbenzyl) -1- [4- (methylisulfonicamino) phenyl] cyclopropanecarboxyamide (12-7, CHK- 719), N- (4-eerc-buliibenciI) -1 - [3-f luoro-4- (methylsulfonylamino) phenyl] cyclopropanecarboxyamide (12-8, CHK-659), N- (4-fer-butylbenzyl) -1- [3-methoxy-4- (methylsulfonylamino) phenyl] cyclopropanecarboxyamide (12-9, CHK-718). 4. Compound according to claim 1 represented by the following general formula (III), pharmaceutically acceptable salt or isomer thereof: wherein Ri to R is independently at least one selected from hydrogen, halogen atom, cyano group, nitro group, lower alkylamine, lower alkoxy group having from 1 to 3 carbon atoms, carboxylic acid, hydroxamic acid, ester group alkyl having 1 to 6 carbon atoms, alkylamide group having 1 to 6 carbon atoms, benzylamide group, five or six membered heterocyclic ring provided that they are not all R to R 4 simultaneously hydrogen atoms; R5 and R6 are independently at least one selected from hydrogen, hydroxyl group, amino group, linear or branched alkyl group having from 1 to 6 carbon atoms, cycloalkyl group having from 1 to 6 carbon atoms and phenyl or benzyl group optionally substituted with at least one selected from halogen atom, amine group and alkyl group having from 1 to 6 carbons, provided that R5 and R6 are not simultaneously a hydrogen atom; B is a group selected from group (1-1) to (I-6) defined in the general formula
- (I) as set forth in claim 1; the asterisk * mark indicates a chiral carbon atom. 5. The compound according to claim 4, wherein said compound is at least one selected from the group consisting of: N- (4-butylbutylbenzyl) -N'-. { 1- [3-fluoro-4- (methylsulfonylamino) phenyl] ethyl} thiourea (15-1, LJO-328), N- (4-ferc-buiibenzyl) -N'-1 - [3-chloro-4- (meilylsulfonylamino) phenyl] eyl} thiourea (15-2, CHK-992), N- (4-ferc-buti-benzyl) -N'-. { 1- [3-methoxy-4- (methylsulfonylamino) phenyl] ethylthiourea (15-3, CHK-575), N- (4-ert-buty-benzyl) -N'-. { 1- [3- (methoxycarbonyl) -4- (methylsulfonylamino) phenyl] ethyl} thiourea (15-4, YHS-187), N- (4- tert -butylbenzyl) -N'-. { 1 - [3-carboxy-4- (methylsulfonylammon) fenyl] ethyl} thiourea (15-5, YHS-209), N- (4-fer-butylbenzyl) -N'-. { (1 R) -1- [4- (Methylsulfonylamino) phenyl] ethyl} thiourea (16-5, SU-388), N- (4-ferc-butylbenzyl) -N'-. { (1S) -1- [4- (Methylsulfonylamino) phenyl] ethyl} thiourea (16-6, SU-400), N- (4-ert-butylbenzyl) -N'-. { (1 R) -1- [3-fluoro-4- (methylsulfonyllamino) phenyl] ethyl} thiourea (17-3, CJU-032), N- (4-butylbenzyl) -N'-. { (1 S) -1- [3-fIuoro-4- (methylsulfonylamino) phenyl] ethyl} thiourea (17-6, CJU-039), N - [(2R) -2-benzyl-3- (pivaloyloxy) propyl] -N, - (1R) -1- [4- (methylsulfonyl-amino) phen L] ethyl} thourea (18-1, MK-229), N - [(2S) -2-benzyl-3- (pivaloIoxi) propyl] -N'-. { (1R) -1- [4- (Methylsulfonylamino) phenyl] eyl} Iiourea (18-2, MK-202), N - [(2R) -2-benzyl-3- (pivaloyloxy) propyl] -N'-. { (1 S) -1 - [4- (Methylsulfonylamino) phenyl] ethyl} thiourea (18-3, MK-230), N - [(2S) -2-benzyl-3- (pivaloyloxypropyl] -N'-IHSIS-l- -methyl-sulfonylamino-J-phenyl-ethyl-thiourea (18-4, MK-228), N- [2 - (3,4-dimethylbenzyl) -3- (pivaloyloxy) propyl] -N'-. {- 1- [4- (methylisuphonyl-amino) phenyl] ethyl} thiourea (18-5, LJO-388), N- [2- (3,4-Dimethylbenzyl) -3- (pivaloyloxy) propyl] -N'-. {(1 R) -1- [4- (methylsulphonylamino) phenyl] ethyl} -flourea (18-) 6, SU-472), N - [(2R) -2- (3,4-dimethylbenzyl) -3- (pivaloyloxy) propyl] -N'- { (1 R) -1 - [4- (meilylsulfonylamino ) phenyl] elyl.). thiourea (18-7, SU-512), N - [(2S) -2- (3,4-dimethylobenzyl) -3- (pivaloyloxy) propyl] -N'- { (1R) -1- [4- (Methylsulfonylamino) phenyl] etiI.} Thiourea (18-8), N- [2- (4-ferc-butylbenzyl) -3- (pivaloyloxy) propyl] -N, - {. 1- [4- (Methylsulfonylamino) phenyl] ethyl} thiourea (18-9, LJO-401), N- [2- (4-Ierc-butylbenzyl) -3- (pivaloiIoxi) propyl] -N '- { 1 (R) - [4- (Methylsulfonyl amino) ethyl] ethyl.} Thiourea (18-10, MK-296), N- [2 (R) - (4-yerc-butylbenzyl) - 3- (pivaloyloxy) propyl] -N'- { 1 (R) - [4- (methylisulfonyl) phenyl] e useful.} thiourea (18-11, MK-334), N- [2 (S) - (4-ert-butylbenzyl) -3- (pivaloyloxy) propyl] -N'-. { 1 (R) - [4- (Methylsulfonylamino) phenyl] ethyl} thiourea (18-12, MK-298), N- [2- (3,4- (dimethylbenzyl) -3- (pivaloyloxy) propiI] -N'- { 1- [3-fluoro-4- (met L-sulfonylamino) phenyl] ethyl} thiourea (18-13, LJO-344), N- [2- (4-ert-butylbenzyl) -3- (pivaloyloxy) propyl] -N'-. {1 - [3-f luoro-4- (mef ilsulf onylamino) f enyl] eiii.] Iourea (18-14, LJO-366), N - [(2R) -3-phenyl-1-pivaloyloxy-2-propyl ] -N '- [(R) -a-methyl-4- (methylsulfonylamino) benzyl] thiourea (19-13, SU-692), N - [(2S) -3-phenyl-1-pivaloyloxy-2-propyl ] -N '- [(R) -a-methyl-4- (methylsuiphenylamino) benzyl] thiourea (19-14), SU-704), N- [(2R) -3-phenyl-1-pivaloyloxy-2-propyl] -N '- [(S) -a-methyl-4- (methylsulfonylamino) benzyl] thiourea (19-15 , SU-720), N - [(2S) -3-phenyl-1-pivaloyloxy-2-propyl] -N '- [(S) - - methyl - 4- (methylsulfonylamino) benzyl] thiourea (19-16, SU-710), N- (4-ert-butylbenz-N'-tl - ^ - methylmethylsulphonylamino-Sf luorofenyl] propyl} thiourea (20-12, LJO-399), N- (4-ert-butylbenzyl) ) -N, - { 1- [4- (Methylsulfonylamino) -3-fluorophenyl] -2-methylpropyl.} Thiourea (20-13, LJO-402), N- (4-yerc-butylbenzyl) -N ' - { [4- (methylsulfonyl) amino-3-fluorophenyl] (phenyl) methyl.} Thourea (20-14, LJO-403), N- (4-ene-butylbenzyl) -N'- { 1 - [4- (Methylsulfonylamino) -3-f luorofenyl] -2-phenylethyl.} Thiourea (20-15, LJO-395), N- (4-fer-butylbenzyl) -N ' - { 1-methyl-1 - [4- (methylsulfonylamino) phenyl] ethyl.}. Thourea (21-7, CHK-593), N- (4-tert-butylbenzyl) -N'- (1-methyl) -1- [3-fluoro-4- (methylsulfonylamino) phenyl] ethyl.} Thiourea (21-8, CHK-660), N- (4-ene-butylbenzyl) -N ' - { 1 -methyl-1 - [3-methoxy-4- (methylsulfonylamino) phenyl ] ethyl.} thiourea (21-9,
- CHK-629), N- (4-ferobutyIbenzyl) -N'-. { 1 - [4- (Methysulfonylamino) phenyl] cyclopropyl} thiourea (22-7, CHK-579), N- (4-fer-butylbenz-N'-fl-p-fluoro ^ -methyl-sulfonylamino-heptyl-cyclopropyl-thiourea (22-8), N- (4-ert-buty-benzyl) -N, - (1, 1- [3-methoxy-4- (methylsulfonylamino) pheny1] cyclopropyl.] Thourea (22-9, CHK-631) 6. Compound according to claim 1 represented by the following general formula (IV) , pharmaceutically acceptable salt or isomer thereof: wherein Ri to R is independently at least one selected from hydrogen, halogen atom, cyano group, nitro group, lower alkylamine, lower alkoxy group having from 1 to 3 carbon atoms, carboxylic acid, hydroxamic acid, ester group alkyl having 1 to 6 carbon atoms, alkylamide group having 1 to 6 carbon atoms, benzylamide group, five or six membered heterocyclic ring;
- R5 and R6 are independently at least one selected from hydrogen, hydroxyl group, amino group, linear or branched alkyl group having from 1 to 6 carbon atoms, cycloalkyl group having from 1 to 6 carbon atoms and phenyl or benzyl group optionally substituted with at least one selected from halogen atom, amine group and alkyl group having from 1 to 6 carbons, provided that R5 and R6 are not simultaneously a hydrogen atom; B is a group selected from the group (1-1) to (I-6) defined in the general formula (I) as set forth in claim 1; the asterisk * mark indicates a chiral carbon atom. The compound according to claim 6, wherein said compound is at least one selected from the group consisting of; N- (4-tert-butylbenzyl) -N'-. { 1 - [4- (methyl sulfonylamino) phenyl] ethyl} urea (23-1, MK-82),
- N- (4-ert-butylbenzyl) -N'-. { 1- [3-fluoro-4- (methylsulfonylamino) phenyl] ethyl} urea (23-2, MK-205). Compound according to claim 1 represented by the following general formula (V), pharmaceutically acceptable salt or isomer thereof: wherein Ri to R4 is independently at least one selected from hydrogen, halogen atom, cyano group, nitro group, lower alkylamine, lower alkoxy group having from 1 to 3 carbon atoms, carboxylic acid, hydroxamic acid, ester group alkyl having 1 to 6 carbon atoms, alkylamide group having 1 to 6 carbon atoms, benzylamide group, five or six membered heterocyclic ring; R5 and R6 are independently at least one selected from hydrogen, hydroxyl group, amino group, linear or branched alkyl group having from 1 to 6 carbon atoms, cycloalkyl group having from 1 to 6 carbon atoms and phenyl or benzyl group optionally substituted with at least one selected from halogen atom, amine group and alkyl group having from 1 to 6 carbons, provided that R5 and R6 are not simultaneously a hydrogen atom;
- B is a group selected from group (1-1) to (I-6) defined in the general formula
- (I) as set forth in claim 1; the asterisk * mark indicates a chiral carbon atom. 9. The compound of claim 8, wherein said compound is at least one selected from the group consisting of; N-. { 1 - [3-f luoro-4- (methylsulfonilamno) f enyl] etll} -3- (4-tert-butylphenyl) acetamide (24-1,
- KMJ-586), N-1- [3-fluoro-4- (methylsulfonylamino) phenyl] ethyl} -3- (4-tert-butylphenyl) propanamide (24-2, KMJ-552), N-. { 1- [3-fIuoro-4- (methylsulfonamino) phenyI] ethyl} -3- (4-tert-butylphenyl) -2-propenamide (24-3, KMJ-570), N-. { 1- [3-fluoro-4- (methylsulfonylamino) phenyl] ethyl} -3- (3,4-dimethylphenyl) propanamide (24-4, CHK-602), N-. { 1- [3-fluoro-4- (methylsulfonylamino) phenyl] eiI} -3- (3,4-dimethylphenyl) -2-propenamide (24-5, CHK-651), N-. { 1- [3-fluoro-4- (methylsulfoniamino) phenyl] ethyl} -3- (4-chlorophenyl) -propanamide (24-6,
- KMJ-534), N-. { 1- [3-fluoro-4- (methylsulfonylamino) phenyl] eyl} -3- (4-chlorophenyl) -2-propenamide (24-7, KMJ-558), N-. { 1 - [3-Fluoro-4- (methylsulfonylamino) f-ethyl] ethyl} -3- (3,4-dimethylphenyl) butanamide (24-8,
- CHK-647). 10. Compound according to any one of claims 1, 2, 4, 6 and 8, in which Ri to R are independently at least one selected from hydrogen, halogen atom, cyano group, nitro group, lower alkylamine, lower alkoxy group having from 1 to 3 carbon atoms, carboxylic acid, hydroxamic acid, alkyl ester group having from 1 to 6 carbon atoms, alkylamide group having from 1 to 6 carbon atoms, benzylamide group, five or six membered heterocyclic ring. 11. Compound according to any one of claims 1, 2, 4, 6 and 8, wherein R5 and R6 are independently at least one selected from hydrogen, hydroxyl group, amino group, linear or branched alkyl group having from 1 to 6 carbon atoms, cycloalkyl group having 1 to 6 carbon atoms and phenyl or benzyl group optionally substituted with at least one selected from halogen atom, amine group and alkyl group having from 1 to 6 carbons.
- 12. A pharmaceutical composition comprising the compound of general formula (I) as set forth in claim 1 as an active ingredient in an effective amount for a vanilloid receptor antagonist together with pharmaceutically acceptable carriers or diluents.
- 13. Pharmaceutical composition according to claim 12, wherein said pain disease is at least one selected from the group consisting of pain, acute pain, chronic pain, neuropathic pain, postoperative pain, migraine, arthralgia, neuropathies, nerve injury, neuropathy diabetic, neurodegeneration, neurotic skin disorder, stroke, urinary bladder hypersensitivity, irritable bowel syndrome, respiratory disorder such as asthma or chronic obstructive pulmonary disease, irritation of the skin, eyes or mucous membrane, fever, cough, ulcer gastroduodenal, inflammatory bowel disease caused by vanilloid receptor antagonist activity.
- 14. Pharmaceutical composition comprising the compound of any one of claims 1, 2, 4, 6 and 8 as active ingredient in an effective amount as an analgesic and anti-inflammatory together with pharmaceutically acceptable carriers or diluents.
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
KR10-2003-0044552 | 2003-07-02 |
Publications (1)
Publication Number | Publication Date |
---|---|
MXPA06000160A true MXPA06000160A (en) | 2006-12-13 |
Family
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