Remedies or preventives for diseases in association with chemokines

专利摘要:
The present invention provides a therapeutic or preventive agent for a chemokine-mediated disease such as MIP-1 alpha or / and MCP-1. That is, the present invention provides a pharmaceutical composition comprising a cyclic amine derivative represented by the following formula (I), a pharmacologically acceptable acid adduct thereof or a pharmaceutically acceptable C 1 -C 6 alkyl adduct thereof as an active ingredient, such as chronic joint rheumatism, A remedy or preventive medicine for a disease involving chemokines.
公开号:KR20020015322A
申请号:KR1020017014579
申请日:2000-05-18
公开日:2002-02-27
发明作者:시오따다쯔끼；미야기후미노리；가미무라다까시；오따도모히로；다까노야스히로；호리우찌히데끼
申请人:야스이 쇼사꾸；데이진 가부시키가이샤；
IPC主号:

专利说明:

BACKGROUND OF THE INVENTION 1. Field of the Invention < RTI ID = 0.0 > [0001] <
[2] A chemokine is a generic term for a group of inflammatory / immunomodulating polypeptides having a molecular weight of 6-15 kD and produced on the middle of the salt by various cells such as macrophages, monocytes, eosinophils, neutrophils, fibroblasts, vascular endothelial cells, smooth muscle cells and mast cells. The chemokines are classified into two large subgroups of CXC chemokines (or alpha chemokines) and CC chemokines (or beta chemokines), with the four being common in the positions of conserved cysteine residues and differences in the chromosomal location of the gene encoding the chemokine. The first two cysteines of the CXC chemokine are separated by one amino acid, but the CC cocaine is adjacent to the cysteine. For example, IL-8 (abbreviation for interleukin-8) and the like are CXC chemokines, while CC chemokines include MIP-1α / β (abbreviation for macrophage inflammatory protein-1α / β), MCP-1 (abbreviation for monocyte chemoattractant protein- ) And RANTES (regulated upon activation normal T-cell expressed and secreted).
[3] There are also chemokines that do not belong to any chemokine subgroup. These include lymphotactin, which has only two cysteines but is classified as C chemokine, or CX3C chemokine, in which the first two cysteines are separated by three amino acids, And fractalkine. Since these chemokines promote cell migration and enhance expression of cell adhesion molecules such as integrins and also have cell adhesion enhancing action, they are thought to be proteins closely related to adhesion and infiltration of leukocyte, etc., to lesion sites such as inflammatory tissues . Chemokine Facts Book, Academic Press, 1997; Horuk, R., Chemoattractant Ligand and Their Receptors, CRC Press, 1996; Ward, G. W et al., Biochem. J., 1998, 333, 457; Luster, A. D., New Engl. J. Med., 1998, 338, 436; Bagglioni, M, Nature, 1998, 392, 565; Rollins, B. J., Blood, 1997, 90, 909; Alam, R. J. Allergy Clin. Immunol., 1997,99, 273; Hancock, W. W., Am. J. Pathol., 1996, 148, 681, Taub. D. D., Cyotkine & Growth Factor Rev., 1996, 7, 335; Strieter, R.M. J. Immunol., 1996, 156, 3583; Furie, M.B. Am. J. Pathol., 1995, 146, 1287; Schall, T.J. See Current Opinion in Immunology, 1994, 6, 865; Edginton, S. M., Biotechnology, 1993, 11, 676, et al.
[4] For example, MIP-1 alpha induces a transient increase in the intracellular calcium ion concentration and is induced by T lymphocytes or cell migration of B lymphocytes (e.g. Taub, DD et al., Science, 1993, 260, 355; Shall, TJ et al., J. Exp. Med. (See, for example, Rot, A. et al., J. Exp. Med., 1992, 176, 1489), cell migration of NK cells (see, for example, Magazachi, AA et al. , J. Immunol., 1994, 153, 4969), the expression of integrins (see, for example, Vaddi, K. et al., J. Immunol., 1994, 153, 4721) and osteoclast differentiation (see, for example, Kukita, T. et al. Et al., Lab. Invest., 1997, 76, 399). MIP-1 alpha also increases IgE and IgG4 production of B cells (see, for example, Kimata, H. et al., J. Exp. Med., 1996, 183, 2397) and inhibits the proliferation of hematopoietic stem cells (see, Keller, JR et al., Blood, 1994, 84, 2175; Eaves, CJ et al., Proc. Natl Acad Sci USA, 1993, 90, 12015 ; Bodine, DM et al., Blood, 1991, 78, 914; Broxmeyer, HE et al., Blood, 1990, 76, 1110, etc.).
[5] The relationship between the action of MIP-1α in vivo or the pathogenesis of the disease is a fever in rabbits (see, for example, Davatelis, G. et al., Science, 1989, 243, 1066) 1α has been reported to cause an inflammatory reaction such as neutrophil, mononuclear infiltration (see, for example, Alam, R. et al., J. Immunol., 1994, 152, 1298).
[6] Neutralizing antibodies against MIP-1 alpha can also be used for the treatment of granulomas (see, for example, Lukacs, NW et al., J. Exp. Med., 1993, 177, 1551), asthma (e.g. Lukacs, NW et al., Eur. (See, for example, Karpus, WJ et al., J. Immunol., 1995, 155, 5003; Karpus et al., J. Immunol., 1995, 25, 245; Lukacs, NW et al., J. Immunol., 1997, 158, 4398) , Smith et al., J. Immunol., 1994, 153, 4704; Smith, RE, Biol. Signals, 1996; WJ et al., J. Leukoc. Biol., 1997, 62, 681) (See, for example, Shanley, TP et al., J. Immunol., 1995, 154, 4793; Standiford, TJ et al., J. Immunol., 1995, 155, 1515), and chronic joint rheumatism (See, for example, Kasama, T. et al., J. Clin. Invest., 1995, 95, 2868). In MIP-1 alpha gene-deficient mice, Viral infection Myocarditis and herpes interstitial keratitis are inhibited. This has been reported (e.g., Cook, D.N. et al., Science, 1995, 269, 1583; see Tumpey, T.M. et al., J.Virology, 1998, 72, 3705).
[7] Also, chronic inflammatory diseases such as chronic pulmonary inflammatory diseases (see, for example, Standiford, TJ et al., J. Immunol., 1993, 151, 2852), hypersensitive pneumonia (such as Denis, M., Am. J. Respir. Crit. Care Med., 1995 (See, for example, Koch, AE et al., J. Clin. Invest., 1994, 93, 921), infectious meningitis (see for example Lahrtz, F. et al., J. Neuroimmunol., 1998 , 85 and 33) and chronic inflammation of muscles (see, for example, Admas, EM et al., Proc. Assoc. Am. Physicians, 1997, 109, 275). These studies indicate that MIP-1α is deeply involved in the localization of various leukocyte subtypes and thus in the development, progression and maintenance of inflammatory diseases.
[8] MIP-1 (alias MCAF (abbreviation for macrophage chemotactic and activating factor) or JE) is a CC chemokine produced by monocyte / macrophage, smooth muscle cells, fibroblasts and vascular endothelial cells, and monocytes Yoshimura, T. et al., J. Immunol., 1989, 142, 1956, Rollins, BJ et al., Biochemistry, 1988, 27, 4162; Matsushima, K. et al., J. Exp. Med., 1989, 169, Jiang, Y. et al., J. Immunol., 1992, 148, 2423, Vaddi, J., et al., Proc Natl Acad Sci USA, 1988, 85, 3738, Rollins, BJ et al., Blood, 1991, (See, for example, K. et al., J. Immunol., 1994, 153, 4721, etc.), memory T lymphocytes (see for example Carr. MW et al., Proc. Natl. Acad. Sci. USA, 1994, 91, Natural killer cells (NK cells) (see, for example, Loetscher, P. et al., J. Immunol., 1996, 156, 322; Allavena, P , Et al., J. Immunol., 1994, 24, 3233), etc., Apparatus functions. In addition, MCP-1 has an action as a histamine releasing factor from a basophil (Alam R. et al., J. Clin. Invest., 1992, 89, 723; Bischoff, SC et al., J. Exp. Med., 1992 , 175, 1271; Kuna, P. et al., J. Exp Med., 1992, 175, 489).
[9] In addition, fibromyalgia (eg Hayes, IM et al., Arterioscler. Thromb. Vasc. Biol., 1998), in which accumulation of monocytes / macrophages and / or T cells is thought to be deeply involved in the onset, Yla-Herttuala, S. et al., Proc. Natl. Acad. Sci., USA, 1991, 88, 5252, Nelken, N.A., 18, 397; Takeya, M. et al., Hum Pathol., 1993, , J. Clin. Invest., 1991, 88, 1121), chronic joint rheumatism (e.g., Koch, AE et al., J. Clin. Invest., 1992, 90, 772; Akahoshi, T. et al., Arthritis Rheum. 1993, 36, 762; Robison, E. et al., Clin. Exp. Immunol., 101, 398), nephritis (e.g. Noris, M. et al., Lab. Invest., 1995, 73, 804; Kidney Int., 1996, 49, 761; Gesualdo, L. et al., Kidney Int., 1997, 51, 155), nephropathy (for example, Saitoh, A. et al., J. Clin. Lab. (See, for example, Sugiyama, Y. et al., Internal Medicine, 1997, 36, pp. 12, 1; Yokoyama, H. et al., J. Leukoc. Biol., 1998, 63, 493), pulmonary edema, pulmonary sarcoidosis 856), asthma (e.g., Karina, M. et al., J. Invest. Allergol. Clin. Immunol., 1997, 7, 254; Stephene, TH, Am. J. Respir. Crit Care Med. (See, for example, McManus, C. et al., J. Neuroimmunol., 1998, 86, 20, 1377; Sousa, AR et al., Am. J. Respir. Cell Mol. Biol., 1994, ), Psoriasis (e.g., Gillitzer, R. et al., J. Invest. (See, for example, Grimm, MC et al., J. Leukoc. Biol., 1996, 59, 804; Reinecker, HC et al., Gastroenterology, 1995, 106, 40) Endometriosis (see, for example, Jolicoeur, C. et al., Am. J. Pathol., 1998, 152, 125), intraperitoneal adhesion (see, for example, Seino, Y. et al., Cytokine, 1995, (See, for example, Zeyneloglu, HB et al., Human Reproduction, 1998, 13, 1194), congestive heart failure (see, for example, Aurust, P., Circulation, 1998, 97, 1136), chronic liver disease (e.g. (See, for example, Lahrtz, F. et al., Eur. J. Immunol., 1997, 27, 2484), Kawasaki disease (see, for example, Wong A significant expression of MCP-1 has been reported in sepsis (see, for example, Salkowski, CA et al., Infect. Immun., 1998, 66, 3569), see J. Rheumatol., 1997, 24, .
[10] In addition, the inhibitory effect or therapeutic effect of the anti-MCP-1 antibody may be evaluated in chronic joint rheumatism (for example, Schimmer, RC et al., J. Immunol., 1998, 160, 1466; Schrier, DJ, J. Leukoc. (See, for example, Karpus, WJ, J. Leukoc. Biol., 1997, 62, 681), nephritis (see, for example, Ogata, H. et al., J. Pathol., 1997, (See, for example, Gonzalo, J.-A. et al., Lloyd, CM et al., J. Exp. Med., 1997, 185, 1371; Wada, T. et al., FASEB J., (See, for example, Guzman, LA et al., Circulation, 1993, 88 (suppl.), J. Exp. Med., 1998, 188, 157; Lukacs, NW, J. Immunol., 1997, 158, 4398). ), I-371), delayed type hypersensitivity (see, for example, Rand, ML et al., Am. J. Pathol., 1996, 148, 855), pulmonary hypertension (for example, Kimura, H, et al., Lab. , 78, 571) and intraperitoneal adhesion (see, for example, Zeyneloglu, HB et al., Am. J. Obstet. Gynecol., 1998, 179, 438).
[11] MCP-1 (9-76), a peptidic antagonist of MCP-1, has also been reported to inhibit arthritis in mouse models (see, for example, Gong, J.-H., J. Exp. Med., 1997, 186, 131). Similarly, studies of MCP-1 gene-deficient mice have shown that in vivo MCP-1 is required for crossover (see, for example, Lu, B. et al., J. Exp. Med., 1998, 187, 601; Gu, L. et al., Moll. Cell, 1998, 2, 275).
[12] These data suggest that chemokines such as MIP-1α and MCP-1 can activate monocytes, lymphocytes, and the like in their lesions to activate their cells, thereby enabling diseases such as monocytes and lymphocytes to be deeply related to lesion progression, For example, there is provided a method for treating a condition selected from the group consisting of biliary arteriosclerosis, chronic joint rheumatism, psoriasis, asthma, ulcerative colitis, nephritis (nephritis), multiple sclerosis, rheumatoid arthritis, myocarditis, hepatitis, pancreatitis, sarcoidosis, (Rovin, BH et al., Am. J. Kindeny. Dis., 1998, 31 (1987)), which is strongly implicated in the development, progression and maintenance of viral meningitis, cerebral infarction, neuropathy, Kawasaki disease and sepsis Ransohoff, RM et al., Trends Neuroscience, 1998, 7, 281; Conti, P. et al., Allergy and Asthma Proc., 1998, 19, 121. Lloyd C. et al., Curr. Opin. Nephrol. , 1998, 21, 154; MacDermott, RP et al., Inflammatory Bowel Diseases, 1998, 4, 54). Therefore, agents that inhibit the action of chemokines on target cells can be expected to be useful as therapeutic and / or preventive agents for these diseases.
[13] On the other hand, it has become clear that the gene encoding a chemokine-specific receptor has been cloned and is a G protein conjugate type 7 transmembrane receptor present on various leukocytes. To date, at least five CXC chemokine receptors (CXCR1-CXCR5) and eight CC chemokine receptors (CCR1-CCR8) have been identified. For example, IL-8 is a ligand of CXCR1 and CXCR2, MIP-1 alpha is a ligand of CCR1 and CCR5, and MCP-I is a ligand of CCR2A and CCR2B (see, for example, Holmes, WE et al., Science 1991, 253, Murphy, PM et al., Science, 253, 1280-1283; Neote, K. et al., Cell, 1993, 72, 415-425; Charo, IF et al., Proc. Natl. Biochem. Biophys. Res. Commun., 1994, 202, 1156-1162; Combadier, C. et al., The Journal of Biological Chemistry, 1995, 270, 16491-16494; Power, CA et al. , Murphy, PM et al., Annual Review of Immunology, 1994, 12, 592-633, J. Biol. Chem., 1995, 270, 19495-19500; Samson, M. et al., Biochemistry, 1996, 35, 3362-3367 ).
[14] In addition, suppression of lung inflammation and granulation formation in CCR1 gene-deficient mice (see, for example, Gao, J.-L. et al., J. Exp. Med., 1997, 185, 1959; Gerard, (See, for example, Boring, L., et al., Nature, 1998, 394, 894; Kuziel, WA), in which the accumulation of macrophages and the formation of atherosclerotic lesions in CCR2 gene- 1997, 186, 1757; Boring, L et al., J. Clin. Invest., 1987, 1997, 100, 2552). Thus, compounds that inhibit the binding of chemokines such as MIP-1 alpha and / or MCP-1 to these receptors, i.e., chemokine receptor antagonists, inhibit the action of chemokines such as MIP-1 alpha and / or MCP- However, a pharmaceutical agent having such an action is not known.
[15] Recently, various cyclic amine derivatives such as piperidine and piperazine have been reported to have chemokine receptor antagonism (see, for example, WO9724325; Hesselgesser, J. et al., J. Biol. Chem., 1998, 273, 15687 ; Howard, OMZ et al., J. Med. Chem., 1998, 41, 2184, WO9744329; WO9802151; WO9825605; WO9825617; WO9825604; WO9831364; WO9856771; WO9909984; WO9904794; WO9917773; WO9937617; WO9937619; WO9737651; WO9938514; WO200014086 ; WO200014089; EP903349; JP9-249566, JP9-25572; JP11-71350, etc.). However, these compounds are different from the compounds used in the present invention.
[1] The present invention relates to a cyclic amine derivative. More specifically, the present invention relates to a cyclic amine derivative, and more particularly, to a cyclic amine derivative which is capable of inhibiting the infiltration of a blood leukocyte component such as a single globe or lymphocyte into a tissue, Neuropathy, acute coronary syndrome, rheumatoid arthritis, psoriasis, asthma, ulcerative colitis, nephritis (nephritis), multiple sclerosis, rheumatoid arthritis, cardiomyopathy, hepatitis, pancreatitis, sarcoidosis, Crohn's disease, endometriosis, congestive heart failure, Kawasaki disease, sepsis, allergic rhinitis, allergic dermatitis, and the like. The present invention also relates to a chemokine receptor antagonist which can be expected to be effective as a therapeutic agent and /
[34] FIG. 1 is a graph showing the effect of Compound No. 1583 on arthritis when administered orally for 12 weeks.
[35] Fig. 2 shows the effect of Compound No. 1583 on the synovial membrane proliferation. Fig.
[36] Fig. 3 is a graph showing the effect of Compound No. 1583 on the destruction of articular cartilage. Fig.
[37] 4 is a graph showing the effect of Compound No. 1583 on bone destruction of cartilage bone.
[38] Fig. 5 is a graph showing the effect of Compound No. 1245 on the swelling of the plantar fungus when administered orally for 3 weeks. Fig.
[39] 6 is a graph showing the effect of compound No. 1583 on inhibition of urinary protein.
[40] 7 is a graph showing the effect of Compound No. 1245 on inhibition of urinary protein.
[41] 8 is a graph showing the effect of Compound No. 1583 in a chronic relapsing experimental allergic encephalomyelitis animal model.
[42] 9 is a graph showing the effect of Compound No. 1245 in a chronic relapsing experimental allergic encephalomyelitis animal model.
[43] BEST MODE FOR CARRYING OUT THE INVENTION
[44] In the formula I R ¹ is a phenyl group, C ₃ -C ₈ cycloalkyl group or a hetero atom represents an aromatic heterocyclic ring having 1-3 oxygen atoms, sulfur atoms and / or nitrogen atoms, a phenyl group or an aromatic heterocyclic in said R ¹ ring group and a benzene ring or a hetero atom condensed aromatic heterocyclic group having 1-3 oxygen atoms, sulfur atoms and / or nitrogen atom and may form a condensed ring, a phenyl group in the R ^1, C ₃ -C ₈ cycloalkyl alkyl group, an aromatic heterocyclic group or condensed ring may be any number of a halogen atom, a hydroxy group of a cyano group, a nitro group, a carboxyl group, a carbamoyl group, C ₁ -C ₆ alkyl, C ₃ -C ₈ cycloalkyl, C ₂ -C ₆ alkenyl group, C ₁ -C ₆ alkoxy group, C ₁ -C ₆ alkylthio, C ₃ -C ₅ alkylene group, C ₂ -C ₄ alkylene group, a C ₁ -C ₃ alkylenedioxy group, a phenyl group, A phenoxy group, a phenylthio group, a benzyl group, a benzyloxy group, a benzoylamino group, C ₂ -C ₇ alkanoyl group, C ₂ -C ₇ alkoxycarbonyl group, C ₂ -C ₇ alkanoyloxy group, C ₂ -C ₇ alkanoylamino group, C ₂ -C ₇ N- alkyl carbamoyl, C ₄ N- -C ₉ cycloalkyl, carbamoyl, C ₁ -C ₆ alkylsulfonyl, C ₃ -C ₈ (alkoxycarbonyl) methyl group, N- phenyl-carbamoyl group, a piperidino group, a morpholino group, a 1 - a divalent group represented by the formula -NH (C = O) O-, a divalent group represented by the formula: -NH (C = S) O-, an amino group, a mono (C ₁ -C ₆ alkyl ) Amino group or a di (C ₁ -C ₆ alkyl) amino group.
[45] The "C ₃ -C ₈ cycloalkyl group" for R ¹ means a cyclic alkyl group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl group and the like, and preferable specific examples thereof include cyclopropyl group, A cyclopentyl group, and a cyclohexyl group.
[46] The "aromatic heterocyclic group having 1 to 3 oxygen atoms, a sulfur atom and / or a nitrogen atom as a hetero atom" for R ¹ includes, for example, thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, Refers to an aromatic heterocyclic group such as a thiazolyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, triazinyl, triazolyl, oxadiazolyl (plazanyl), thiadiazolyl group and the like, Furyl, pyrrolyl, isoxazolyl and pyridyl groups.
[47] The "condensed ring" in R ¹ means that the phenyl group or the aromatic heterocyclic ring group is formed by condensing at any arbitrary position with a benzene ring or an aromatic heterocyclic ring group having 1 to 3 oxygen atoms, a sulfur atom and / or a nitrogen atom as a hetero atom 2-cyclic aromatic heterocyclic group, and preferable specific examples thereof include naphthyl, indolyl, benzofuranyl, benzothienyl, quinolyl, benzoimidazolyl, benzoxazolyl, benzotriazolyl, benzoxadiazolyl Naphthyl group, and the like.
[48] Among them, R ¹ is particularly preferably a phenyl group, an isoxazolyl group or an indolyl group.
[49] The "halogen atom" as a substituent of the phenyl group, C ₃ -C ₈ cycloalkyl group, aromatic heterocyclic group or condensed ring in R ¹ means a fluorine atom, a chlorine atom, a bromine atom, an iodine atom and the like, An atom, a chlorine atom, and a bromine atom.
[50] The "C ₁ -C ₆ alkyl group" as the substituent of R ¹ is, for example, methyl, ethyl, n-propyl, n-butyl, Means a C ₁ -C ₆ straight or branched alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, neopentyl, tert-pentyl, isohexyl, Examples include methyl, ethyl, propyl and isopropyl groups.
[51] "C ₃ -C ₈ cycloalkyl group" as the substituent of R ¹ is as defined in the "C ₃ -C ₈ cycloalkyl group" in the above R ¹ and, there may be mentioned the same groups as preferable specific examples.
[52] The "C ₂ -C ₆ alkenyl group" as the substituent for R ¹ includes, for example, vinyl, allyl, 1-propenyl, 2-butenyl, 3-butenyl, -hexenyl, there may be mentioned 4-methyl-3 means a C ₂ -C ₆ straight-chain or branched alkenyl group such as a pentenyl group, and the preferred specific examples include a vinyl group and 2-methyl-1-propenyl group, etc. .
[53] The "C ₁ -C ₆ alkoxy group" as a substituent of R ^{1 means} a group consisting of the above C ₁ -C ₆ alkyl group and an oxy group, and specific examples thereof include a methoxy group and an ethoxy group.
[54] The "C ₁ -C ₆ alkylthio group" as the substituent of R ^{1 means} a group consisting of the above-mentioned C ₁ -C ₆ alkyl group and a thio group, and specific examples thereof include a methylthio group and an ethylthio group.
[55] "C ₃ -C ₅ alkylene groups" as the substituent of R ¹ is, for example trimethylene, tetramethylene, pentamethylene, a divalent C ₃ -C _5, such as 1-methyl-trimethylene group means an alkylene group, and the preferred embodiments Examples include a trimethylene group and a tetramethylene group.
[56] The "C ₂ -C ₄ alkyleneoxy group" as the substituent of R ¹ includes, for example, ethyleneoxy (-CH ₂ CH ₂ O-), trimethyleneoxy (-CH ₂ CH ₂ CH ₂ O-), tetramethyleneoxy Means a group consisting of a divalent C ₂ -C ₄ alkylene group such as ₂ CH ₂ CH ₂ CH ₂ O-, 1,1-dimethylethyleneoxy (-CH ₂ C (CH ₃ ) ₂ O-) group and the like and an oxy group And specific preferred examples thereof include an ethyleneoxy group, a trimethyleneoxy group and the like.
[57] "C ₁ -C ₃ alkylenedioxy group" is, for example methylenedioxy (-OCH ₂ O-) as the substituent of R ^1, ethylenedioxy (-OCH ₂ CH ₂ O-), trimethylene dioxy (-OCH ₂ Means a group consisting of a C ₁ -C ₃ divalent alkylene group and two oxy groups such as CH ₂ CH ₂ O-, propylene dioxy (-OCH ₂ CH (CH ₃ ) O-) group and the like, Methylenedioxy group, ethylenedioxy group and the like.
[58] The "C ₂ -C ₇ alkanoyl group" as the substituent of R ¹ is, for example, acetyl, propanoyl, butanoyl, pentanoyl, hexanoyl, heptanoyl, isobutyryl, 3-methylbutanoyl, Means a C ₂ -C ₇ linear or branched alkanoyl group such as pyrrolyl, pivaloyl, 4-methylpentanoyl, 3,3-dimethylbutanoyl, 5-methylhexanoyl group and the like, .
[59] The "C ₂ -C ₇ alkoxycarbonyl group" as the substituent of R ¹ means a group consisting of the above C ₁ -C ₆ alkoxy group and a carbonyl group, and specific examples thereof include a methoxycarbonyl group and an ethoxycarbonyl group.
[60] The "C ₂ -C ₇ alkanoyloxy group" as the substituent of R ^{1 means} a group consisting of the C ₂ -C ₇ alkanoyl group and the oxy group, and specific examples thereof include an acetyloxy group and the like.
[61] The "C ₂ -C ₇ alkanoylamino group" as the substituent of R ¹ means a group consisting of the C ₂ -C ₇ alkanoyl group and an amino group, and specific examples thereof include an acetylamino group and the like.
[62] The "C ₂ -C ₇ alkylcarbamoyl group" as the substituent of R ¹ means a group consisting of the above C ₁ -C ₆ alkyl group and a carbamoyl group, and specific examples thereof include an N-methylcarbamoyl group, Diary, and the like.
[63] The "C ₄ -C ₉ N-cycloalkylcarbamoyl group" as the substituent of R ^{1 means} a group consisting of the C ₃ -C ₈ cycloalkyl group and the carbamoyl group, and specific examples thereof include N-cyclopentylcarbamoyl group, N-cyclohexylcarbamoyl group and the like.
[64] The "C ₁ -C ₆ alkylsulfonyl group" as the substituent of R ^{1 means} a group comprising the above C ₁ -C ₆ alkyl group and a sulfonyl group, and specific examples thereof include a methylsulfonyl group and the like.
[65] The "C ₃ -C ₈ (alkoxycarbonyl) methyl group" as the substituent of R ¹ means a group consisting of the C ₂ -C ₇ alkoxycarbonyl group and the methyl group, and specific examples thereof include (methoxycarbonyl) methyl group, Carbonyl) methyl group and the like.
[66] The "mono (C ₁ -C ₆ alkyl) amino group" as the substituent of R ¹ means an amino group substituted with the above C ₁ -C ₆ alkyl group, and specific examples thereof include a methylamino group and an ethylamino group.
[67] The "di (C ₁ -C ₆ alkyl) amino group" as a substituent of R ¹ means an amino group substituted by the same or different two C ₁ -C ₆ alkyl groups, and specific examples thereof include dimethylamino group, diethylamino group, N -Ethyl-N-methylamino group and the like.
[68] Among the above, a phenyl group in R ^1, C ₃ -C ₈ cycloalkyl group, a substituent of the aromatic heterocyclic group or condensed ring a halogen atom, a hydroxy group, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl group, C ₁ - C ₆ alkoxy group, C ₁ -C ₆ alkylthio, C ₂ -C ₄ alkylene group, a methylene-dioxide group, N- phenyl-carbamoyl group, amino group, mono (C ₁ -C ₆ alkyl) amino groups and di (C for ₁ -C ₆ alkyl) amino groups may be mentioned as a particularly preferred embodiment.
[69] The substituent of the phenyl group, the C ₃ -C ₈ cycloalkyl group, the aromatic heterocyclic group or the condensed ring at R ¹ may be any of a halogen atom, a hydroxyl group, an amino group, a trifluoromethyl group, a C ₁ -C ₆ alkyl group or C Which may be further substituted by _{1 to 6} alkoxy groups. Here, the halogen atom, the C ₁ -C ₆ alkyl group and the C ₁ -C ₆ alkoxy group are the same as defined with respect to the substituent of the phenyl group, C ₃ -C ₈ cycloalkyl group, aromatic heterocyclic group or condensed ring in R ¹ above And the same group can be given as a preferable example.
[70] In formula (I), R ² represents a hydrogen atom, a C ₁ -C ₆ alkyl group, a C ₂ -C ₇ alkoxycarbonyl group, a hydroxy group or a phenyl group, and the C ₁ -C ₆ alkyl group or phenyl group in R ² may be any number of halogen atoms , A hydroxy group, a C ₁ -C ₆ alkyl group or a C ₁ -C ₆ alkoxy group. However, when j = 0, R ² is not a hydroxy group.
[71] In R ² C ₁ -C ₆ alkyl group or a C ₂ -C ₇ alkoxycarbonyl group is a phenyl group in R ^1, C ₃ -C ₈ cycloalkyl group, the same as that defined for the respective substituents of the aromatic heterocyclic group or a condensed ring, and , Each of which is the same as the preferred embodiment.
[72] C ₁ -C ₆ alkyl group or a halogen atom as the substituent of the phenyl group at R ^2, C ₁ -C ₆ alkyl group and C ₁ -C ₆ alkoxy group on the phenyl group in the R ^1, C ₃ -C ₈ cycloalkyl group, aromatic heterocyclic And the substituent of the condensed ring, and the same examples can be given as preferable specific examples.
[73] Among them, it is particularly preferable that R ² represents a hydrogen atom.
[74] In formula (I), j represents an integer of 0-2. It is particularly preferable that j is 0.
[75] In the formula (I), k represents an integer of 0-2, and m represents an integer of 2-4. Substituted pyrrolidine in which k is 0 and m is 3, 3-substituted pyrrolidine in which k is 1 and m is 2, 3-substituted piperidine in which k is 1 and m is 3, Particularly preferred are 4-substituted piperidines in which k is 2 and m is 2, or 3-substituted hexahydroazepines in which k is 1 and m is 4.
[76] In the formula (I), n represents 0 or 1.
[77] In particular, 4- (amidomethyl) piperidine is particularly preferred when k is 1, m is 2 and n is 0, and 3-amidopyrrolidine and k is 2, m is 2 and n is 1 have.
[78] In the above formula (I), R ³ is a hydrogen atom or a substituted or unsubstituted phenyl group, which may be substituted with the same or different arbitrary number of halogen atoms, a hydroxy group, a C ₁ -C ₆ alkyl group or a C ₁ -C ₆ alkoxy group Or an optionally substituted C ₁ -C ₆ alkyl group.
[79] C ₁ -C ₆ alkyl group in R ³ are the same as defined with regard to a phenyl group, C ₃ -C ₈ cycloalkyl group, the aromatic substituent of the heterocyclic group or the condensed ring in the above R ^1, and the preferred specific examples, methyl, ethyl And a propyl group.
[80] R a C ₁ -C ₆ group as the substituent of the alkyl group in the ³ halogen atoms as the substituent, C ₁ -C ₆ alkyl group and C ₁ -C ₆ alkoxy group, each phenyl group in the R ^1, C ₃ -C ₈ cycloalkyl group, Aromatic heterocyclic group or condensed ring, and the same examples are given as preferred examples.
[81] Among them, R ³ is particularly preferably a hydrogen atom.
[82] In the formula I R ⁴ and R ⁵ are the same or different a hydrogen atom, a hydroxy group, a phenyl group or a C ₁ -C ₆ alkyl group, R ⁴ and C ₁ -C ₆ alkyl group in R ⁵ is a halogen atom of any number of Import, a hydroxy group, a cyano group, a nitro group, a carboxyl group, a carbamoyl group, a mercapto group, a guanidino group, a C ₃ -C ₈ cycloalkyl, C ₁ -C ₆ alkoxy group, C ₁ -C ₆ alkyl group, ( any number of halogen atoms, hydroxy groups, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy or benzyloxy with a phenyl group that may be substituted), a phenoxy group, a benzyloxy group, a benzyloxycarbonyl group, C ₂ -C ₇ alkanoyl group, C ₂ -C ₇ alkoxycarbonyl group, C ₂ -C ₇ alkanoyloxy group, C ₂ -C ₇ alkanoylamino group, C ₂ -C ₇ N- alkyl carbamoyl, C ₁ -C ₆ alkylsulfonyl An amino group, a mono (C ₁ -C ₆ alkyl) amino group, a di (C ₁ -C ₆ alkyl) amino group or (an oxygen atom, a sulfur atom and / An aromatic heterocyclic group having 1 to 3 nitrogen atoms or a condensed ring formed by condensation with the benzene ring), or R ⁴ and R ⁵ may be all combined to form a 3-6 membered cyclic hydrocarbon .
[83] The C ₁ -C ₆ alkyl group in R ⁴ and R ⁵ is the same as defined with respect to the substituent of the phenyl group, C ₃ -C ₈ cycloalkyl group, aromatic heterocyclic group or condensed ring in R ¹ , Specific examples include:
[84] R ⁴ and R a halogen atom as the substituent of the C ₁ -C ₆ alkyl group at the ^5, C ₁ -C ₆ alkoxy group, C ₁ -C ₆ alkyl thio, C ₂ -C ₇ alkanoyl group, C ₂ -C ₇ alkoxycarbonyl group, C ₂ -C ₇ alkanoyloxy group, C ₂ -C ₇ alkanoylamino group, C ₂ -C ₇ N- alkyl carbamoyl, C ₁ -C ₆ alkylsulfonyl group, a mono (C ₁ -C ₆ Alkyl) amino group and di (C ₁ -C ₆ alkyl) amino group are the same as those defined for the substituent of the phenyl group, C ₃ -C ₈ cycloalkyl group, aromatic heterocyclic group or condensed ring in R ¹ , Can be mentioned as preferred specific examples.
[85] A C ₃ -C ₈ cycloalkyl group as a substituent of the C ₁ -C ₆ alkyl group in R ⁴ and R ⁵ and an aromatic heterocyclic group having an oxygen atom, a sulfur atom and / or a nitrogen atom as a hetero atom in the number of ¹ to ³ , And the same example can be given as a preferable example.
[86] R ⁴ and halogen atom as a C ₁ -C ₆ alkyl group as a substituent a phenyl substituent in R ^5, C ₁ -C ₆ alkyl group and C ₁ -C ₆ alkoxy group is a phenyl group in the R ^1, C ₃ -C ₈ cycloalkyl group , An aromatic heterocyclic group or a condensed ring, and each of the same examples is a preferred embodiment.
[87] Preferred examples of the "3- to 6-membered cyclic hydrocarbon comprising R ⁴ , R ⁵ and adjacent carbon atoms" include cyclopropane, cyclobutane, cyclopentane and cyclohexane.
[88] Among them, a hydrogen atom and a C ₁ -C ₆ alkyl group are particularly preferable examples of R ⁴ and R ⁵ .
[89] In the formula (I), p represents 0 or 1, and q represents 0 or 1. It is particularly preferable that p and q are both 0.
[90] In the formula (I), G is a group selected from the group consisting of -CO-, -SO ₂ -, -CO-O-, -NR ⁷ -CO-, -CO-NR ⁷ -, -NH- , -NR ⁷ -SO ₂ -, -SO ₂ -NR ⁷ -, -NH-CO-O- or -O-CO-NH-. Here, R ⁷ represents a hydrogen atom or a C ₁ -C ₆ alkyl group, or R ⁷ may be combined with R ⁵ to form a C ₂ -C ₅ alkylene group.
[91] Here, -CO- represents a carbonyl group, -SO ₂ - represents a sulfonyl group, and -CS- represents a thiocarbonyl group, respectively. Particularly preferred examples of G include groups represented by -NR ⁷ -CO- and -NH-CO-NH-.
[92] The C ₁ -C ₆ alkyl group at R ⁷ is the same as defined with respect to the substituent of the phenyl group, C ₃ -C ₈ cycloalkyl group, aromatic heterocyclic group or condensed ring at R ¹ , .
[93] The "C ₂ -C ₅ alkylene group" composed of R ⁵ and R ⁷ is, for example, a linear or branched C ₂ -C ₅ such as methylene, ethylene, propylene, trimethylene, tetramethylene, 1-methyltrimethylene, And specific examples thereof include ethylene, trimethylene, and tetramethylene groups.
[94] Among them, as R ^{7, a} hydrogen atom is particularly preferable.
[95] In the formula (I), R ⁶ represents a phenyl group, a C ₃ -C ₈ cycloalkyl group, a C ₃ -C ₆ cycloalkenyl group, a benzyl group or an aromatic heterocyclic ring having 1 to 3 oxygen atoms, a sulfur atom and / or a nitrogen atom as a hetero atom And the phenyl, benzyl or aromatic heterocyclic group in R ⁶ is condensed with an aromatic heterocyclic group having 1 to 3 oxygen atoms, a sulfur atom and / or a nitrogen atom as a benzene ring or a hetero atom to form a condensed ring and, also a phenyl group in the R ^6, C ₃ -C ₈ cycloalkyl, C ₃ -C ₆ cycloalkenyl group, a benzyl group, an aromatic heterocyclic group, or condensed ring is any number of halogen atoms, hydroxy, mercapto A C ₁ -C ₆ alkyl group, a C ₃ -C ₈ cycloalkyl group, a C ₂ -C ₆ alkenyl group, a C ₁ -C ₆ alkenyl group, a cyano group, a nitro group, a thiocyanato group, a carboxyl group, a carbamoyl group, a trifluoromethyl group, C ₆ alkoxy group, C ₃ -C ₈ cycloalkyloxy , C ₁ -C ₆ alkylthio import, C ₁ -C ₃ alkylenedioxy group, a phenyl group, a phenoxy group, a phenyl group, a benzyl group, a benzoyl group, phenyl sulfinyl group, phenylsulfonyl group, a 3-phenyl-ureido group, C ₂ -C ₇ alkanoyl group, C ₂ -C ₇ alkoxycarbonyl group, C ₂ -C ₇ alkanoyloxy group, C ₂ -C ₇ alkanoylamino group, C ₂ -C ₇ N- alkyl carbamoyl, C ₁ -C ₆ alkylsulfonyl group, phenyl-carbamoyl, N, N- di (C ₁ -C ₆ alkyl) sulfamoyl group, an amino group, a mono (C ₁ -C ₆ alkyl) amino group, di (C ₁ -C ₆ alkyl) amino group , A benzylamino group, a C ₂ -C ₇ (alkoxycarbonyl) amino group, a C ₁ -C ₆ (alkylsulfonyl) amino group or a bis (C ₁ -C ₆ alkylsulfonyl) amino group.
[96] The C ₃ -C ₈ cycloalkyl group in R ⁶ , the aromatic heterocyclic group having 1 to 3 oxygen atoms, the sulfur atom and / or the nitrogen atom as the hetero atom and the condensed ring are the same as those defined with respect to R ¹ , The same example is a preferred embodiment.
[97] The "C ₃ -C ₈ cycloalkenyl group" for R ^{6 means} a cyclic alkenyl group such as cyclopentenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl group and the like, and preferred specific examples thereof include 1- A cyclopentenyl group, a 1-cyclohexenyl group, and the like.
[98] Among them, particularly preferable examples of R ⁶ include a phenyl group, a furyl group and a thienyl group.
[99] Phenyl group in the R ^6, C ₃ -C ₈ cycloalkyl, C ₃ -C ₈ cycloalkenyl group, a benzyl group, a halogen atom, C ₁ -C ₆ alkyl group as the substituent of the aromatic heterocyclic group or a fused ring, C ₂ -C ₆ alkenyl group, C ₁ -C ₆ alkoxy group, C ₁ -C ₆ alkylthio import, C ₁ -C ₃ alkylenedioxy group, C ₂ -C ₇ alkanoyl group, C ₂ -C ₇ alkoxycarbonyl group, C ₂ -C ₇ alkanoyloxy group, C ₂ -C ₇ alkanoylamino group, C ₂ -C ₇ N- alkyl carbamoyl, C ₁ -C ₆ alkylsulfonyl group, a mono (C ₁ -C ₆ alkyl) amino groups and di (C ₁ -C ₆ alkyl) amino group is the same as defined with respect to the substituent of the phenyl group, C ₃ -C ₈ cycloalkyl group, aromatic heterocyclic group or condensed ring in R ¹ , and each of the same examples is a preferred embodiment .
[100] The C ₃ -C ₈ cycloalkyl group as a substituent of R ⁶ is the same as defined with respect to the C ₃ -C ₈ cycloalkyl group in R ¹ , and the same examples can be given as preferred examples.
[101] The "C ₃ -C ₈ cycloalkyloxy group" as the substituent of R ^{6 means} a group consisting of the above C ₃ -C ₈ cycloalkyl group and an oxy group, and preferable specific examples thereof include a cyclopropyloxy group, a cyclopentyloxy group, Time and so on.
[102] The "N, N-di (C ₁ -C ₆ alkyl) sulfamoyl group" as the substituent of R ⁶ means a sulfamoyl group substituted by the same or different two C ₁ -C ₆ alkyl groups, For example, N, N-dimethylsulfamoyl group, N, N-diethylsulfamoyl group and N-ethyl-N-methylsulfamoyl group.
[103] The "C ₂ -C ₇ (alkoxycarbonyl) amino group" as the substituent of R ^{6 means} a group composed of the above-mentioned C _{2 -} C ₇ alkoxycarbonyl group and an amino group, and specific preferred examples thereof include a (methoxycarbonyl) amino group, Amino group and the like.
[104] The "C ₁ -C ₆ (alkylsulfonyl) amino group" as a substituent of R ⁶ means a group consisting of the above-mentioned C ₁ -C ₆ alkylsulfonyl group and an amino group, and specific examples thereof include (methylsulfonyl) amino group and the like have.
[105] The "bis (C ₁ -C ₆ alkylsulfonyl) amino group" as the substituent of R ⁶ means an amino group substituted by the same or different two C ₁ -C ₆ alkylsulfonyl groups, and specific examples thereof include bis Sulfonylamino group and the like.
[106] Among them, the substituent of the phenyl group, C ₃ -C ₈ cycloalkyl group, C ₃ -C ₈ cycloalkenyl group, benzyl group, aromatic heterocyclic group or condensed ring in R ⁶ is preferably a halogen atom, a mercapto group, a nitro group, C ₁ -C ₆ alkyl group, C ₁ -C ₆ alkoxy group, phenyl group, phenylsulfonyl group, C ₂ -C ₇ alkanoylamino group, amino group and the like are particularly preferable examples.
[107] The substituent of the phenyl group, the C ₃ -C ₈ cycloalkyl group, the C ₃ -C ₈ cycloalkenyl group, the benzyl group, the aromatic heterocyclic group or the condensed ring at R ⁶ may be any arbitrary number of halogen atoms, cyano groups, Import group with an amino group, trifluoromethyl, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy group, C ₁ -C ₆ alkylthio group, mono (C ₁ -C ₆ alkyl) amino groups or di (C ₁ -C ₆ alkyl ) Amino group.
[108] Phenyl group in the R ^6, C ₃ -C ₈ cycloalkyl, C ₃ -C ₈ cycloalkenyl group, benzyl group, aromatic heterocyclic halogen atom as the substituent of the substituent of the ring group or a condensed ring, C ₁ -C ₆ alkyl, C ₁ (C ₁ -C ₆ alkyl) amino group and a di (C ₁ -C ₆ alkyl) amino group may be substituted with a phenyl group in R ¹ , a C ₃ -C ₈ cycloalkyl group, a C ₁ -C ₆ alkoxy group, a C ₁ -C ₆ alkylthio group, An alkyl group, an aromatic heterocyclic group, or a condensed ring, and each of the same examples is a preferred embodiment.
[109] The compound represented by the formula (I), a pharmaceutically acceptable acid addition product thereof or a pharmaceutically acceptable C ₁ -C ₆ alkyl adduct thereof may be produced by mixing a therapeutically effective amount thereof with a pharmaceutically acceptable carrier and / A composition which inhibits binding of the chemokine of the present invention to a receptor on a target cell on the target cell or a drug having an action of inhibiting the binding of the chemokine to a target cell phase and a disease which is considered to be involved in chemokine or chemokine receptor It can be a remedy or preventive medicine. That is, the cyclic amine derivative represented by the above formula (I), its pharmaceutically acceptable acid addition group or its pharmaceutically acceptable C ₁ -C ₆ alkyl adduct may be administered orally or intravenously, subcutaneously, intramuscularly, transdermally, Parenterally such as in the rectum.
[110] Examples of formulations for oral administration include tablets, pills, granules, powders, solutions, suspensions, capsules and the like.
[111] In the form of tablets, excipients such as lactose, starch, crystalline cellulose and the like; Binders such as carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone and the like; Disintegrating agents such as sodium alginate, sodium hydrogen carbonate, sodium lauryl sulfate and the like, and the like.
[112] Similarly, pills, powders, and granules can be formed by a conventional method using the above-mentioned excipients and the like. The liquid agent and the suspending agent are formed by a conventional method using, for example, glycerin esters such as tricaprylin, triacetin and the like, alcohols such as ethanol and the like. The capsules are formed by filling capsules such as granules, powders or liquids into capsules such as gelatin.
[113] Examples of formulations for subcutaneous, intramuscular, intravenous administration include injections in the form of aqueous or non-aqueous solutions. For the aqueous solution, physiological saline, for example, is used. Examples of the non-aqueous solution include propylene glycol, polyethylene glycol, olive oil, ethyl oleate, and the like, and preservatives, stabilizers, and the like are added to them if necessary. Injections are sterilized by appropriately performing filtration, bactericidal formulation treatment through a bacterial retention filter.
[114] Examples of formulations for transdermal administration include ointments and creams, ointments such as castor oil, olive oil and petrolatum, and creams such as fatty oils or emulsifiers such as diethylene glycol and sorbitan mono fatty acid esters. And is molded in a conventional manner.
[115] Conventional suppositories such as gelatin soft capsules are used for rectal administration.
[116] The dose of the cyclic amine derivative, its pharmaceutically acceptable acid addition product or its pharmaceutically acceptable C ₁ -C ₆ alkyl adduct used in the present invention may vary depending on the kind of disease, route of administration, age and sex of the patient And the degree of the disease, but is usually 1-500 mg / day for an adult.
[117] As preferred specific examples of the cyclic amine derivative of the above formula (I), there can be mentioned the compounds containing the respective substituents shown in the following Tables 1.1-1.206.
[118] In Table 1.1-1.206, "table" means "table", "compound number" means "compound number", and "chirality" means "absolute arrangement", ie, cyclic amine- ≪ / RTI > "S" means that the asymmetric carbon atom has an absolute configuration of S, "-" means a racemate or the compound is a cyclic amine ≪ / RTI > does not have an asymmetric carbon atom.
[119] [Table 1.1]
[120]
[121] [Table 1.2]
[122]
[123] [Table 1.3]
[124]
[125] [Table 1.4]
[126]
[127] [Table 1.5]
[128]
[129] [Table 1.6]
[130]
[131] [Table 1.7]
[132]
[133] [Table 1.8]
[134]
[135] [Table 1.9]
[136]
[137] [Table 1.10]
[138]
[139] [Table 1.11]
[140]
[141] [Table 1.12]
[142]
[143] [Table 1.13]
[144]
[145] [Table 1.14]
[146]
[147] [Table 1.15]
[148]
[149] [Table 1.16]
[150]
[151] [Table 1.17]
[152]
[153] [Table 1.18]
[154]
[155] [Table 1.19]
[156]
[157] [Table 1.20]
[158]
[159] [Table 1.21]
[160]
[161] [Table 1.22]
[162]
[163] [Table 1.23]
[164]
[165] [Table 1.24]
[166]
[167] [Table 1.25]
[168]
[169] [Table 1.26]
[170]
[171] [Table 1.27]
[172]
[173] [Table 1.28]
[174]
[175] [Table 1.29]
[176]
[177] [Table 1.30]
[178]
[179] [Table 1.31]
[180]
[181] [Table 1.32]
[182]
[183] [Table 1.33]
[184]
[185] [Table 1.34]
[186]
[187] [Table 1.35]
[188]
[189] [Table 1.36]
[190]
[191] [Table 1.37]
[192]
[193] [Table 1.38]
[194]
[195] [Table 1.39]
[196]
[197] [Table 1.40]
[198]
[199] [Table 1.41]
[200]
[201] [Table 1.42]
[202]
[203] [Table 1.43]
[204]
[205] [Table 1.44]
[206]
[207] [Table 1.45]
[208]
[209] [Table 1.46]
[210]
[211] [Table 1.47]
[212]
[213] [Table 1.48]
[214]
[215] [Table 1.49]
[216]
[217] [Table 1.50]
[218]
[219] [Table 1.51]
[220]
[221] [Table 1.52]
[222]
[223] [Table 1.53]
[224]
[225] [Table 1.54]
[226]
[227] [Table 1.55]
[228]
[229] [Table 1.56]
[230]
[231] [Table 1.57]
[232]
[233] [Table 1.58]
[234]
[235] [Table 1.59]
[236]
[237] [Table 1.60]
[238]
[239] [Table 1.61]
[240]
[241] [Table 1.62]
[242]
[243] [Table 1.63]
[244]
[245] [Table 1.64]
[246]
[247] [Table 1.65]
[248]
[249] [Table 1.66]
[250]
[251] [Table 1.67]
[252]
[253] [Table 1.68]
[254]
[255] [Table 1.69]
[256]
[257] [Table 1.70]
[258]
[259] [Table 1.71]
[260]
[261] [Table 1.72]
[262]
[263] [Table 1.73]
[264]
[265] [Table 1.74]
[266]
[267] [Table 1.75]
[268]
[269] [Table 1.76]
[270]
[271] [Table 1.77]
[272]
[273] [Table 1.78]
[274]
[275] [Table 1.79]
[276]
[277] [Table 1.80]
[278]
[279] [Table 1.81]
[280]
[281] [Table 1.82]
[282]
[283] [Table 1.83]
[284]
[285] [Table 1.84]
[286]
[287] [Table 1.85]
[288]
[289] [Table 1.86]
[290]
[291] [Table 1.87]
[292]
[293] [Table 1.88]
[294]
[295] [Table 1.89]
[296]
[297] [Table 1.90]
[298]
[299] [Table 1.91]
[300]
[301] [Table 1.92]
[302]
[303] [Table 1.93]
[304]
[305] [Table 1.94]
[306]
[307] [Table 1.95]
[308]
[309] [Table 1.96]
[310]
[311] [Table 1.97]
[312]
[313] [Table 1.98]
[314]
[315] [Table 1.99]
[316]
[317] [Table 1.100]
[318]
[319] [Table 1.101]
[320]
[321] [Table 1.102]
[322]
[323] [Table 1.103]
[324]
[325] [Table 1.104]
[326]
[327] [Table 1.105]
[328]
[329] [Table 1.106]
[330]
[331] [Table 1.107]
[332]
[333] [Table 1.108]
[334]
[335] [Table 1.109]
[336]
[337] [Table 1.110]
[338]
[339] [Table 1.111]
[340]
[341] [Table 1.112]
[342]
[343] [Table 1.113]
[344]
[345] [Table 1.114]
[346]
[347] [Table 1.115]
[348]
[349] [Table 1.116]
[350]
[351] [Table 1.117]
[352]
[353] [Table 1.118]
[354]
[355] [Table 1.119]
[356]
[357] [Table 1.120]
[358]
[359] [Table 1.121]
[360]
[361] [Table 1.122]
[362]
[363] [Table 1.123]
[364]
[365] [Table 1.124]
[366]
[367] [Table 1.125]
[368]
[369] [Table 1.126]
[370]
[371] [Table 1.127]
[372]
[373] [Table 1.128]
[374]
[375] [Table 1.129]
[376]
[377] [Table 1.130]
[378]
[379] [Table 1.131]
[380]
[381] [Table 1.132]
[382]
[383] [Table 1.133]
[384]
[385] [Table 1.134]
[386]
[387] [Table 1.135]
[388]
[389] [Table 1.136]
[390]
[391] [Table 1.137]
[392]
[393] [Table 1.138]
[394]
[395] [Table 1.139]
[396]
[397] [Table 1.140]
[398]
[399] [Table 1.141]
[400]
[401] [Table 1.142]
[402]
[403] [Table 1.143]
[404]
[405] [Table 1.144]
[406]
[407] [Table 1.145]
[408]
[409] [Table 1.146]
[410]
[411] [Table 1.147]
[412]
[413] [Table 1.148]
[414]
[415] [Table 1.149]
[416]
[417] [Table 1.150]
[418]
[419] [Table 1.151]
[420]
[421] [Table 1.152]
[422]
[423] [Table 1.153]
[424]
[425] [Table 1.154]
[426]
[427] [Table 1.155]
[428]
[429] [Table 1.156]
[430]
[431] [Table 1.157]
[432]
[433] [Table 1.158]
[434]
[435] [Table 1.159]
[436]
[437] [Table 1.160]
[438]
[439] [Table 1.161]
[440]
[441] [Table 1.162]
[442]
[443] [Table 1.163]
[444]
[445] [Table 1.164]
[446]
[447] [Table 1.165]
[448]
[449] [Table 1.166]
[450]
[451] [Table 1.167]
[452]
[453] [Table 1.168]
[454]
[455] [Table 1.169]
[456]
[457] [Table 1.170]
[458]
[459] [Table 1.171]
[460]
[461] [Table 1.172]
[462]
[463] [Table 1.173]
[464]
[465] [Table 1.174]
[466]
[467] [Table 1.175]
[468]
[469] [Table 1.176]
[470]
[471] [Table 1.177]
[472]
[473] [Table 1.178]
[474]
[475] [Table 1.179]
[476]
[477] [Table 1.180]
[478]
[479] [Table 1.181]
[480]
[481] [Table 1.182]
[482]
[483] [Table 1.183]
[484]
[485] [Table 1.184]
[486]
[487] [Table 1.185]
[488]
[489] [Table 1.186]
[490]
[491] [Table 1.187]
[492]
[493] [Table 1.188]
[494]
[495] [Table 1.189]
[496]
[497] [Table 1.190]
[498]
[499] [Table 1.191]
[500]
[501] [Table 1.192]
[502]
[503] [Table 1.193]
[504]
[505] [Table 1.194]
[506]
[507] [Table 1.195]
[508]
[509] [Table 1.196]
[510]
[511] [Table 1.197]
[512]
[513] [Table 1.198]
[514]
[515] [Table 1.199]
[516]
[517] [Table 1.200]
[518]
[519] [Table 1.201]
[520]
[521] [Table 1.202]
[522]
[523] [Table 1.203]
[524]
[525] [Table 1.204]
[526]
[527] [Table 1.205]
[528]
[529] [Table 1.206]
[530]
[531] In the present invention, an acid addition product of a cyclic amine compound may also be used. Examples of such acids include mineral acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, and carbonic acid; And organic acids such as maleic acid, citric acid, malic acid, tartaric acid, fumaric acid, methanesulfonic acid, trifluoroacetic acid, formic acid and the like.
[532] In the present invention, a cyclic amine such as, for example, 1- (4-chlorobenzyl) -1-methyl-4 - [[N- (3-trifluoromethylbenzoyl) glycidyl] aminomethyl] piperidinium iodide C ₁ -C ₆ alkyl adducts of the compounds may also be used. Examples of the alkyl group include alkyl groups such as methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, isopropyl, isobutyl, Isopentyl, neopentyl, tert-pentyl, 2-methylpentyl and 1-ethylbutyl are preferable examples, but particularly preferred examples thereof include methyl and ethyl. In addition, preferred examples of the large anion of the ammonium cation include halide anions such as fluoride, chloride, bromide, iodide and the like.
[533] In the present invention, racemates of the compounds represented by the above formula (I) and all possible optically active substances may be used.
[534] The compound represented by the above formula (I) can be synthesized by using any of the general production methods described below in WO9925686.
[535] (Preparation Method 1)
[536] ≪ RTI ID =
[537]
[538] [Wherein R ¹ , R ² , R ³ , j, k, m and n are the same as the respective definitions of the above-mentioned formula (I)
[539]
[540] In the absence of acid or of 0.1 to 10 equivalents of the reactive derivative represented by ^{[wherein, R 4, R 5, R} 6, G, p and q are the same as the respective definitions in the above general formula I] solvent Or in the presence of a solvent.
[541] The reactive derivative of the carboxylic acid represented by the above formula (III) means a carboxylic acid derivative having high reactivity, which is commonly used in synthetic organic chemistry such as acid halide, acid anhydride, mixed acid anhydride and the like.
[542] Such a reaction may be carried out in the presence of an appropriate amount of dehydrating agent such as molecular sieves or the like; (DCCI), N-ethyl-N'- (3-dimethylaminopropyl) carbodiimide (EDCI or WSC), carbonyldiimidazole (CDI), N- hydroxysuccinimide Hexafluorophosphate (PyBOP), 2- (1H-benzotriazol-1-yl) oxotris (pyrrolidinol) phosphonium hexafluorophosphate (HBTU), 2- (1H-benzotriazol-1-yl) -1,1,3,3-tetramethyluronium (HBTU), 1,1,3,3-tetramethyluronium hexafluorophosphate = Tetrafluoroborate (TBTU), 2- (5-norbornene-2,3-dicarboxyimide) -1,1,3,3-tetramethyluronium = tetrafluoroborate (TNTU) (PyroP), such as tetraethylorthosilicate (N-succinimidyl) -1,1,3,3-tetramethyluronium tetrafluoroborate (TSTU), bromotris (pyrrolidino) phosphonium hexafluorophosphate ; (Piperidinomethyl) polystyrene, (morpholinomethyl) polystyrene, (dimethylaminomethyl) polystyrene, (dimethylaminomethyl) polystyrene, and the like. Polystyrene, poly (4-vinylpyridine), and the like can be more smoothly proceeded.
[543] (Preparation 2)
[544] (IV) <
[545]
[546] [Wherein R ¹ , R ² and j are the same as the respective definitions of the above-mentioned formula (I), and X represents a halogen atom, an alkylsulfonyloxy group or an arylsulfonyloxy group] with an equivalent of an alkylating reagent represented by the following formula V
[547]
[548] Ratio of 0.1-10 equivalents of a compound represented by: ^{wherein, R 3, R 4, R} 5, R 6, G, k, m, n, p and q are the same as the respective definitions in the above general formula I] solvent In the presence or in the presence of a solvent.
[549] This reaction can proceed more smoothly by appropriately using the same base as in Preparation Process 1 above. Further, in the present production method, the iodide such as potassium iodide, sodium iodide and the like may coexist to promote the reaction.
[550] In Formula (IV), X represents a halogen atom, an alkylsulfonyloxy group, or an arylsulfonyloxy group. The halogen atom is preferably a chlorine atom, a bromine atom or an iodine atom. Preferable specific examples of the alkylsulfonyloxy group include a methylsulfonyloxy group, a trifluoromethylsulfonyloxy group and the like. A preferable specific example of the arylsulfonyloxy group is a tosyloxy group.
[551] (Preparation Method 3)
[552] Wherein R <
[553]
[554] [Wherein R ¹ and R ² are the same as the respective definitions of the above-mentioned formula (I), and j represents 1 or 2]
[555] Or < RTI ID =
[556] R < ^{1 >} -CHO (VII)
[557] 1 equivalent of an aldehyde represented by the formula (I) in which R ¹ is the same as defined for R ¹ in the formula (I) and j represents 0) and 0.1-10 equivalents of the compound represented by the formula (V) In the presence or in the presence of a solvent.
[558] Such a reaction is generally referred to as a reductive amination reaction. Examples of the reduction conditions include catalytic hydrogenation using a catalyst containing a metal such as palladium, platinum, nickel, rhodium, lithium aluminum hydride, sodium borohydride, Sodium hydride, sodium hydride, sodium triacetoxy hydride, etc., and a hydrogenation reaction or an electrolytic reduction reaction using borane.
[559] (Preparation 4)
[560] (VIII)
[561]
[562] Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁷ , j, k, m, n, p and q are as defined for each of the above- Equivalents of a compound of formula < RTI ID =
[563] HO-A-R < / RTI > ⁶ (IX)
[564] [Wherein, R ⁶ is as defined in R ⁶ of Formula I and, A is a carbonyl group or a sulfonyl group represents - a carboxylic acid or sulfonic acid or a reactive derivative thereof 0.1-10 equivalents represented by the non-solvent in the presence or In the presence of a solvent.
[565] The reactive derivative of carboxylic acid or sulfonic acid represented by Formula IX means a carboxylic acid or a sulfonic acid derivative having high reactivity generally used in synthetic organic chemistry such as acid halide, acid anhydride, mixed acid anhydride and the like . Such a reaction can proceed more smoothly by suitably using the same dehydrating agent, condensing agent or base as in Preparation Process 1 above.
[566] (Preparation 5)
[567] 1 equivalent of the compound represented by the above formula (VIII)
[568] ^{Z = C = NR 6 (X} )
[569] Wherein 0.1 to 10 equivalents of an isocyanate or isothiocyanate represented by the formula (I) in which R ⁶ is the same as defined for R ⁶ in the above formula (I) and Z represents an oxygen atom or a sulfur atom are reacted in the presence or in the presence of a solvent Lt; / RTI >
[570] (Preparation 6)
[571] ≪ RTI ID =
[572]
[573] Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , j, k, m, n, p and q have the same meanings as defined in the above formula (I) and A represents a carbonyl group or a sulfonyl group ] With one equivalent of a compound represented by the following formula XII
[574] R ⁶ -NH ₂ (XII)
[575] Wherein R < ⁶ > is the same as defined for R < ⁶ > in the above formula (I) in the presence of or in the presence of a solvent.
[576] This reaction can proceed more smoothly by suitably using the same dehydrating agent, condensing agent or base as in Preparation Process 1
[577] In the case where the substrate used in each reaction in Preparation Process 1-6 has a substituent which is generally reacted at each reaction condition of organic synthetic chemistry or is likely to adversely affect the reaction, the functional group is protected with an appropriate known protecting group After the reaction, the desired compound can be obtained by deprotection using a conventionally known method.
[578] In addition, the compound used in the present invention can be prepared by using a known reaction which is generally used in organic synthesis chemistry such as an alkylation reaction, an acylation reaction, a reduction reaction and the like, and the substituent (single or plural) And then further converting it.
[579] Examples of the reaction solvent include halogenated hydrocarbons such as dichloromethane and chloroform, aromatic hydrocarbons such as benzene and toluene, ethers such as diethyl ether and tetrahydrofuran, esters such as ethyl acetate, dimethylformamide, dimethyl Aprotic polar solvents such as sulfoxide, acetonitrile and the like, alcohols such as methanol, ethanol, isopropyl alcohol and the like can be suitably used according to the reaction.
[580] In any production method, the reaction temperature is in the range of -78 ° C to + 150 ° C, preferably 0 ° C to 100 ° C. After completion of the reaction, the desired cyclic amine compound represented by the above formula (I) can be isolated by carrying out usual isolation and purification operations, that is, concentration, filtration, extraction, solid phase extraction, recrystallization, chromatography and the like. In addition, they can be converted into pharmaceutically acceptable acid adducts or C ₁ -C ₆ alkyl adducts in a conventional manner.
[16] DISCLOSURE OF INVENTION
[17] A low molecular weight compound having an activity of inhibiting binding of a chemokine such as MIP-1 alpha and / or MCP-1 to a receptor on a target cell is used to bind a chemokine such as MIP-1 alpha and / or MCP-1 to a receptor on a target cell It is an object of the present invention to provide a method for treating a disease which is one of the etiologies.
[18] As a result of intensive studies, the present inventors have found that a cyclic amine derivative having an arylalkyl group, a pharmaceutically acceptable C ₁ -C ₆ alkyl adduct thereof or a pharmaceutically acceptable acid adduct thereof, And / or MCP-1. The present invention also provides a therapeutic drug for a disease in which these compounds are thought to be involved in a chemokine such as MIP-1 alpha and / or MCP-1 Or a preventive drug, and have completed the present invention.
[19] That is, the present invention relates to a pharmaceutical composition comprising a compound represented by the following formula (I), a pharmacologically acceptable acid adduct thereof, or a chemokine or chemokine receptor comprising a pharmaceutically acceptable C ₁ -C ₆ alkyl adduct thereof as an active ingredient A therapeutic or preventive agent for a disease:
[20]
[21] Wherein R ¹ represents a phenyl group, a C ₃ -C ₈ cycloalkyl group or an aromatic heterocyclic group having 1 to 3 oxygen atoms, a sulfur atom and / or a nitrogen atom as a hetero atom. The phenyl group or aromatic heterocyclic group in R ¹ may be condensed with an aromatic heterocyclic group having 1-3 oxygen atoms, a sulfur atom and / or a nitrogen atom as a benzene ring or a hetero atom to form a condensed ring, and the R ^one phenyl group, C ₃ -C ₈ cycloalkyl group, aromatic heterocyclic group or condensed ring may be any number of a halogen atom, a hydroxy group of a cyano group, a nitro group, a carboxyl group, a carbamoyl group, C ₁ -C ₆ alkyl, C ₃ -C ₈ cycloalkyl group, C ₂ -C ₆ alkenyl, C ₁ -C ₆ alkoxy group, C ₁ -C ₆ alkylthio import, C ₃ -C ₅ alkylene group, C ₂ -C ₄ alkyleneoxy group, C ₁ -C ₃ alkylenedioxy group, a phenyl group, a phenoxy group, phenylthio, benzyl, benzyloxy group, benzoyl group, C ₂ -C ₇ alkanoyl group, C ₂ -C ₇ alkoxycarbonyl group, C ₂ -C ₇ Al Cano-yloxy group, C ₂ -C ₇ alkanoylamino group, C ₂ -C ₇ N- alkyl carbamoyl, C ₄ -C ₉ cycloalkyl N- carbamic Group, a C ₁ -C ₆ alkylsulfonyl, C ₃ -C ₈ (alkoxycarbonyl) methyl group, N- phenyl-carbamoyl group, a piperidino group, a morpholino group, a 1-pyrrolidinyl group, the formula: - NH (C = O) represented by the top 2 O-, formula: -NH (C = S) to the top 2 represented by O-, amino groups, mono (C ₁ -C ₆ alkyl) amino groups or di (C ₁ -C optionally substituted by a ₆ alkyl) amino group is, those of the phenyl group, C ₃ -C ₈ cycloalkyl group, the substituent of the aromatic heterocyclic group or condensed ring is a methyl group in any number of a halogen atom, a hydroxy group, an amino group, a trifluoro of, C ₁ C ₆ alkyl group or a C ₁ -C ₆ alkoxy group.
[22] R ² represents a hydrogen atom, a C ₁ -C ₆ alkyl group, a C ₂ -C ₇ alkoxycarbonyl group, a hydroxy group or a phenyl group. The C ₁ -C ₆ alkyl group or phenyl group of R ² may be substituted with any number of halogen atoms, a hydroxy group, a C ₁ -C ₆ alkyl group or a C ₁ -C ₆ alkoxy group. However, when j = 0, R ² is not a hydroxy group.
[23] j represents an integer of 0-2.
[24] k represents an integer of 0-2.
[25] m represents an integer of 2-4.
[26] n represents 0 or 1;
[27] R ³ represents a hydrogen atom or C (which may be substituted with the same or different arbitrary number of halogen atoms, a hydroxy group, a C ₁ -C ₆ alkyl group or one or two phenyl groups which may be substituted with a C ₁ -C ₆ alkoxy group) Represents a C ₁ -C ₆ alkyl group.
[28] R ⁴ and R ⁵ are the same or different and each represents a hydrogen atom, a hydroxy group, a phenyl group or a C ₁ -C ₆ alkyl group. These R ⁴ and C ₁ -C ₆ alkyl group in R ⁵ are any number of a halogen atom, a hydroxy group, a cyano group, a nitro group, a carboxyl group, a carbamoyl group, a mercapto group, a guanidino group, a C ₃ -C ₈ cycloalkyl, C ₁ -C ₆ alkoxy group, C ₁ -C ₆ alkylthio group, a (any number of halogen atoms, hydroxy groups, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy group or a substituted benzyloxycarbonyl is a phenyl group which may optionally), a phenoxy group, a benzyloxy group, a benzyloxycarbonyl group, C ₂ -C ₇ alkanoyl group, C ₂ -C ₇ alkoxycarbonyl group, C ₂ -C ₇ alkanoyloxy group, C ₂ -C ₇ alkynyl (C ₁ -C ₆ alkyl) amino group, a di (C ₁ -C ₆ alkyl) amino group or a heteroaryl group having a heteroatom (C ₁ -C ₆ alkyl) amino group, a C ₂ -C ₇ N-alkylcarbamoyl group, a C ₁ -C ₆ alkylsulfonyl group, An aromatic heterocyclic group having 1 to 3 oxygen atoms, a sulfur atom and / or a nitrogen atom as an atom, or a condensed ring formed by condensation with a benzene ring thereof) All of which may be unsubstituted or is R ⁴ and R ⁵ are in one body to form a 3-6 membered cyclic hydrocarbon.
[29] p represents 0 or 1;
[30] q represents 0 or 1;
[31] G is _{-CO-, -SO 2 -, -CO-} O-, NR 7 -CO-, -CO-NR 7 -, -NH-CO-NH-, -NH-CS-NH-, -NR 7 - SO ₂ -, -SO ₂ -NR ⁷ -, -NH-CO-O- or -O-CO-NH-. Here, R ⁷ represents a hydrogen atom or a C ₁ -C ₆ alkyl group, or R ⁷ may be combined with R ⁵ to form a C ₂ -C ₅ alkylene group.
[32] R ⁶ represents a phenyl group, a C ₃ -C ₈ cycloalkyl group, a C ₃ -C ₆ cycloalkenyl group, a benzyl group or an aromatic heterocyclic group having 1 to 3 oxygen atoms, a sulfur atom and / or a nitrogen atom as a hetero atom. The phenyl, benzyl or aromatic heterocyclic group in R ⁶ may be condensed with an aromatic heterocyclic group having 1 to 3 oxygen atoms, a sulfur atom and / or a nitrogen atom as a benzene ring or a hetero atom to form a condensed ring, The phenyl group, the C ₃ -C ₈ cycloalkyl group, the C ₃ -C ₆ cycloalkenyl group, the benzyl group, the aromatic heterocyclic group or the condensed ring in the R ⁶ may be any of a halogen atom, a hydroxyl group, a mercapto group, C ₁ -C ₆ alkyl group, C ₃ -C ₈ cycloalkyl group, C ₂ -C ₆ alkenyl group, C ₁ -C ₆ alkoxy group, nitro group, nitro group, thiocyanato group, carboxyl group, carbamoyl group, trifluoromethyl group, group, a C ₃ -C ₈ cycloalkyloxy groups, C ₁ -C ₆ alkylthio, C ₁ -C ₃ alkylenedioxy group, a phenyl group, a phenoxy group, a phenyl group, a benzyl group, a benzoyl group, phenyl sulfinyl group, phenyl A sulfonyl group, a 3-phenylureido group, a C ₂ -C ₇ alkanoyl group, a C ₂ -C ₇ alkoxy group Viterbo group, a C ₂ -C ₇ alkanoyloxy group, C ₂ -C ₇ alkanoylamino group, C ₂ -C ₇ N- alkyl carbamoyl, C ₁ -C ₆ alkylsulfonyl group, phenyl carbamoyl group, N, N- di (C ₁ -C ₆ alkyl) sulfamoyl group, an amino group, a mono (C ₁ -C ₆ alkyl) amino group, di (C ₁ -C ₆ alkyl) amino group, benzyl amino group, C ₂ -C ₇ (alkoxycarbonyl carbonyl) amino, C ₁ -C ₆ (alkylsulfonyl) amino groups or bis (C ₁ -C ₆ alkylsulfonyl) group optionally substituted with an amino group is, those of the phenyl group, C ₃ -C ₈ cycloalkyl, C ₃ -C ₈ cycloalkenyl group, benzyl group, aromatic heterocyclic group, or a substituent of the condensed ring is a methyl group in any number of a halogen atom, a cyano group, a hydroxy group, an amino group, a trifluoro of, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy group, import C ₁ -C ₆ alkylthio, mono or may be further substituted with (C ₁ -C ₆ alkyl) amino groups or di (C ₁ -C ₆ alkyl) amino group].
[33] Herein, the compound represented by the above formula (I) inhibits the binding of chemokines such as MIP-1α and / or MCP-1 to target cells and inhibits the binding activity of chemokine such as MIP-1α and / or MCP- And has an activity of inhibiting physiological action.
[581] Hereinafter, the present invention will be described in detail with reference to examples. However, the present invention is not limited to the compounds described in these examples. The compound numbers (Compd. No.) attached to each compound in the following examples correspond to the compound numbers (Compd. No.) attached to the compounds of the specific preferred examples in Table 1.1-1.206.
[582] [Referential Example 1] Synthesis of 3-amino-1- (4-chlorobenzyl) pyrrolidine dihydrochloride
[583] To a solution of 4 - chlorobenzyl chloride (4.15 g, 25.8 mmol) and ⁱ Pr ₂ NEt (6.67 g, 51.6 mmol) in 3 - [(tert- butoxycarbonyl) amino] pyrrolidine DMF solution (50 mL). The reaction mixture is stirred at 70 < 0 > C for 15 hours and the solvent is removed under reduced pressure. The desired 3 - [(tert-butoxycarbonyl) amino] -1- (4-chlorobenzyl) pyrrolidine (6.43 g, 80%) was obtained as a yellowish white solid by recrystallization (acetonitrile, 50 mL).
[584]
[585] ; Purity is determined by RPLC / MS (98%). ESI / MS m / e 311.0 (M ⁺ + H, C ₁₆ H ₂₄ ClN ₂ O ₂ )
[586] To a methanol (80 mL) solution of 3 - [(tert-butoxycarbonyl) amino] -1- (4-chlorobenzyl) pyrrolidine (6.38 g, 20.5 mmol) was added 1 M HCl-Et ₂ O And stirred at 25 占 폚 for 15 hours. The solvent was removed under reduced pressure to obtain a solid which was purified by recrystallization (methanol / acetonitrile = 1: 2, 130 mL) to obtain 3.939 g (85%) of 3-amino- 1- (4- chlorobenzyl) pyrrolidine dihydrochloride ) As a white powder.
[587]
[588] ; Purity is determined by RPLC / MS (> 99%). ESI / MS m / e 211.0 (M ⁺ + H, C ₁₁ H ₁₆ ClN ₂ )
[589] (S) -3-amino-1- (4-chlorobenzyl) pyrrolidine dihydrochloride corresponding to optically active (R) -3-amino-1- (4-chlorobenzyl) pyrrolidine dihydrochloride And synthesized according to the above method using the raw material. The product shows the same ¹ H NMR as the racemate.
[590] [Example 1] Synthesis of 3- (N-benzoylglycyl) amino-1- (4-chlorobenzyl) pyrrolidine (Compound No. 1)
[591] N-benzoylglycine (9.3 mg, 0.055 mmol), 3-ethyl-1- [3- (dimethylamino) propyl] carbodiimide hydrochloride (EDCI) (10.5 mg) and 1-hydroxybenzotriazole hydrate HOBt) (7.4 mg) was added to a solution of 3-amino-1- (4-chlorobenzyl) pyrrolidine dihydrochloride (14.2 mg, 0.050 mmol) and triethylamine (15.2 mg) in chloroform . The reaction mixture was stirred at 25 DEG C for 16 hours and then washed with 2M NaOH aqueous solution (2 mL x 2) and brine. After filtration through a PTFE membrane filter, the solvent was removed under reduced pressure to obtain 3- (N- benzoylglycyl) 1- (4-chlorobenzyl) pyrrolidine (Compound No. 1) was obtained as a yellowish white oil (17.7 mg, 95%). Purity is determined by RPLC / MS (95%). ESI / MS m / e 372.0 (M <^+> + H, C ₂₀ H ₂₂ ClN ₃ O ₂ )
[592] [Example 2-32]
[593] The compounds used in the present invention are synthesized according to the method of Example 1 using the corresponding raw materials and reactants, respectively. ESI / MS data, yield and yield are summarized in Table 2.
[594] [Table 2]
[595]
[596] * Yield of trifluoroacetic acid salt
[597] Referential Example 2 Synthesis of (R) -3 - [(N-tert-butoxycarbonyl) glycyl] amino-1- (4-chlorobenzyl) pyrrolidine
[598] A mixture of (R) -3-amino-1- (4-chlorobenzyl) pyrrolidine dihydrochloride (4.54 g, 16.0 mmol), 2M NaOH solution (80 mL) and ethyl acetate (80 mL) , And the aqueous layer was extracted with ethyl acetate (80 mL x 2). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the liberated (R) -3-amino-1- (4-chlorobenzyl) pyrrolidine (3.35 g, 99%).
[599] To the dichloromethane (80 mL) solution of (R) -3-amino-1- (4-chlorobenzyl) pyrrolidine (3.35 g, 16 mmol) was added triethylamine (2.5 mL, 17.6 mmol) Carbonyl glycine (2.79 g, 16.0 mmol), EDCI (3.07 g, 16.0 mmol) and HOBt (12.16 g, 16 mmol) are added. The reaction mixture is stirred at 25 &lt; 0 &gt; C for 16 hours and then 2M NaOH solution (80 mL) is added. The organic layer was separated, and the aqueous layer was extracted with dichloromethane (100 mL x 3). The combined organic layers were washed with water (100 mL x 2) and brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. Column chromatography (R) for the purpose of (SiO _2, ethyl acetate) -3- [N- (tert- butoxycarbonyl) glycyl] amino-1- (4-chlorobenzyl) pyrrolidine (5.40g, 92%).
[600] [Referential Example 3] Synthesis of (R) -1- (4-chlorobenzyl) -3- (glycylamino) pyrrolidine
[601] To a methanol (60 mL) solution of (R) -3- [N- (tert- butoxycarbonyl) glycyl] amino- 1- (4- chlorobenzyl) pyrrolidine (5.39 g, 14.7 mmol) (38 mL) is added. This solution is stirred at room temperature for 2 hours. The reaction mixture is concentrated and 2M NaOH solution (80 mL) is added. The mixture was extracted with dichloromethane (80 mL x 3), and the combined extracts were dried over anhydrous sodium sulfate and concentrated. Column chromatography (SiO _2, ethyl acetate / ethanol / triethylamine = 90: 5: 5) to (R) -3- (glycyl) -1- (4-chlorobenzyl) pyrrolidine (3.374g, 86%).
[602]
[603] Other 3-acylamino-1- (4-chlorobenzyl) pyrrolidines are also synthesized according to the methods of Referential Examples 2 and 3 respectively using the corresponding starting materials and reactants.
[604] (S) -1- (4-chlorobenzyl) -3- (glycylamino) pyrrolidine: 3.45 g, 79%
[605] 3.79 g, 85% (2 steps) of (R) -3- (β-alaninylamino)
[606] (S) -3- (β-alaninylamino) -1- (4-chlorobenzyl) pyrrolidine: 3.72 g, 86%
[607] (2 steps): 368 mg, 65%. (2-Step) To a solution of (R) -3 - [((S) -alaninylamino)
[608] (2 steps): 425 mg, 75% (2 steps) of (R) -3 - [((R)
[609] (2 steps) (566 mg, 78%) of (R) -3 - [(2S) -2-amino-3-thienylpropanoyl] amino-
[610] (2 steps), 5.85 mg, 81% (2 steps) of (R) -3 - [(2R) -2-amino-
[611] 404 mg, 66% (two steps) of (R) -3- (2-amino-2-methylpropanoyl) amino-
[612] (2 steps): 535 mg, 72%. (2 steps) To a solution of (R) -3 - [(2S) -2-amino-
[613] (R) -3- (glycylamino) -1- (4-methylbenzyl) pyrrolidine, (R) -1- (3,5-dimethylisoxazol-4-ylmethyl) -3- (4-methylbenzyl) (Glycylamino) pyrrolidine are also synthesized according to the methods of Reference Examples 1, 2 and 3 respectively using the corresponding starting materials and reactants.
[614] (Yield: 62%) (yield: from 3 - [(tert-butoxycarbonyl) amino] pyrrolidine: )
[615] (R) -3-amino-1- (4-bromobenzyl) piperidine was obtained in a yield of 68% Lt; / RTI &gt;
[616]
[617] (Tert-Butoxycarbonyl) amino] pyrrolidine was obtained as a colorless oil from 1.56 g (yield: 58%) of (R) -1- (2,4-dimethylbenzyl) -3- Yield);
[618]
[619] 3.14 g, yield 45% (3 - [(tert-butoxycarbonyl) pyridin-2-ylmethyl] Amino)] pyrrolidine &lt; / RTI &gt;
[620] Example 33 Synthesis of (S) -3- [N- [3,5-bis (trifluoromethyl) benzoyl] glycyl] amino-1- (4-chlorobenzyl) pyrrolidine synthesis
[621] A chloroform solution (0.4 mL) of 3,5-bis (trifluoromethyl) benzoyl chloride (0.060 mmol) was added to a solution of (S) -1- (4- chlorobenzyl) -3- (glycylamino) pyrrolidine 0.050 mmol) and triethylamine (0.070 mmol) in chloroform (1.0 mL). After the reaction mixture was stirred at room temperature for 2.5 hours, (aminomethyl) polystyrene resin (1.04 mmol / g, 50 mg, 50 mmol) was added and the mixture was stirred at room temperature for 12 hours. The reaction mixture is filtered and the resin is washed with dichloromethane (0.5 mL). The filtrate and washings were combined and dichloromethane (4 mL) was added, the solution was washed with 2M aqueous NaOH solution (0.5 mL) and concentrated to give (S) -3- [N- [3,5- bis (trifluoromethyl) benzoyl] Glycyl] amino-1- (4-chlorobenzyl) pyrrolidine (Compound No. 5) (14.4 mg, 57%). Purity is determined by RPLC / MS (97%). ESI / MS m / e 508.0 ( M + + H, C 22 H 20 ClF 6 N 3 O 2)
[622] [Examples 34-239]
[623] The compounds used in the present invention are synthesized according to the method of Example 33 using the corresponding starting materials and reactants, respectively. ESI / MS data, yield and yield are summarized in Table 3.
[624] [Table 3a
[625]
[626] [Table 3b]
[627]
[628] [Table 3c]
[629]
[630] [Table 3d]
[631]
[632] [Table 3e]
[633]
[634] [Table 3f]
[635]
[636] Example 240 Synthesis of (R) -3- [N- [3-fluoro-5- (trifluoromethyl) benzoyl] glycyl] amino-1- (3,5-dimethylisoxazol- ) Pyrrolidine (Compound No. 1191) Synthesis of
[637] A dichloromethane solution (1 mL) of 3-fluoro-5- (trifluoromethyl) benzoyl chloride (0.058 mmol) was added dropwise to a solution of (R) -1- (3,5-dimethylisoxazol- Is added to a solution of chloroform (0.2 mL) and dichloromethane (0.75 mL) in tetrahydrofuran (0.025 mmol) - (glycylamino) pyrrolidine (0.050 mmol) and piperidinomethyl polystyrene (58 mg). The reaction mixture was stirred at room temperature for 2 hours, methanol (1.0 mL) was added, and the mixture was stirred at room temperature for 10 hours. The reaction mixture is placed on a Varian ^占 SCX column and rinsed with methanol (16 mmol). The product was eluted with a 2M NH ₃ solution in methanol (6 mL) and concentrated to give (R) -3- [N- [3-fluoro-5- (trifluoromethyl) benzoyl] glycyl] amino- , 5-dimethylisoxazole-4-ylmethyl) pyrrolidine (Compound No. 1191) (19.5 mg, 88%). Purity is determined by RPLC / MS (100%). ESI / MS m / e 443.2 (M ⁺ + H, C ₂₀ H ₂₂ F ₄ N ₄ O ₃ )
[638] [Examples 241 to 265]
[639] The compounds used in the present invention are synthesized according to the method of Example 240 using the corresponding starting materials and reactants, respectively. ESI / MS data, yield and yield are summarized in Table 4.
[640] [Table 4]
[641]
[642] Example 266: Synthesis of (R) -1- (4-chlorobenzyl) -3 - [[N- (4-dimethylaminobenzoyl) glycyl] amino] pyrrolidine
[643] (0.021 mL, 0.15 mmol), 4- (4-chlorobenzyl) pyrrolidine (13.8 mg, 0.052 mmol) in chloroform (10 mg, 0.061 mmol), EDCI (10.2 mg, 0.053 mmol) and HOBt (7.5 mg, 0.055 mmol) were added. The reaction mixture is stirred at room temperature for 15 hours. The solution was washed with 2M NaOH aqueous solution (2 mL x 2) and brine (2 mL), and filtered with a PTFE membrane using dichloromethane (3 mL) and dried. (R) -1- (4-chlorobenzyl) -3 - [[N- (4-dimethylaminobenzoyl) glycyl] amino] pyrrolidine (Compound No. 952) is obtained by concentration (24.9 mg). Purity is determined by RPLC / MS (91%). ESI / MS m / e 415.0 (M ⁺ + H, C ₂₂ H ₂₇ ClN ₄ O ₂ )
[644] [Examples 267 to 347]
[645] The compounds used in the present invention are synthesized according to the method of Example 266, using the corresponding starting materials and reactants, respectively. If desired, the product is purified by solid-phase extraction (Varian ^占 SCX column) or chromatography (HPLC- _C18 ). ESI / MS data, yield and yield are summarized in Table 5.
[646] [Table 5a]
[647]
[648] [Table 5b]
[649]
[650] [Table 5c]
[651]
[652] * Yield of trifluoroacetic acid salt
[653] Example 348: Synthesis of (R) -1- (4-chlorobenzyl) -3 - [[N- (2-amino-5-chlorobenzoyl) glycyl] amino] pyrrolidine
[654] To a chloroform (2 mL) solution of (R) -1- (4-chlorobenzyl) -3- (glycylamino) pyrrolidine (0.050 mmol) Carbodiimide (0.060 mmol) is added. The reaction mixture is stirred at room temperature for 15 hours. The solution is placed on a Varian ^™ SCX column and rinsed with methanol (15 mL). The product was eluted with a 2M NH ₃ in methanol (5 mL) solution and concentrated to give (R) -1- (4-chlorobenzyl) -3- [N- [2-amino-5-chlorobenzoyl) glycyl] amino] (Compound No. 1084) (12.7 mg, 60%). Purity is determined by RPLC / MS (87%). ESI / MS m / e 421.0 (M <^+> + H, C ₂₀ H ₂₂ Cl ₂ N ₄ O ₂ )
[655] [Examples 349 to 361]
[656] The compounds used in the present invention are synthesized according to the method of Example 348 using the corresponding starting materials and reactants, respectively. When the amine as a raw material remains, a solution of isocyanatomethylated polystyrene (50 mg) in chloroform (1 mL) is added and reacted at room temperature, followed by filtration and concentration to obtain the desired product. Table 6 summarizes ESI / MS data, yield and yield.
[657] [Table 6]
[658]
[659] Example 362: Synthesis of (R) -1- (4-chlorobenzyl) -3 - [[N- (3-bromo-4-methylbenzoyl) glycyl] amino] pyrrolidine
[660] To a solution of (R) -1- (4-chlorobenzyl) -3- (glycylamino) pyrrolidine (0.050 mmol) in chloroform (1.35 mL) and tert- -Methylbenzoic acid (0.060 mL), diisopropylcarbodiimide (0.060 mmol) and HOBt (0.060 mmol) are added. The reaction mixture is stirred at room temperature for 15 hours. The mixture is placed on a Varian ^™ SCX column and rinsed with methanol / chloroform = 1: 1 (12 mL) and methanol (12 mL). The product was eluted with a 2M NH ₃ solution in methanol (5 mL) and concentrated to give (R) -1- (4-chlorobenzyl) -3 - [[N- (3-bromo-4-methylbenzoyl) glycyl] amino ] Pyrrolidine (Compound No. 1098) (11.6 mg, 50%). Purity is determined by RPLC / MS (94%). ESI / MS m / e 466.0 (M <^+> + H, C ₂₁ H ₂₃ BrClN ₃ O ₂ )
[661] [Examples 363-572]
[662] The compound used in the present invention is synthesized according to the method of Example 362 using the corresponding starting materials and reactants, respectively. If desired, the desired product is obtained by preparative TLC. ESI / MS data, yield and yield are summarized in Table 7.
[663] The following three compounds can be obtained as by-products of Compound Nos. 1415, 1416 and 1417, respectively.
[664] Compound No. 1419: 7.9 mg, yield 38%, ESI / MS m / e 419.0 (C ₂₀ H ₂₃ ClN ₄ O ₂ S)
[665] Compound No. 1420: 7.1 mg, yield 36%, ESI / MS m / e 399.2 (C ₂₃ H ₂₆ N ₄ O ₂ S)
[666] Compound No. 1421: 7.4㎎, yield 37%, ESI / MS m / e 404.2 (C 19 H 25 N 5 O 3 S)
[667] [Table 7a]
[668]
[669] [Table 7b]
[670]
[671] [Table 7c]
[672]
[673] [Table 7d]
[674]
[675] [Table 7e]
[676]
[677] [Table 7f]
[678]
[679] For example, Compound No. 1583 represents the following NMR.
[680]
[681] Referential Example 4 Synthesis of (S) -3- [N- [3- (trifluoromethyl) benzoyl] glycyl] aminopyrrolidine
[682] (2.93 g, 6.66 mmol) and Pd (OH) ₂ ( ₂ mL) were added to a solution of (S) -1- (4- chlorobenzyl) -3- [N- [3- (trifluoromethyl) benzoyl] glycyl] aminopyrrolidine 5% formic acid / methanol (70 mL) was stirred at 60 占 폚 for 3 hours. The palladium catalyst is removed by celite filtration and the filtrate is concentrated. 2M NaOH solution (100 mL) was added to the residue, and the mixture was extracted with ethyl acetate (100 mL x 3). The combined extracts are washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. Column chromatography (SiO _2, ethyl acetate / methanol / triethylamine = 85: 10: 5 to 60: 30: 5) to give (S) -3- [(trifluoromethyl) N- [3- benzoyl ] Glycyl] aminopyrrolidine (1.70 g, 81%) as an oily product.
[683]
[684] Also, (R) -3- [N- [3- (trifluoromethyl) benzoyl] glycyl] aminopyrrolidine is synthesized according to the above method using the corresponding starting materials and reactants. 1.49 g, 68%; The product shows the same ¹ H NMR and ESI / MS as that of the (S) -isomer.
[685] Also, (R) -3- [N- [2-amino-5- (trifluoromethyl) benzoyl] glycyl] aminopyrrolidine is synthesized according to the above method using the corresponding starting materials and reactants. 316 mg, 93%; ESI / MS m / e 331.2 (M ⁺ + H, C ₁₄ H ₁₇ F ₃ N ₄ O ₂ )
[686] Then, using the corresponding raw materials and reactants, (R) -3- [N- [2- (tert-butoxycarbonylamino) -5- (trifluoromethoxy) benzoyl] glycyl] aminopyrrolidine And synthesized according to the above method. Quantitative yield;
[687]
[688] [Example 573] (R) -3 - [[N- [2- (tert-Butoxycarbonylamino) -5-trifluoromethylbenzoyl] glycyl] amino] Synthesis of pyrrolidine
[689] (2.9 mL, 20.5 mmol) was added to a solution of (R) -1- (4-chlorobenzyl) -3- (glycylamino) pyrrolidine (5.0 g, 18.7 mmol) in dicyclomethane (6.27g, 20.5mmol), EDCI (3.0g, 20.5mmol) and HOBt (2.8g, 20.5mmol) were added to a solution of 2- (tert-butoxycarbonylamino) -5- (trifluoromethyl) benzoic acid. The reaction mixture is stirred at room temperature overnight. To the reaction mixture was added a 2 M aqueous NaOH solution (80 mL) and extracted with dichloromethane. The extract is dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. Column chromatography (SiO _2, hexane / ethyl acetate = 1: 1-1: 4) to give (R) -3 - [a [N- (2-tert- butoxycarbonylamino) -5-trifluoromethyl Methylbenzoyl) glycyl] amino] -1- (4-chlorobenzyl) pyrrolidine (9.41 g, 91%) as a white amorphous solid. ESI / MS m / e 555.2 (M ⁺ + H, C ₂₆ H ₃₀ ClF ₃ N ₄ O ₄ )
[690] Referential Example 5 Synthesis of (R) -3 - [[N- (2- (tert-butoxycarbonylamino) -5-trifluoromethylbenzoyl) glycyl] amino] pyrrolidine
[691] (R) -3 - [[N- (2- (tert-butoxycarbonylamino) -5-trifluoromethylbenzoyl) glycyl] amino- 1- (4- chlorobenzyl) pyrrolidine , 11.4 mmol), Pd (OH) ₂ (1.68 g), formic acid (3.7 mL) and methanol (80 mL) is stirred at 50 <0> C overnight. After cooling the mixture to room temperature, the palladium catalyst is removed by celite filtration and the filtrate is concentrated. (R) -3 - [[N- (2- (tert-butoxycarbonylamino) -5-trifluoromethylpyridazinone) was obtained by purification by column chromatography (SiO ₂ , ethyl acetate / methanol = (4-methoxybenzyl) glycyl] amino] pyrrolidine (4.42 g, 90%) as a white solid.
[692]
[693] Example 574: Synthesis of (S) -1-benzyl-3- [N- [3- (trifluoromethyl) benzoyl] glycyl] aminopyrrolidine (Compound No. 239)
[694] (2.6 mL) of a solution of (Piperidinomethyl) polystyrene (2.6 mL) and a solution of (S) -3- [N- [3- (trifluoromethyl) benzoyl] glycyl] aminopyrrolidine 2.8 mmol / g, 30 mg) was added to a solution of benzyl bromide (0.050 mmol) in acetonitrile (0.4 mL). The reaction mixture is stirred at 45 캜 for 5 hours. After the mixture is cooled to room temperature, the resin is removed by filtration and the filtrate is concentrated. The residue is dissolved in acetonitrile (1.0 mL) and phenylisocyanate (0.008 mL, 0.05 mmol) is added. The mixture was stirred at room temperature for 1 hour, placed on a Varian ^占 SCX column and rinsed with methanol (15 mL). The product was eluted with 2M NH ₃ in methanol (6 mL) and concentrated to give (S) -1-benzyl-3- [N-3- (trifluoromethyl) benzoyl] glycyl] aminopyrrolidine ) (9.0 mg, 44%). The purity is determined by RPLC / MS (99%). ESI / MS m / e 406.0 (M ⁺ H, C ₂₁ H ₂₂ F ₃ N ₃ O ₂ )
[695] Example 575 Synthesis of (R) -1- (4-butylbenzyl) -3 - [[N-3- (trifluoromethylbenzoyl) glycyl] amino] pyrrolidine
[696] (R) -3- [N- [3- ( trifluoromethyl) benzoyl] glycyl] aminopyrrolidine (0.050nmo1), 4- butyl-benzaldehyde _{(0.18mmo1), NaBH 3 CN (} 0.23mmo1) and methanol (1.85 mL) was added acetic acid (0.060 mL). The reaction mixture is stirred at 60 占 폚 for 12 hours. Cool to room temperature, place on a Varian ^™ SCX column and rinse with methanol (15 mL). The product was eluted with a 2M NH3 solution in methanol (5 mL) and concentrated to give (R) -1- (4-butylbenzyl) -3- [N- [3- (trifluoromethylbenzoyl) glycyl] amino] (Compound No. 1648) (20.6 mg, 89%). Purity is determined by RPLC / MS (91%). ESI / MS m / e 462.2 (M ⁺ + H, C ₂₅ H ₃₀ F ₃ N ₃ O ₂ )
[697] [Examples 576-738]
[698] The compounds used in the present invention are synthesized according to the method of Example 574 or 575, respectively, using corresponding starting materials and reactants. If desired, the target is obtained by purification using preparative TLC or chromatography (HPLC- _C18 ). ESI / MS data, yield and yield are summarized in Table 8.
[699] [Table 8a]
[700]
[701] [Table 8b]
[702]
[703] [Table 8c]
[704]
[705] [Table 8d]
[706]
[707] [Table 8e]
[708]
[709] * Yield of trifluoroacetic acid salt
[710] [Examples 739-748]
[711] The compounds used in the present invention are synthesized according to the method of Example 575, using the corresponding starting materials and reactants, respectively. If necessary, the desired product is obtained by purification by preparative TLC. Table 9 summarizes the ESI / MS data, yield and yield.
[712] [Table 9]
[713]
[714] Example 749. Synthesis of (R) -3 - [[N- (2-amino-5-trifluoromethoxybenzoyl) glycyl] amino] -1- (3-hydroxy-4-methoxybenzyl) (Compound No. 1896) Synthesis of
[715] (0.050 mmol) of 3-hydroxy-4-hydroxy-4- (trifluoromethoxy) benzoyl] glycyl] aminopyrrolidine Acetic acid (0.050 mmol) is added to a mixture of methoxybenzaldehyde (0.060 mmol), NaBH ₃ CN (0.15 mmol) and methanol (1.3 mL). The reaction mixture is stirred at 60 占 폚 for 8 hours. After cooling to room temperature, place on a Varian ^™ SCX column, elute with methanol (10 mL) solution and wash. The product was eluted and concentrated with methanol (5mL) solution of 2M NH _3. To the resulting residue is added a 4M solution of HCl in 1,4-dioxane, and the solution is stirred at room temperature overnight. (R) -3 - [[N- (2-amino-5-trifluoromethoxybenzoyl) glycyl] amino] -1- (3-hydroxy-4-methoxy Benzyl) pyrrolidine (Compound No. 1896) (9.1 mg, 38%). The purity is determined by RPLC / MS (93%). ES / MS m / e 483 ( M + + H, C 22 H 25 F 3 N 4 O 5)
[716] [Examples 750 to 757]
[717] The compound used in the present invention is synthesized according to the method of Example 749 using the corresponding raw materials and reactants, respectively. ESI / MS data, yield and yield are summarized in Table 10.
[718] [Table 10]
[719]
[720] Example 758: Synthesis of (R) -3 - [[N- (2-amino-5-trifluoromethyl) benzoyl) glycyl] amino] -1- (4-vinylbenzyl) pyrrolidine ) Synthesis of
[721] (0.050 mmol), 4-vinylbenzyl chloride (9.9 mg, 0.065 mL, 0.050 mmol), and N, N-dimethylacetamide ), Piperidinomethyl polystyrene (60 mg), acetonitrile (1.0 mL) and chloroform (0.03 mL) was stirred at 50 ° C for 12 hours. The reaction mixture is cooled to room temperature and placed on a Varian ^™ SCX column and rinsed with methanol (15 mL). The product was eluted and concentrated using a 2M NH ₃ in methanol (5 mL) solution to give (R) -3 - [[N- (2-amino-5- (trifluoromethyl) benzoyl) - (4-vinylbenzyl) pyrrolidine (Compound No. 1701) (19.6 mg, 88%). Purity is determined by RPLC / MS (92%). ESI / MS m / e 547.2 (M ⁺ + H, C ₂₃ H ₂₅ ClF ₃ N ₄ O ₂ )
[722] [Example 759-762]
[723] The compound used in the present invention is synthesized according to the method of Example 758 using the corresponding raw materials and reactants, respectively. If necessary, the desired product is obtained by purification by preparative TLC. ESI / MS data, yield and yield are summarized in Table 11.
[724] [Table 11]
[725]
[726] [Example 763] (R) -3 - [[N- (2-Amino-5- (trifluoromethoxy) benzoyl) glycyl] amino] -1- (2,4-dichlorobenzyl) pyrrolidine Compound No. 1905)
[727] (0.050 mmol), 2,4-dichlorobenzyl chloride (0.066 mL), and N, N-dimethylacetamide were added to a solution of (R) -3 - [[N- , Piperidinomethyl polystyrene (60 mg), acetonitrile (0.8 mL) and chloroform (0.5 mL) was stirred at 60 占 폚 for 12 hours. The reaction mixture is cooled to room temperature and placed on a Varian ^™ SCX column and washed with 50% chloroform / methanol (10 mL) and methanol (10 mL). The product was eluted and concentrated with methanol (5mL) solution of 2M NH _3. To the resulting residue was added a solution of 4M HCl in 1,4 dioxane (2 mL), and the mixture was stirred at room temperature overnight. Amino-5- (trifluoromethoxy) benzoyl) glycyl] amino] -1- (2,4-dichlorobenzyl) piperidine was obtained by concentrating and purifying by preparative TLC. Pyrrolidine (Compound No. 1905) (17.6 mg, 70%). The purity is determined by RPLC / MS (93%). ESI / MS m / e 505 (M ⁺ + H, C ₂₁ H ₂₁ C ₁₂ F ₃ N ₄ O ₃ )
[728] [Example 764-770]
[729] The compounds used in the present invention are synthesized according to the method of Example 763 using the corresponding starting materials and reactants, respectively. ESI / MS data, yield and yield are shown in Table 12
[730] .
[731] [Table 12]
[732]
[733] Example 771 Synthesis of (R) -3 - [[N- (2-amino-5-trifluoromethoxybenzoyl) glycyl] amino] -1- (2-amino-4-chlorobenzyl) pyrrolidine Compound No. 1921)
[734] (0.050 mmol), 4-chloro-2-nitrobenzyl chloride (0.050 mmol), and N, N-dimethylformamide , Piperidinomethyl polystyrene (60 mg), acetonitrile (1.0 mL) and chloroform (0.7 mL) was stirred overnight at 50 占 폚. The reaction mixture is cooled and placed on a Varian ^™ SCX column and washed with 50% chloroform / methanol (10 mL) and methanol (10 mL). The product was eluted with methanol (5mL) solution of 2M NH ₃ and concentrated. Ethanol (3 mL) and 10% palladium carbon were added to the obtained residue, and the solution was stirred at room temperature for 1.5 hours under a hydrogen atmosphere. (R) -3 - [[N- (2-amino-5-trifluoromethoxybenzoyl) glycyl] amino] -1- Benzyl) pyrrolidine (Compound No. 1921) (2.2 mg, 6%). Purity is determined by RPLC / MS (81%). ESI / MS m / e 486.2 (M ⁺ + H, C ₂₁ H ₂₃ ClF ₃ N ₅ O ₃ )
[735] Example 772 Synthesis of (R) -3 - [[N- (2-amino-5-trifluoromethylbenzoyl) glycyl] amino] (Compound No. 2120) Synthesis of
[736] (0.050 mmol), 4-bromo-2 (4-fluoro-2-methylphenyl) A solution of NaBH3CN (0.25 mmol) in methanol (0.50 mL) is added to a mixture of ₄ -fluorobenzaldehyde (0.015 mmol), methanol (1.5 mL) and acetic acid (0.016 mL). The reaction mixture is stirred at 50 占 폚 overnight. After cooling to room temperature, place on a Varian ^™ SCX column and rinse with methanol (5 mL x 2). The product was eluted and concentrated with methanol (5mL) solution of 2M NH _3. The residue is dissolved in methanol (0.25 mL) and a dioxane solution of 4 M HCl is added. The solution is stirred at room temperature for 5 hours and concentrated. The residue is dissolved in methanol, loaded on a Varian ^占 SCX column and washed with methanol (5 mL x 2). The product is eluted with a solution of 2M NH3 in methanol (5 mL) and concentrated. The resulting residue was dissolved in ethyl acetate (0.5 mL), loaded on a Varian ^™ SCX column, eluted with ethyl acetate / methanol = 5: 1 (6 mL) and concentrated to give (R) -3- [ (Compound No. 2120) (16.0 mg, 31%) was obtained as a colorless amorphous solid from methyl 2- (trifluoromethyl) benzyl) glycyl] amino] -1- (4-bromo-2- fluorobenzyl) pyrrolidine Purity is determined by RPLC / NIS (99%). ESI / MS 517.O (M ⁺ + H, C ₂₁ H ₂₁ BrF ₄ N ₄ O ₂ )
[737] [Example 773-793]
[738] The compound used in the present invention is synthesized according to the method of Example 772 using the corresponding starting materials and reactants, respectively. ESI / MS data, yield and yield are summarized in Table 13.
[739] [Table 13]
[740]
[741] [Example 794] (R) -3 - [[N- (2-amino-5-trifluoromethylmancoyl) glycyl] amino] -1- (2,4-dimethoxypyrimidin- Ylmethyl) pyrrolidine (Compound No. 2175) Synthesis of
[742] Amino] pyrrolidine (17.2 mg, 0.04 mmol) was dissolved in THF (1 mL) and a solution of 2,4 (2,4,6-tetramethylpiperidin- (6.7 mg, 0.04 mmol) was added followed by sodium triacetoxy borohydride (12.7 mg, 0.06 mmol) and glacial acetic acid (2.4 mg, 0.04 mmol). The mixture is stirred at 50 &lt; 0 &gt; C for 24 hours and then concentrated. The residue is dissolved in dichloromethane (1 mL) and washed with 1 M aqueous NaOH (1 mL). The organic layer was collected and concentrated, and a dichloromethane (1 mL) solution of 25% trifluoroacetic acid was added. The mixture was stirred at room temperature for 1 hour and then concentrated. The residue was purified by HPLC to give (R) -3 - [[N- (2-amino-5-trifluoromethylbenzoyl) glycyl] amino] -1- (2,4-dimethoxypyrimidin- Ylmethyl) pyrrolidine (Compound No. 2175) (18.6 mg, 78%). The purity is determined by RPLC / MS (98%). ESI / MS m / e 483 (M ⁺ + H, C ₂₁ H ₂₅ F ₃ N ₆ O ₄ )
[743] [Examples 795-803]
[744] The compounds used in the present invention are synthesized according to the method of Example 794 using the corresponding starting materials and reactants, respectively. ESI / MS data, yield and yield are summarized in Table 14.
[745] [Table 14]
[746]
[747] Example 804 Synthesis of (R) -1- (2-amino-4,5-methylenedioxybenzyl) -3 - [[ Pyrrolidine (Compound No. 2127) Synthesis of
[748] Amino] -1- (4,5-methylenedioxy-2-nitrobenzyl) pyrrolidine (prepared from (R) -3 - [[ 30.5 mg), 10% Pd carbon (6 mg) and methanol (3 mL) was stirred at room temperature for 10 hours under a hydrogen atmosphere. The palladium catalyst is filtered with celite and the filtrate is concentrated. Purified by solid phase extraction (Bond Elut ^TM SI, 20% methanol / ethyl acetate) (R) -1- (2- Amino-4, 5-methylenedioxy-benzyl) -3 - [[N- (2- amino- (5-trifluoromethylbenzoyl) glycyl] amino] pyrrolidine (Compound No. 2127) (21.9 mg, 76%). Purity is determined by RPLC / MS (95%). ESI / MS m / e 48.0 (M ⁺ + H, C ₂₂ H ₂₄ F ₃ N ₅ O ₄ )
[749] [Example 805-806]
[750] The compounds used in the present invention are synthesized according to the method of Example 804, using the corresponding starting materials and reactants, respectively. ESI / MS data, yield and yield are summarized in Table 15.
[751] [Table 15]
[752]
[753] [Example 807] (2-amino-5-trifluoromethylbenzoyl) glycyl] amino] pyrrolidine ( Compound No. 2132)
[754] (4-chloro-3-nitrobenzyl) pyrrolidine (32.6 mg), 10 &lt; RTI ID = 0.0 &gt; % Palladium on carbon (8 mg), ethyl acetate (2.7 mL) and methanol (0.3 mL) was stirred at room temperature for 15 hours under a hydrogen atmosphere. The palladium catalyst is removed by filtration and the filtrate is concentrated. Purified by solid phase extraction (Bond Elut ^TM SI, 20% methanol / ethyl acetate) (R) -1- (3- amino-4-chloro menjil) -3 - [[N- (2- amino-5-trifluoromethyl (Methylthiobenzoyl) glycyl] amino] pyrrolidine (Compound No. 2132) (10.5 mg, 34%). Purity is determined by RPLC / MS (84%). ESI / MS m / e 470.2 (M + H, C ₂₁ H ₂₃ F ₃ N ₅ O ₂ )
[755] [Example 808] (R) -1- (2-Amino-4,5-methylenedioxybenzyl) -3 - [[N- (2- (tert-butoxycarbonylamino) -5- Methylbenzoyl) glycyl] amino] pyrrolidine Synthesis of
[756] (R) -3 - [[N- (2- (tert-butoxycarbonylamino) -5-trifluoromethylbenzoyl) glycyl] amino] pyrrolidine, oxy-2-methanol (1.50mL) solution of the nitrobenzaldehyde _{(0.45 mmol), NaBH 3 CN} (0.75mmol) in a mixture of methanol (4.5mL) and acetic acid (0.048mL) was added. The reaction mixture is stirred at 50 占 폚 overnight. Cool to room temperature, place on a Varian ^™ SCX column and rinse with methanol. By eluting the product with 2M NH ₃ in methanol and concentrated (R) -3 - [[N- (2- (tert- butoxycarbonylamino) -5-trifluoromethyl-benzoyl) glycyl] amino] - To obtain 1- (4,5-methylenedioxy-2-nitrobenzyl) pyrrolidine.
[757] The resulting (R) -3 - [[N- (2- (tert-butoxycarbonylamino) -5- trifluoromethylbenzoyl) glycyl] amino] -1- (4,5- (Nitrobenzyl) pyrrolidine (0.150 mmol), 10% Pd carbon (22 mg) and methanol (4.5 mL) was stirred overnight at room temperature under a hydrogen atmosphere. The palladium catalyst was removed by filtration and the filtrate was concentrated to obtain (R) -1- (2-amino-4,5-methylenedioxybenzyl) -3 - [[N- (2- (tert- ) -5-trifluoromethylbenzoyl) glycyl] amino] pyrrolidine (87.1 mg, quantitative). By-products that should be noted are not detected in TLC.
[758] In addition, the reaction of (R) -1- (3-amino-4-methoxybenzyl) -3 - [[N- (2- (tert- butoxycarbonylamino) -5- trifluoromethylbenzoyl) glycyl] Amino] pyrrolidine and (R) -1- (3-amino-4-methylbenzyl) -3 - {[N- (2- (tert- butoxycarbonylamino) -5- trifluoromethylbenzoyl) Glycyl] amino] pyrrolidine was synthesized according to the method of Example 808 using the corresponding starting materials and reactants, respectively.
[759] (R) -1- (3-amino-4-methoxybenzyl) -3 - [[N- (2- (tert- butoxycarbonylamino) -5- trifluoromethylbenzoyl) glycyl] amino] Pyrrolidine: 101 mg, quantitative; By-products that should be noted are not detected in TLC.
[760] (R) -1- (3-amino-4-methylbenzyl) -3- [[N- (2- (tert- butoxycarbonylamino) -5- trifluoromethylbenzoyl) glycyl] amino] Lt; / RTI &gt;: 97.2 mg, quantitative; By-products that should be noted are not detected in TLC.
[761] [Example 809] (R) -1- (3-Amino-4-chlorobenzyl) -3 - [[N- (2- (tert- butoxycarbonylamino) -5-trifluoromethylbenzoyl) Lysyl] amino] pyrrolidine &lt; / RTI &gt;
[762] (0.150 mmol), 4-chloro-3- (3-fluorophenyl) propyl] amino] methanol (1.50mL) solution of the nitrobenzaldehyde _{(0.45mmol), NaBH 3 CN (} 0.75mmol) in a mixture of methanol (4.5mL) and acetic acid (0.048mL) was added. The reaction mixture is stirred at 50 占 폚 overnight. Cool to room temperature, place on a Varian ^™ SCX column and rinse with methanol. By eluting the product with 2M NH ₃ in methanol and concentrated (R) -3 - [[N- (2- (tert- butoxycarbonylamino) -5-trifluoromethyl-benzoyl) glycyl] amino] - 1- (4-chloro-3-nitrobenzyl) pyrrolidine.
[763] (4-chloro-3-nitrobenzyl) glycyl] amino] -1- (4-chlorobenzyl) Pyrrolidine, 10% Pd carbon (22 mg), ethyl acetate (2.7 mL) and methanol (0.3 mL) was stirred at room temperature for 15 hours under a hydrogen atmosphere. The palladium catalyst was removed by filtration and the filtrate was concentrated to obtain (R) -1- (3-amino-4-chlorobenzyl) -3 - [[N- (2- (tert-butoxycarbonylamino) Trifluoromethylbenzoyl) glycyl] amino] pyrrolidine (89.7 mg, quantitative). By-products that should be noted are not detected in TLC.
[764] [Example 810] (2-amino-5-trifluoromethylbenzoyl) glycyl] amino] pyrrolidine (Compound No. 2187) Synthesis of
[765] (3-amino-4-hydroxybenzyl) -3 - [[N- (2- (tert- butoxycarbonylamino) -5-trifluoromethylbenzoyl ) Glycyl] amino] pyrrolidine (20 mg) in 4 M HCl dioxane (2.0 mL) was stirred at room temperature overnight. After concentrating the solution, the residue is dissolved in methanol, placed on a Varian ^™ SCX column, washed with methanol, and eluted with 2M NH ₃ in methanol. After concentration preparative TLC (SiO _2, ethyl acetate / methanol = 4: 1) to give (R) -1- (3- amino-4-hydroxybenzyl) -3 - [[N- (2- amino- (5-trifluoromethylbenzoyl) glycyl] amino] pyrrolidine (Compound No. 2187) (9.6 mg, 59%). Purity is determined by RPLC / MS (86%). ESI / MS m / e 452.3 (M ⁺ + H, C ₂₁ H ₂₄ F ₃ N ₅ O ₃ )
[766] Example 811: Synthesis of (R) -3 - [[N- (2-amino-5-trifluoromethylbenzoyl) glycyl] amino] Lt; / RTI &gt; (Compound No. 2133) Synthesis of
[767] (R) -1- (3-amino-4-chlorobenzyl) -3 - [[N- (2- (tert- butoxycarbonylamino) -5- trifluoromethylbenzoyl) glycyl] amino] a pyrrolidine (44.9㎎), methanol (0.95mL), acetic acid (0.05mL) and 37% NaBH ₃ CN (38㎎) in a mixture of HCHO aqueous solution (0.15mL) was added. The reaction mixture is stirred at 50 占 폚 overnight. After cooling to room temperature and concentration, 2M NaOH aqueous solution and ethyl acetate were added to the residue, and the organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layers are combined, dried and concentrated. The residue is placed on a Varian ^占 SCX column and rinsed with methanol. The product is eluted with 2M NH ₃ in methanol and concentrated. The residue is dissolved in 50% concentrated hydrochloric acid / dioxane and stirred at room temperature for 1 hour. The reaction solution was adjusted to pH 10 with 5M aqueous NaOH solution and extracted with ethyl acetate (twice). The combined extracts are dried over Na ₂ SO ₄ , filtered and concentrated. Purified by preparative TLC (SiO _2, 20% methanol / ethyl acetate) (R) -3 - [[ N- ( 2-methylbenzoyl-amino-5-trifluoromethylbenzyl) glycyl] amino] -1- [4- Chloro-3- (dimethylamino) benzyl] pyrrolidine (Compound No. 2133) (10.9 mg, 28%). Purity is determined by RPLC / MS (95%). ESI / MS m / e 498.3 (M ⁺ + H, C ₂₃ H ₂₇ ClF ₃ N ₅ O ₂ )
[768] [Example 812-814]
[769] The compounds used in the present invention are synthesized according to the method of Example 811 using the corresponding starting materials and reactants, respectively. ESI / MS data, yield and yield are summarized in Table 16.
[770] [Table 16]
[771]
[772] [Example 815] (2-amino-5-trifluoromethylbenzoyl) glycylamino] -1- (3-methylamino-4-hydroxybenzyl) pyrrolidine (Compound No. 2158) Synthesis of
[773] Amino] -4-hydroxybenzyl) -3 - [[N- (2- (tert- butoxycarbonylamino) -5-trifluoromethylbenzoyl) glycyl] amino] avoid pyrrolidine (27.3㎎, 0.049mmol), 37% HCHO solution _{(4.0㎎, 0.049mmol), NaBH 3} CN (9.2㎎) in a mixture of acetic acid (0.10mL) and methanol (1.3mL) is added. The reaction mixture is stirred at 60 占 폚 overnight. Cool to room temperature, place on a Varian ^™ SCX column and wash with methanol (5 mL x 2). The product was eluted using a methanol solution (8mL) of 2M NH ₃ and concentrated.
[774] The residue obtained is dissolved in methanol (1 mL) and a dioxane solution of 4M HCl (1.0 mL) is added. After stirring at room temperature for 3 hours, it is concentrated. The residue is dissolved in methanol (1 mL), loaded on a Varian ^™ SCX column, washed with methanol (5 mL x 2) and eluted with 2 M NH ₃ in methanol (8 mL). It was concentrated, purified by preparative _{TLC (SiO 2) (R)} -3 - [[N- ( 2-methylbenzoyl-amino-5-trifluoromethylbenzyl) glycyl] amino] -1- (3-methylamino- 4-hydroxybenzyl) pyrrolidine (Compound No. 2158) (4.3 mg, 19%). Purity is determined by RPLC / MS (71%). ESI / MS m / e 480.0 ( M + + H, C 22 H 26 F 3 N 5 O 3)
[775] Example 816: Synthesis of (R) -1- (3-Acetylamino-4-methoxybenzyl) -3 - [[N- (2-amino-5-trifluoromethylbenzoyl) glycyl] amino] (Compound No. 2152) Synthesis of
[776] Amino] -4-hydroxybenzyl) -3 - [[N- (2- (tert- butoxycarbonylamino) -5-trifluoromethylbenzoyl) glycyl] amino] To a solution of pyrrolidine (50.5 mg) in pyridine (1 mL) was added acetic anhydride (1 mL). The reaction mixture is stirred at room temperature over night and methanol is added. After concentration, 1M aqueous NaOH solution is added, extracted with ethyl acetate and the organic layer is concentrated. Purified by preparative _{TLC (SiO 2) (R)} -1- (3- acetylamino-4-methoxybenzyl) -3 - [[N- (2- (tert- butoxycarbonylamino) -5-tree Fluoromethylbenzoyl) glycyl] amino] pyrrolidine.
[777] The obtained (R) -1- (3-acetylamino-4-methoxybenzyl) -3 - [[N- (2- (tert- butoxycarbonylamino) -5- trifluoromethylbenzoyl) glycyl] Amino] pyrrolidine are dissolved in a dioxane solution of 50% 6M hydrochloric acid and stirred at room temperature for 2 hours. The mixture is adjusted to pH 10 with 5M NaOH solution and extracted with ethyl acetate. The organic layer was concentrated and purified by preparative TLC (SiO ₂ ) to give (R) -1- (3-acetylamino-4-methoxybenzyl) -3 - {[N- (2-amino-5-trifluoromethylbenzoyl ) Glycyl] amino] pyrrolidine (Compound No. 2152) (3.7 mg, 8%). The purity is determined by RPLC / MS (100%). ESI / MS m / e 508.3 (M ⁺ + H, C ₂₄ H ₂₈ F ₃ N ₅ O ₄ )
[778] [Example 817-819]
[779] The compounds used in the present invention are synthesized according to the method of Example 816, using the corresponding starting materials and reactants, respectively. ESI / MS data, yield and yield are summarized in Table 17.
[780] [Table 17]
[781]
[782] Example 820: Synthesis of (R) -3 - [[N- (2-amino-5-trifluoromethylbenzoyl) glycyl] amino] -1- (benz [d] oxazol- (Compound No. 2189) Synthesis of
[783] Synthesis of (R) -1- (3-amino-4-hydroxybenzyl) -3 - [[N- (2- (tert-butoxycarbonylamino) -5- Trimethyl orthoformate (0.20 mL, 3.3 eq.) And pyridinium p-toluenesulfonate (1.2 mg, 0.4 eq.) Were added to a THF (2 mL) solution of . The reaction mixture is stirred under reflux overnight. After cooling to room temperature, it is concentrated. The residue was dissolved in ethyl acetate and, placed on BondElut ^TM Si column, ethyl acetate / methanol = 4: elute with a 1 concentration.
[784] The resulting residue is dissolved in ethyl acetate (1.5 mL) and a dioxane solution of 4M HCl is added. The solution is stirred at room temperature overnight, adjusted to pH 10 with 5M aqueous NaOH solution and extracted with ethyl acetate. (R) -3 - [[N- (2-amino-5-trifluoromethylbenzoyl) glycyl] amino] propionic acid was obtained by concentrating the extract and purifying by preparative TLC (SiO ₂ , ethyl acetate / methanol = 4: -1- (benz [d] oxazol-5-yl) pyrrolidine (Compound No. 2189) (0.5 mg, 3%). The purity is determined by RPLC / MS (97%). ESI / MS m / e 462.3 ( M + + H, C 22 H 22 F 3 N 5 O 3)
[785] Example 821: Synthesis of (R) -3 - [[N- (2-amino-5-trifluoromethylbenzoyl) glycyl] amino] -1- (benzo [c] thiadiazol- Lt; / RTI &gt; (Compound No. 2183) Synthesis of
[786] Methanesulfonyl chloride (0.0042 mL) was added to a mixture of 5- (hydroxymethyl) benzo [c] thiadiazole (8.3 mg, 0.050 mmol), (piperidinomethyl) polystyrene (86 mg) and chloroform And the mixture was stirred at room temperature for 1.5 hours. (0.060 mmol) of (R) -3 - [[N- (2- (tert-butoxycarbonylamino) -5-trifluoromethylbenzyl) glycyl] amino] pyrrolidine And the mixture was stirred at 50 ° C for 3 hours. After cooling to room temperature, phenyl isocyanate (30 mg) was added and stirred for 1 hour at room temperature, placed on a Varian ^™ SCX column, and washed with methanol (5 mL) and chloroform (5 mL). The product is eluted with 2M NH ₃ in methanol (3 mL) and concentrated.
[787] The resulting material is dissolved in dichloromethane (1 mL) and a dichloromethane solution of 1M chlorotrimethylsilane and 1M phenol (1 mL) is added. The solution is stirred at room temperature for 5 hours, placed on a Varian ^™ SCX column, and washed with methanol and dichloromethane. The product is eluted with 2M NH ₃ in methanol and concentrated.
[788] Preparative TLC (SiO _2, ethyl acetate / methanol = 3: 1) to give (R) -3 - [[N- (2- amino-5-methylbenzoyl trifluoromethyl) glycyl] amino] -1- ( Benzo [c] thiadiazol-5-yl) pyrrolidine (Compound No. 2183) (11.5 mg, 48%). Purity is determined by RPLC / MS (86%). ESI / MS m / e 479.2 (M ⁺ + H, C ₂₁ H ₂₁ F ₃ N ₆ O ₂ S)
[789] Reference Example 6 Synthesis of 4 - [[N- (1- (9-fluorenylmethoxycarbonyl) pyrrolidin-3-yl) carbamoylmethyl] aminomethyl] -3- methoxyphenyloxymethyl-polystyrene Synthesis of
[790] Acetic acid (0.3 mL), triacetoxyhydrogenase (0.3 mL), and triethylamine were added to a solution of (R) -1- (9-fluorenylmethoxycarbonyl) -3-glycylaminopyrrolidine hydrochloride (4.38 g, 10 mmol) in DMF Sodium boron (1.92 g) and 4-formyl-3- (methoxyphenyloxymethyl) -polystyrene (1 mmol / g, 200 g) are added. The mixture is shaken for 2 hours and then filtered. The resin is washed with methanol, DMF, dichloromethane and methanol and dried to obtain the object (2.73 g).
[791] [Example 822-912] Solid phase synthesis of 3-aminopyrrolidine
[792] Diisopropylethylamino (3.6 mL) is added to a mixture of the corresponding carboxylic acid (1.6 mmol), HBTU (1.6 mmol) and DMF (6 mL) and shaken for 2 hours. 4-yl) carbamoylmethylaminomethyl] -3-methoxyphenyloxymethyl-polystyrene (400 mg, 0.4 &lt; RTI ID = 0.0 & mmol), shake for 1 hour, and then filter. The resin is washed with DMF and dichloromethane and dried.
[793] The resulting resin, a mixture of piperidine (3.2 mL) and DMF (12.8 mL) is shaken for 10 minutes and then filtered. The resin is washed with DMF and dichloromethane and dried.
[794] To this dried resin (0.05 mL) is added a mixture of NaBH (OAc) ₃ (0.25 mmol), acetic acid (0.025 mL) and DMF (1 mL). (2.5 mmol) of the corresponding aldehyde is added thereto, and the mixture is shaken for 2 hours, filtered, and washed with methanol, 10% diisopropylethylamine in DMF, DMF, dichloromethane and methanol. The mixture of resin, water (0.050 mL) and trifluoroacetic acid (0.95 mL) is shaken for 1 hour and then filtered. The resin is washed with dichloromethane and methanol. The filtrate and the washing solution are combined and concentrated. The resulting crude product is placed on a Varian ^™ SCX column and washed with methanol (15 mL). The product was eluted and concentrated with methanol (5mL) solution of 2M NH _3.
[795] If desired, the desired product is obtained by purification by preparative TLC or HPLC. ESI / MS data, yield and yield are summarized in Table 18.
[796] [Table 18a]
[797]
[798] [Table 18b]
[799]
[800] [Table 18c]
[801]
[802] [Table 18d]
[803]
[804] * Yield of trifluoroacetic acid salt
[805] [Referential Example 7] Synthesis of 2-carbamoyl-1- (4-chlorobenzyl) pyrrolidine
[806] triethylamine (7.45 mL) and 4-chlorobenzyl chloride (3.88 g, 24.1 mmol) were added to a solution of dl-prolinamide hydrochloride (2.5 g, 21.8 mmol) in acetonitrile (35 mL). The reaction mixture is stirred at 70 占 폚 for 4 hours and then at 25 占 폚 for 16 hours. The resulting mixture is diluted with dichloromethane (20 mL) and washed with water (30 mL x 3). The organic layer is dried (MgSO ₄ ) and concentrated. Chromatography (SiO ₂ , methanol-dichloromethane) afforded 2-carbamoyl-1- (4-chlorobenzyl) pyrrolidine (5.21 g, 81%).
[807] [Referential Example 8] Synthesis of 2- (aminomethyl) -1- (4-chlorobenzyl) pyrrolidine
[808] 2-carbamoyl-1- (4-chlorobenzyl) pyrrolidine was dissolved in 1M BH ₃ -THF (9.4mL) is heated to 70 ℃. 16 hours and 2 hours after 25 hours, again 1 M BH ₃ -THF (0.5 eq.) Is added. After 40 hours, 1 M hydrochloric acid was added, refluxed for 3 hours, 3M hydrochloric acid (6 mL) was added, and the reaction mixture was heated and stirred for another 3 hours. Cool to 25 ° C, make alkaline with 6M aqueous NaOH and extract with dichloromethane (4 × 15 mL). Chromatography _{(SiO 2, PrOH / H 2} O / NH 4 OH = 8: 1: 1) to give 2- (aminomethyl) -1- (4-chlorobenzyl) pyrrolidine (1.21g, 86%) .
[809] In addition, the optically active (S) -2- (aminomethyl) -1- (4-chlorobenzyl) pyrrolidine and (R) -2- (aminomethyl) -1- (4- chlorobenzyl) pyrrolidine Are synthesized according to the above method using the corresponding raw materials and reactants, respectively.
[810] (S) -2- (aminomethyl) -1- (4-chlorobenzyl) pyrrolidine:
[811]
[812] (R) -2- (aminomethyl) -1- (4-chlorobenzyl) pyrrolidine represents the same ¹ H NMR as the (S) -isomer.
[813] [Example 913] Synthesis of 2 - [(N-benzoylyl) aminomethyl] -1- (4-chlorobenzyl) pyrrolidine (Compound No. 344)
[814] EDCI (23 mg) and HOBt (16.2 mg, 0.10 mmol) were added to a chloroform (1 mL) solution of 2- (aminomethyl) -1- (4- chlorobenzyl) pyrrolidine Mg) and triethylamine (15.2 μL), and the mixture was stirred at 25 ° C for 16 hours. The reaction mixture was diluted with dichloromethane (0.5 mL), washed with 2M aqueous NaOH solution (0.75 mL x 2), filtered through a PTFE membrane, dried and concentrated to give 2 - [(N-benzoylyl) - (4-chlorobenzyl) pyrrolidine (Compound No. 344) (74 mg, quantitative). Purity is determined by RPLC / MS (85%). ESI / MS m / e 442 (M ⁺ + H, C ₂₃ H ₃₂ ClN ₃ O ₂ )
[815] [Examples 914-933]
[816] The compounds used in the present invention are synthesized according to the method of Example 913, using the corresponding starting materials and reactants, respectively. If necessary, the product is purified by chromatography (HPLC-C ₁₈ , acetonitrile / H ₂ O, TFA) to obtain the desired product as a TEA salt. Table 19 summarizes the ESI / MS data, yield and yield. Further, Compound Nos. 339 and 340 each show the following ¹ H NMR.
[817] [Table 19]
[818]
[819] * Yield of trifluoroacetic acid salt
[820] [Example 934]
[821] Compound No. 339 : 82%;
[822]
[823] [Example 935]
[824] Compound No. 340 : 68%;
[825]
[826] Referential Example 9 Synthesis of 3- (aminomethyl) -1- (4-chlorobenzyl) pyrrolidine
[827] To a mixture of 4-carboxy- 1- (4-chlorobenzyl) pyrrolidin-2-one (5.05 g, 20 mmol), EDCI (2.85 g, 22 mmol), HOBt (2.97 g, 22 mmol) and dichloromethane A dioxane solution of 0.5 M ammonia (60 mL, 30 mmol) is added. The reaction mixture is stirred at room temperature for 15 hours, and washed with 2M HCl (3 times) and 2M aqueous NaOH solution (100 mL x 4). The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated to obtain 4-carbamoyl-1- (4-chlorobenzyl) pyrrolidin-2-one (1.49 g) as a colorless solid.
[828] To a THF (15 mL) solution of 4-carbamoyl-1- (4-chlorobenzyl) pyrrolidin-2-one (1.49 g) in THF (25 mL) is added 1.0 M BH ₃ . The reaction mixture is stirred at room temperature for 15 hours. After cooling to room temperature, the solvent is removed under reduced pressure. Water (30 mL) and concentrated hydrochloric acid (10 mL) were added and the mixture was stirred at 100 ° C for 2 hours and at room temperature for 1 hour. 2M aqueous NaOH solution (100 mL) was added, and the mixture was extracted with ethyl acetate (50 mL 3). The organic layers are combined, dried over K ₂ CO ₃ , filtered, and concentrated. Purification by column chromatography (SiO ₂ , 15% methanol-5% triethylamine / dichloromethane) afforded 3- (aminomethyl) -1- (4- chlorobenzyl) pyrrolidine (860 mg, 19% It is obtained as an oil.
[829] [Referential Example 10] Synthesis of l- (4-chlorobenzyl) -3 - [(glycylamino) methyl] pyrrolidine
[830] (860 mg, 3.8 mmol), triethylamine (5.7 mmol), N-tert-butoxycarbonylglycine (704 mg), EDCI ( 594 mg), HOBt (673 mg) and dichloromethane (20 mL) was stirred at room temperature for 15 hours. Dichloromethane (50 mL) was added and the solution was washed with 2M aqueous NaOH solution (50 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 3 - [[N- (tert-butoxycarbonyl) glycyl] ] -1- (4-chlorobenzyl) pyrrolidine (1.31 g, 90%).
[831] To a methanol (10 mL) solution of 3 - [[N- (tert- butoxycarbonyl) glycyl] aminomethyl] -1- (4- chlorobenzyl) pyrrolidine (804 mg, 2.11 mmol) Add dioxane solution (5 mL). After stirring at room temperature for 3.5 hours, concentrate and add 1 M aqueous NaOH solution (20 mL). The resulting mixture was extracted with dichloromethane (20 mL x 3), and the combined extracts were dried over sodium sulfate and concentrated to give 1- (4-chlorobenzyl) -3 - [(glycylamino) methyl] pyrrolidine (599 mg, 100%) . The purity is determined by RPLC / MS (100%). ESI / MS m / e 282.2 ( M + + H, C 14 H 2O ClN 3 O)
[832] [Example 936] Synthesis of 3 - [[N- [3-trifluoromethylbenzoyl) glycyl] aminomethyl] -1- (4-chlorobenzyl) pyrrolidine (Compound No. 1463)
[833] 3- [(glycylamino) methyl] pyrrolidine (0.050 mmol) was added to a solution of 3- (trifluoromethyl) benzoyl chloride (0.058 mmol) in dichloromethane In dichloromethane (0.2 mL) and a solution of piperidinomethyl polystyrene (60 mg) in dichloromethane (1 mL). The reaction mixture is stirred at room temperature for 2.5 hours, then methanol (0.30 mL) is added and the reaction mixture is placed on a Varian ^™ SCX column and washed with methanol (15 mL). The product was eluted with a 2M NH ₃ in methanol (5 mL) solution and concentrated to give (3 - [[N- [3-trifluoromethylbenzoyl) glycyl] aminomethyl] -1- (4- chlorobenzyl) pyrrolidine (Compound No. 1463) (22.4 mg, 99%). The purity is determined by RPLC / MS (97%). ESI / MS m / e 454.2 (M ⁺ + H, C ₂₂ H ₂₃ ClF ₃ N ₃ O ₂ )
[834] [Examples 937-944]
[835] The compounds used in the present invention are synthesized according to the method of Example 936, using the corresponding raw materials and reactants, respectively. Table 20 summarizes ESI / MS data, yield and yield.
[836] [Table 20]
[837]
[838] Example 945 Synthesis of 3 - [[N- (2-amino-4,5-difluorobenzoyl) glycyl] aminomethyl] -1- (4-chlorobenzyl) pyrrolidine (Compound No. 1506)
[839] To a solution of the chloroform (1.35 mL) and tert-butanol (0.05 mL) of 1- (4-chlorobenzyl) -3 - [(glycylamino) methyl] pyrrolidine (0.060 mmol), diisopropylcarbodiimide (0.060 mmol) and HOBt (0.060 mmol) were added. The reaction mixture was stirred at room temperature for 19 hours, then placed on a Varian ^™ SCX column and washed with methanol / chloroform = 1: 1 (10 mL) and methanol (10 mL). The product was eluted with a 2M NH ₃ in methanol (5 mL) solution and concentrated to give 3 - [[N- [2-amino-4,5-difluorobenzoyl) glycyl] aminomethyl] ) Pyrrolidine (Compound No. 1506) (22.0 mg, quantitative). Purity is determined by RPLC / MS (92%). ESI / MS m / e 437 (M ⁺ + H, C ₂₁ H ₂₃ ClF ₂ N ₄ O ₂ )
[840] [Examples 946-952]
[841] The compounds used in the present invention are synthesized according to the method of Example 945 using the corresponding starting materials and reactants, respectively. ESI / MS data, yield and yield are summarized in Table 21.
[842] [Table 21]
[843]
[844] [Reference Example 11] Synthesis of 1- (4-chlorobenzyl) nipecotinic acid
[845] 4-Chlorobenzyl chloride (6.42 g, 39.9 mmol) and ⁱ Pr ₂ NEt (7.74 g, 40.0 mmol) were added to a solution of ethyl nipecotate (6.29 g, 40.0 mmol) in acetonitrile (15 mL). The reaction mixture was stirred at 70 占 폚 for 1.5 hours, and then the solvent was removed under reduced pressure. To the residue was added a saturated aqueous solution of NaHCO ₃ (50 mL) and extracted with ethyl acetate (100 mL). The organic layer was washed with a saturated NaHCO ₃ aqueous solution and dried with Na ₂ SO _4. The solvent was removed under reduced pressure to obtain ethyl 1- (4-chlorobenzyl) nipecotate as a red-yellow oil (11.0 g, 97.8%). It is used without purification. The purity is determined by RPLC / MS (97%). ESI / MS m / e 382.2 (M ⁺ + H, C ₁₅ H ₂₁ ClNO ₂ )
[846] A solution of LiOH (1.66 g) in H ₂ O (25 mL) is added to a solution of ethyl 1- (4-chlorobenzyl) ethylnicotinate in THF (60 mL). The reaction mixture is stirred at room temperature for 1.5 hours. The solvent is removed under reduced pressure to give an amorphous solid. Column chromatography purification (SiO _2, 50% methanol: dichloromethane) to give 1- (4-chlorobenzyl) you Chapeco tinsan (9.75g, 98.2%) as a pale yellow amorphous solid. Purity is determined by RPLC / MS (> 95%). ESI / MS m / e 254.0 (M ⁺ + H, C ₁₃ H ₁₇ ClNO ₂ )
[847] [Referential Example 12] Synthesis of l- (4-chlorobenzyl) -3 - [(tert-butoxycarbonyl) amino] piperidine
[848] To a solution of l- (4-chlorobenzyl) nipecotinic acid (7.06 g, 27.8 mmol) in ^t BuOH (500 mL) was added triethylamine (3.38 g) and activated 3-Molecular sieve (30 g). Diphenylphosphoryl azide (8.58 g) was added and the reaction mixture was stirred under reflux for 18 hours. The organic layer was washed with a saturated aqueous solution of NaHCO ₃ (100 mL × 2) and brine (50 mL), dried (Na ₂ SO ₄ ) and evaporated under reduced pressure Lt; / RTI &gt; The residue was purified by chromatography (SiO ₂ , 25% ethyl acetate-hexane) to give 1- (4-chlorobenzyl) -3 - [(tert- butoxycarbonyl) amino] piperidine (2.95 g, 32.6% Obtained as a crystalline solid. _{^{1 H NMR (CDCl 3, 300㎒}} ) δ1.4-1.75 (br, 4H), 2.2-2.7 (br, 4H), 3.5 (br, 2H), 3.8 (br, 4H), 7.3 (br, 4H) ; Purity is determined by RPLC / MS (&gt; 99%). ESI / MS m / e 269.2 (M ⁺ + H-56, C ₁₇ H ₂₆ ClN ₂ O ₂ )
[849] [Referential Example 13] Synthesis of 3-amino-1- (4-chlorobenzyl) piperidine
[850] To a methanol (25 mL) solution of 1- (4-chlorobenzyl) -3 - [(tert-butoxycarbonyl) amino] piperidine (2.55 g, 7.85 mmol) was added 1 M HCl-Et ₂ O do. The reaction mixture is stirred at 25 占 폚 for 15 hours. The solvent was removed under reduced pressure to obtain 3-amino-1- (4-chlorobenzyl) piperidine dihydrochloride as an amorphous solid (2.49 g, quantitative). Purity is determined by RPLC / MS (> 95%). ESI / MS m / e 225.2 (M ⁺ + H, C ₁₂ H ₁₈ ClN ₂ )
[851] Example 953: Synthesis of 1- (4-chlorobenzyl) -3 - [[N- (3-methylbenzoyl) glycyl] amino] piperidine (Compound No. 355)
[852] (10.6 mg, 0.055 mmol), EDCI (10.5 mg) and 1-hydroxybenzotriazole hydrate (7.4 g) were added to a solution of 1- (4-chlorobenzyl) -3-aminopiperidine Dihydrochloride (14.9 mg, 0.050 mmol) and triethylamine (15.2 mg) in chloroform (2.5 mL). The reaction mixture was stirred at 25 占 폚 for 16 hours and washed with 2N aqueous NaOH solution (2 mL x 2) and brine (1 mL). After filtration through a PTFE membrane, the solvent was removed under reduced pressure to obtain 1- (4-chlorobenzyl) -3 - [[N- (3-methylbenzoyl) glycyl] amino] piperidine (Compound No. 355) 17.4 mg, 87%). The purity is determined by RPLC / MS (97%). ESI / MS m / e 400.0 (M <^+> + H, C ₂₂ H ₂₆ ClN ₃ O ₂ )
[853] [Example 954-982]
[854] The compound used in the present invention is synthesized according to the method of Example 953, using the corresponding starting materials and reactants, respectively. ESI / MS data, yields and yields are summarized in Table 22. Compound No. 358 shows the following ¹ H NMR.
[855] [Table 22]
[856]
[857] [Example 982] Compound No. 358 ;
[858]
[859] [Referential Example 14] Synthesis of 1-benzyl-4 - [[N- (tert-butoxycarbonyl) glycyl] amino] piperidine
[860] (Tert-butoxycarbonyl) glycine (3.48 g, 20 mmol), EDCI (4.02 g, 21 mmol) and 4-amino-1-benzylpiperidine (3.80 g, 20 mmol) in dichloromethane Add HOBt (2.83 g, 21 mmol). The reaction mixture is stirred at room temperature for 12 hours and 2M NaOH solution is then added. The organic layer was separated, and the aqueous layer was extracted with dichloromethane (20 mL x 2). The combined organic layers were washed with water (20 mL) and brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated. Column chromatography (SiO _2, ethyl acetate / methanol / triethylamine = 85: 12: 3) to give a 1-Benzyl -4- [N- (tert- butoxycarbonyl) glycyl] aminopiperidine (6.59 g, 95%).
[861] [Referential Example 15] Synthesis of 1-benzyl-4- (glycylamino) piperidine
[862] To a solution of 1-benzyl-4- [N- (tert-butoxycarbonyl) glycyl] aminopiperidine (6.59 g) in methanol (80 mL) was added a solution of 4 M HCl in dioxane. This solution was stirred at room temperature for 2 hours. After concentration, 2M aqueous NaOH solution (20 mL) is added, extracted with dichloromethane (40 mL), the combined extracts are dried over anhydrous sodium sulfate and concentrated. Column chromatography (SiO _2, ethyl acetate / methanol / triethylamine = 85: 12: 3) 1-Benzyl-4- (glycyl-amino) to give the piperidine obtained (3.91g, 83%):
[863]
[864] Other 4-acylamino-1-benzylpiperidine is synthesized according to the methods of Reference Examples 14 and 15 using the corresponding starting materials and reactants, respectively.
[865] 4- (β-alaninylamino) -1-benzylpiperidine: 2.46 g, 51% (two steps).
[866] 1-Benzyl-4 - ((S) -ylxylamino) piperidine: 1.78 g, 74% (2 steps).
[867] 1-Benzyl-4 - ((R) -ylxylamino) piperidine: 1.48 g, 61% (2 steps).
[868] [Example 983] Synthesis of 4- (N-benzoylglycyl) amino-1-benzylpiperidine (Compound No. 386)
[869] A solution of benzoyl chloride (0.060 mmol) in chloroform (0.4 mL) is added to a solution of 1-benzyl-4- (glycylamino) piperidine (0.050 mmol) and triethylamine (0.070 mmol) in chloroform . After the reaction mixture was shaken at room temperature for 12 hours, (aminomethyl) polystyrene resin (1.04 mmol / g, 50 mg, 50 mmol) was added and the mixture was shaken at room temperature for 12 hours. The reaction mixture is filtered and the resin is washed with dichloromethane (0.5 mL). Dichloromethane (4 mL) was added to the filtrate and the washing solution, and the solution was washed with 2 M aqueous NaOH solution (0.5 mL) to obtain 4- (N-benzoylglycyl) amino-1-benzylpiperidine (Compound No. 386) (11.3 mg, 64%). Purity is determined by RPLC / MS (94%). ESI / MS m / e 352.0 (M ⁺ + H, C ₂₁ H ₂₅ N ₃ O ₂ )
[870] [Examples 984-1034]
[871] The compound used in the present invention is synthesized according to the method of Example 983 using the corresponding starting materials and reactants, respectively. ESI / MS data, yield and yield are summarized in Table 23.
[872] [Table 23a]
[873]
[874] [Table 23b]
[875]
[876] * Yield of trifluoroacetic acid salt
[877] [Referential Example 16] Synthesis of 3-carbamoyl-1- (4-chlorobenzyl) piperidine
[878] Triethylamine (7.0 mL, 50 mmol) and 4-chlorobenzyl chloride (8.05 g, 50 mmol) were added to a solution of nepecotamide (6.40 g, 50 mmol) in acetonitrile (150 mL) and ethanol (20 mL). The reaction mixture is stirred at 50 占 폚 for 16 hours. After cooling to room temperature, a saturated aqueous solution of NaHCO ₃ (50 mL) and water (150 mL) were added, extracted with ethyl acetate (150 mL × 3), and the extract was washed with brine. Dry with Na ₂ SO ₄ and concentrate to give a light red solid. This crude solid was washed with ether (100 mL) to give 3-carbamoyl-1- (4-chlorobenzyl) piperidine (6.98 g, 54%
[879] [Reference Example 17] Synthesis of 3- (aminomethyl) -1- (4-chlorobenzyl) piperidine
[880] 3-Carbamoyl-1- (4-chlorobenzyl) piperidine (3.80 g, 15 mmol) was dissolved in THF (30 mL), 1M BH ₃ -THF (9.4 mL) was added and the mixture was stirred at 70 ° C for 15 hours . After cooling to 0 ° C, 2M hydrochloric acid (50 mL) was added, and the mixture was stirred at room temperature for another 3 hours, made alkaline with 4M NaOH aqueous solution, and extracted with ethyl acetate (100 mL × 3). The combined extracts are washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. Column chromatography (SiO _2, ethyl acetate / ethanol / triethylamine = 80: 15: 5) to give 3- (aminomethyl) -1- (4-chlorobenzyl) piperidine (2.05g, 55%) Lt; / RTI &gt;
[881]
[882] Example 1035 Synthesis of 3 - [(N-benzoylglycyl) amino] methyl-1- (4-chlorobenzyl) piperidine (Compound No. 434)
[883] A solution of benzoyl chloride (0.060 mmol) in chloroform (0.4 mL) was added to a solution of 3 - [(glycylamino) methyl] -1- (4- chlorobenzyl) piperidine (0.050 mmol) and triethylamine (1.0 mL). After the reaction mixture was shaken at room temperature for 2.5 hours, (aminomethyl) polystyrene resin (1.04 mmol / g, 50 mg, 50 mmol) was added and the mixture was shaken at room temperature for 12 hours. Filter and wash the resin with dichloromethane (0.5 mL). The filtrate and the washing solution were combined, dichloromethane (4 mL) was added and the mixture was washed with 2M aqueous NaOH solution (0.5 mL) and concentrated to obtain 3 - [(N-benzoylglycyl) amino] methyl- (Compound No. 434) (14.7 mg, 74%). Purity is determined by RPLC / MS (91%). ESI / MS m / e 400 (M ⁺ + H, C ₂₂ H ₂₆ ClN ₃ O ₂ )
[884] [Examples 1036-1058]
[885] The compounds used in the present invention are synthesized according to the method of Example 1035, using the corresponding starting materials and reactants, respectively. ESI / MS data, yield and yield are summarized in Table 24.
[886] [Table 24]
[887]
[888] [Referential Example 18] Synthesis of 4- (aminomethyl) -1- (4-chlorobenzyl) piperidine
[889] K ₂ CO ₃ (3.02 g) and 4-chlorobenzyl chloride (3.52 g, 21.8 mmol) were added in turn to a solution of 4- (aminomethyl) piperidine (7.00 g, 61.3 mmol) in acetonitrile . The reaction mixture is stirred at 60 占 폚 for 16 hours, then cooled to 25 占 폚 and concentrated. The residue was partitioned between dichloromethane (75 mL) and water (50 mL) and washed with water (50 mL x 2) and brine (50 mL x 1). The organic layer was dried (MgSO ₄ ), concentrated and then purified by chromatography (SiO ₂ , 4% H ₂ O - ⁱ PrOH) to give 4- (aminomethyl) -1- (4- chlorobenzyl) piperidine g, 69%).
[890] Example 1059: Synthesis of 4 - [(N-benzoylglycyl) amino] methyl-1- (4-chlorobenzyl) piperidine (Compound No. 458)
[891] To the dichloromethane (1 mL) solution of 4- (aminomethyl) -1- (4-chlorobenzyl) piperidine (50 mg, 0.21 mmol) was added the terminal uric acid (38 mg, 0.21 mmol), EDCI mmol), HOBt (31 mg, 0.23 mmol) and triethylamine (38 L, 0.27 mmol). The reaction mixture was shaken at 25 ° C for 16 hours, then diluted with 1 mL of dichloromethane, washed with 2 M aqueous NaOH (0.75 mL x 2), dried (MgSO ₄ ) and concentrated. Purified by chromatography (SiO _2, 6-8% methanol / dichloromethane) 4 - [(N- benzoyl-glycyl) amino] get-1- (4-chlorobenzyl) piperidine (Compound No. 458) . This was treated with TFA to give the TFA salt (105 mg, 97%). Purity is determined by RPLC / MS (85%). ESI / MS m / e 400 (M ⁺ + H, C ₂₂ H ₂₆ ClN ₃ O ₂ )
[892] [Examples 1060-1086]
[893] The compound used in the present invention is synthesized according to the method of Example 1059 using the corresponding raw materials and reactants, respectively. ESI / MS data, yield and yield are summarized in Table 25.
[894] [Table 25]
[895]
[896] [Reference Example 19] Synthesis of l- (4-chlorobenzyl) -4- [N- (3,3-diphenylpropyl) aminomethyl] piperidine
[897] In acetonitrile in the presence of 4- (aminomethyl) -1- (4-chlorobenzyl) piperidine (120 mg) and NaI (2.6 eq.) At 70 ° C for 16 hours in the presence of 3,3- Nate (1.0 eq.). After treating with a usual method, the residue was purified by column chromatography (SiO ₂ ) to obtain 1- (4-chlorobenzyl) -4- [N- (3,3-diphenylpropyl) aminomethyl] piperidine , 54%). Purity is determined by RPLC / MS (98%).
[898] [Referential Example 20] Synthesis of l- (4-chlorobenzyl) -4- [N- (2,2-diphenylethyl) aminomethyl] piperidine
[899] (120 mg) was obtained by reacting 4- (aminomethyl) -1- (4-chlorobenzyl) piperidine (120 mg) with 2,2-diphenylacetaldehyde (0.66 eq.) And polymer- Followed by a conventional workup and column chromatography (SiO ₂ ) to give 1- (4-chlorobenzyl) -4- [N- (2,2-diphenylethyl) aminomethyl] Piperidine (70 mg, 49%). Purity is determined by RPLC // MS (98%).
[900] Example 1087: Synthesis of 4- [N- (N-benzoylglycyl) -N- (2,2-diphenylethyl) aminomethyl] -1- (4-chlorobenzyl) piperidine synthesis
[901] To the dichloromethane solution of 1- (4-chlorobenzyl) -4- [N- (2,2-diphenylethyl) aminomethyl) piperidine (0.084 mmol) was added horseradish acid (1.1 equivalents), HBTU ) And HOBt (1.1 eq.). The reaction mixture is stirred at 40 占 폚 for 24 hours. Conventional treatment methods and preparative TLC (SiO ₂₎ with 4- [N- (N- benzoyl-glycyl) -N- (2,2- diphenyl-ethyl) aminomethyl] -1- (4-chlorobenzyl) piperidine (Compound No. 524) (8.5 mg, 17%). The purity is determined by RPLC / MS (98%). ESI / MS m / e 580 (M ⁺ + H, C ₃₆ H ₃₈ ClN ₃ O ₂ )
[902] [Examples 1088-1090]
[903] The compound used in the present invention is synthesized according to the method of Example 1087 using the corresponding starting materials and reactants, respectively. ESI / MS data, yield and yield are summarized in Table 26.
[904] [Table 26]
[905]
[906] [Referential Example 21] Synthesis of l- (4-chlorobenzyl) -4 - [(barylamino) methyl] piperidine
[907] To a solution of 4- (aminomethyl) -1- (4-chlorobenzyl) piperidine (1.0 g, 4.2 mmol) in dichloromethane (21 mL) was added triethylamine (0.76 mL, 5.44 mmol) Butoxycarbonyl) valine (1.09 g, 5.03 mmol), EDCI (883 mg, 4.61 mmol) and HOBt (623 mg, 4.61 mmol). The reaction mixture was stirred at 25 ° C for 16 hours, diluted with dichloromethane (20 mL), washed with 2M NaOH solution (20 mL × 2), brine (20 mL × 1), dried (MgSO ₄ ) and concentrated. Chromatography (SiO _2, 3% methanol / dichloromethane) to give 1- (4-chlorobenzyl) -4 - [[(N- Boc- baril) amino] methyl] piperidine (1.1g, 60%) Is obtained as a light amber oil. ESI / MS m / e 438 (M &lt; ⁺ & gt ^; + H)
[908] A solution of l- (4-chlorobenzyl) -4 - [[(N-Boc-valyl) amino] methylpiperidine (1.1 g, 2.51 mmol) was dissolved in 3M HCl- methanol solution (25 mL) Stir time. The reaction mixture is concentrated and the resulting salt is dissolved in ^t BuOH / H ₂ O = 3: 1 (25 mL). The anion (OH ^- ) exchange resin is added until the solution becomes slightly basic. Filtration and concentration afforded 1- (4-chlorobenzyl) -4 - [(barylamino) methyl] piperidine (819 mg, 97%). This compound does not require further purification. ESI / MS m / e 338.1 (M ⁺ + H, C ₁₈ H ₂₈ ClN ₃ O)
[909] Further, other 4 - [(acylamino) methyl] -1- (4-chlorobenzyl) piperidine are synthesized according to the method of Reference Example 21 using the corresponding starting materials and reactants, respectively.
[910] (2 steps), ESI / MS 269 (M &lt; ⁺ & gt ^; + H), 0.830 g (67%) of 1- (4- chlorobenzyl) -4 - [(glycylamino) methyl] piperidine:
[911] 0.286 g, 20% (2 steps), ESI / MS 326 (M &lt; ⁺ & gt ^; + H)
[912] 65% (2 steps), ESI / MS 310 (M ⁺ + H), 1.20 g of 4 - [(alanylamino) methyl] -1- (4- chlorobenzyl) piperidine:
[913] (2 steps), ESI / MS 336 (M ⁺ + H), 1.48 g (yield: 86%
[914] (2 steps), ESI / MS 367 (M &lt; ⁺ & gt ^; + H)
[915] (2 steps), ESI / MS 324 (M &lt; ⁺ & gt ^; + H), 2.24 g (62%) of 1- (4-chlorobenzyl) -4-
[916] (2 steps), ESI / MS 340 (M &lt; ⁺ & gt ^; + H)
[917] (2 steps), ESI / MS 322 (M &lt; ⁺ & gt ^; + H), 2.03 g (82%) of 1- (4-chlorobenzyl) -4-
[918] 58% (2 steps), ESI / MS 352 (M &lt; ⁺ & gt ^; + H), 1.30 g of 1- (4-chlorobenzyl) -4-
[919] 56% (2 steps), ESI / MS 416 (M ⁺ + H) &lt; RTI ID ^{= 0.0} &gt;
[920] Referential Example 22 Synthesis of 1- (tert-butoxycarbonyl) -4 - [[N- (9-fluorenylmethyloxycarbonyl) glycyl] aminomethyl] piperidine
[921] To the dichloromethane (150 mL) solution of 4- (aminomethyl) -1- (tert-butoxycarbonyl) piperidine (5.72 g) was added triethylamine (3.51 g), N- (9- Carbonyl) glycine (7.93 g, 26.7 mmol), EDCI (3.80 g) and HOBt (4.33 g). The reaction mixture was stirred at room temperature for 18 hours, then washed with water (100 mL x 3) and brine (100 mL x 2), dried over anhydrous sodium sulfate and concentrated. And recrystallized from acetonitrile / methanol (150 mL / 1 mL) at 0 ° C to give 1- (tert-butoxycarbonyl) -4 - [[N- (9- fluorenylmethyloxycarbonyl) glycyl] aminomethyl] Feridine (5.75 g, 44%) is obtained as yellowish white crystals.
[922] [Reference Example 23] Synthesis of 4 - [[N- (9-fluorenylmethyloxycarbonyl) glycyl] aminomethyl] piperidine
[923] Aminomethyl] piperidine piperidine (3.17 g, 6.42 mmol) was added to a solution of 4 - [[N- (9-fluorenylmethyloxycarbonyl) glycyl] Dioxane solution. This solution was stirred at room temperature for 5 hours and then concentrated to obtain 3.85 g of 4 - [[N- (9-fluorenylmethyloxycarbonyl) glycyl] aminomethyl] piperidine as a yellowish white solid. This product is used without further purification.
[924] Referential Example 24 Synthesis of 4 - [[N- (9-fluorenylmethyloxycarbonyl) glycyl] aminomethyl] -1- (4-methylthiobenzyl) piperidine
[925] To a 1% acetic acid / DMF (15 mL) solution of 4 - [[N- (9-fluorenylmethyloxycarbonyl) glycyl] aminomethyl] piperidine (1.00 g, 2.33 mmol) was added 4- methylthiobenzaldehyde 1.24 g) and NaBH (OAc) ₃ (2.56 g). The reaction mixture is stirred at 60 &lt; 0 &gt; C for 1 hour, cooled to room temperature and concentrated. A saturated aqueous NaHCO ₃ solution (50 mL) was added and extracted with ethyl acetate (50 mL x 2). The combined extracts are dried over anhydrous sodium sulfate, filtered and concentrated. By 4 - (dichloromethane, SiO _2, 50% -10% methanol) column chromatography, [[N- (9- fluorenyl-methyl-oxycarbonyl) glycyl] aminomethyl] -1- (4-methylthio-benzyl ) Piperidine (602 mg) as a colorless oil.
[926] [Reference Example 25] Synthesis of 1- (4-ethylbenzyl) -4 - [[N- (9-fluorenylmethyloxycarbonyl) glycyl] aminomethyl] piperidine
[927] Ethylbenzaldehyde (1.09 g, 2.33 mmol) was added to a 2.5% acetic acid / methanol (80 mL) solution of 4 - [[N- (9- fluorenylmethyloxycarbonyl) glycyl] aminomethyl] piperidine the g, 8.16mmol) and _{NaBH 3 CN (6.59g, 10.5 mmol} ) is added. The reaction mixture is stirred at 60 占 폚 for 13 hours. After cooling to room temperature, 1 M aqueous NaOH solution (50 mL) and dichloromethane (50 mL) are added. The organic layer was separated, and the aqueous layer was extracted with dichloromethane (50 mL x 3). The organic layers are combined, washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. Column chromatography (SiO _2, methanol / ethyl acetate = 2: 8) to 1- (4-ethylbenzyl) -4 - [[N- (9- fluorenyl-methyl-oxycarbonyl) glycyl] aminomethyl] P (740 mg, 62%).
[928] [Referential Example 26] Synthesis of 4 - [(glycylamino) methyl] -1- (4-methylthiobenzyl) piperidine
[929] (590 mg) of 4 - [[N- (9-fluorenylmethyloxycarbonyl) glycyl] aminomethyl] -1- (4-methylthiobenzyl) piperidine and piperidine 4 mL) was stirred at 60 占 폚 for 2 hours. After concentration, column chromatography (SiO _2, triethylamine / methanol / dichloromethane = 1: 1: 9) to give the 4 - [(glycyl) methyl] -1- (4-methylthio-benzyl) (365 mg) as a white solid.
[930]
[931] In addition, 1- (4-ethylbenzyl) -4 - [(glycylamino) methyl] piperidine is synthesized according to the method of Reference Example 26 using the corresponding starting materials and reactants: 333 mg, 79% .
[932] [Referential Example 27] Synthesis of 4 - [(glycylamino) methyl] -1- (4-fluorobenzyl) piperidine
[933] (1.50 g, 3.49 mmol), 4-fluorobenzyl bromide (0.478 mL, 3.84 mmol) and triethylamine A solution of ethylamine (1.47 mL, 10.5 mmol) in acetonitrile (200 mL) was stirred at room temperature for 13 hours. Column chromatography (SiO _2, 10% methanol / dichloromethane) to 4 - [[N- (9- fluorenyl-methyl-oxycarbonyl) glycyl] aminomethyl] piperidine and the obtained blood-piperidine. A DMF (5 mL) solution of 4 - [[N- (9-fluorenylmethyloxycarbonyl) glycyl] aminomethyl] piperidine and piperidine (5 mL) was stirred at room temperature for 17 hours. After concentration, column chromatography (SiO _2, triethylamine / methanol / dichloromethane, 0.5: 2: 8) to give 4 - [(glycyl) methyl] -1- (4-fluorobenzyl) piperidine (453 mg, 46%).
[934] [Referential Example 28] Synthesis of 4 - [(glycylamino) methyl] -1- (4-N-phenylcarbamoyl) benzyl] piperidine
[935] (1.27 g, 2.96 mmol), triethylamine (1.25 mL, 8.88 mmol), KI (50 mg, 2.96 mmol) were added to a solution of 4- [[N- (9- fluorenylmethyloxycarbonyl) glycyl] aminomethyl] piperidine Acetonitrile (100 mL) solution of 4- (N-phenylcarbamoyl) benzyl chloride (800 mg, 3.26 mmol) was added dropwise to a mixture of acetonitrile (0.30 mmol) and acetonitrile (200 mL). The mixture was stirred at room temperature for 19 hours and then at 60 占 폚 for 5 hours. After concentration, column chromatography (SiO _2, 5% methanol / dichloromethane-triethylamine / methanol / dichloromethane = 2: 2: 96) to give 4 - [(glycyl) methyl] -1- [ 4- (N-phenylcarbamoyl) benzyl] piperidine (340 mg, 30%).
[936] Example 1091: Synthesis of 1- (4-chlorobenzyl) -4 - [[N- (3-cyanobenzoyl) valyl] aminomethyl] piperidine (Compound No. 619)
[937] To the dichloromethane (0.60 mL) solution of 1- (4-chlorobenzyl) -4 - [(barylamino) methyl] piperidine (20 mg, 0.059 mmol) in triethylamine (0.011 mL, 0.077 mmol) Cyanobenzoic acid (28 mg, 0.071 mmol), EDCI (13 mg, 0.065 mmol) and HOBt (9 mg, 0.065 mmol) were added. The reaction mixture is stirred at 25 占 폚 for 16 hours. The resulting solution was diluted with dichloromethane (0.75 mL), washed with 2M aqueous NaOH (0.75 mL x 2) and dried by filtration through a PTFE membrane. Concentration is used to obtain 1- (4-chlorobenzyl) -4 - [[N- (3-cyanobenzoyl) valyl] aminomethyl] piperidine (Compound No. 619) (24.2 mg, 88%). This does not require further purification. Purity is determined by RPLC / MS (85%). ESI / MS m / e 467 (M ⁺ + H, C ₂₆ H ₃₁ ClN ₄ O ₂ )
[938] [Example 1092-1543]
[939] The compound used in the present invention is synthesized according to the method of Example 1091 using the corresponding starting materials and reactants, respectively. ESI / MS data, yield and yield are summarized in Table 27.
[940] [Table 27a]
[941]
[942] [Table 27b]
[943]
[944] [Table 27c]
[945]
[946] [Table 27d]
[947]
[948] [Table 27e]
[949]
[950] [Table 27f]
[951]
[952] [Table 27g]
[953]
[954] [Table 27h]
[955]
[956] [Table 27i]
[957]
[958] [Table 27j]
[959]
[960] [Table 27k]
[961]
[962] [Table 271]
[963]
[964] [Table 27m]
[965]
[966] * Yield of trifluoroacetic acid salt
[967] Example 1544: Synthesis of 1- (4-chlorobenzyl) -4 - [[N- (3,5-bis (trifluoromethyl) benzoyl) glycyl] aminomethyl] piperidine
[968] A solution of 3,5-bis (trifluoromethyl) benzoyl chloride (0.058 mmol) in dichloromethane (1 mL) was added to a solution of 1- (4-chlorobenzyl) -4 - [(glycylamino) methyl] piperidine 0.050 mmol), chloroform (0.2 mL), piperidinomethyl polystyrene (58 mg), and dichloromethane (0.75 mL). The reaction mixture was stirred at room temperature for 2 hours, methanol (1.0 mL) was added, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture is placed on a Varian ^占 SCX column and rinsed with methanol (16 mL). The product was eluted with a 2M NH ₃ in methanol (6 mL) solution and concentrated to give 1- (4-chlorobenzyl) -4 - [[N- (3,5- bis (trifluoromethyl) benzoyl) ] Piperidine (Compound No. 1213) (24.0 mg, 90%). The purity is determined by RPLC / MS (100%). ESI / MS m / e 536.2 (M ⁺ + H, C ₂₄ H ₂₄ ClF ₆ N ₃ O ₂ )
[969] [Examples 1545-1547]
[970] The compound used in the present invention is synthesized according to the method of Example 1544 using the corresponding starting materials and reactants, respectively. ESI / MS data, yield and yield are summarized in Table 28.
[971] [Table 28]
[972]
[973] Example 1548: Synthesis of 4 - [[N- (3-bromo-4-methylbenzoyl) glycyl] aminomethyl] -1- (4-chlorobenzyl) piperidine (Compound No. 1113)
[974] To a solution of the chloroform (1.35 mL) and tert-butanol (0.15 mL) in a mixture of 1- (4-chlorobenzyl) -4 - [(glycylamino) methyl) piperidine (0.050 mmol) Methylbenzoic acid (0.060 mmol), diisopropyl carbodiimide (0.060 mmol) and HOBt (0.060 mmol) were added. The reaction mixture is stirred at room temperature for 15 hours. The mixture Varian ^TM SCX column placed in methanol / chloroform = 1: 1 and washed with (12mL) and methanol (12mL) product was 2M NH ₃ in methanol (5mL) 4 and concentrated by elution with a solution - [[N- (Compound No. 1113) (16.1 mg, 65%) was obtained as a yellow oil. Purity is determined by RPLC / MS (95%). ESI / MS m / e 494.0 (C ₂₃ H ₂₇ BrClN ₃ O ₂ )
[975] [Examples 1549 to 1619]
[976] The compound used in the present invention is synthesized according to the method of Example 1548 using the corresponding starting materials and reactants, respectively. If necessary, purified by preparative TLC to give the desired compound. ESI / MS data, yield and yield are summarized in Table 29.
[977] Compound No. 1422 is obtained as a by-product of Compound No. 1418: 5.6 mg, yield: 25%; ESI / MS m / e 447.2 ( C 22 H 27 ClN 4 O 2 S)
[978] [Table 29a]
[979]
[980] [Table 29b]
[981]
[982] [Table 29c]
[983]
[984] For example, Compound Nos. 1245 and 1600 show the following NMR spectra.
[985] Compound No. 1245:
[986]
[987] Compound No. 1600:
[988]
[989] Example 1620: Synthesis of 1- (4-chlorobenzyl) -4 - [[N- (4-isopropylphenylsulfonyl) glycyl] aminomethyl] piperidine (Compound No. 869)
[990] To a chloroform (2 mL) solution of 1- (4-chlorobenzyl) -4 - [(glycylamino) methyl] piperidine (14.8 mg, 0.05 mmol) / g) and 4-isopropylbenzenesulfonyl chloride (1.5 eq.) were added, and the mixture was stirred at 25 占 폚 for 16 hours. After filtration and concentration, 22.1 mg (92%) of 1- (4-chlorobenzyl) -4 - [[N- (4-isopropylphenylsulfonyl) glycyl] aminomethyl] piperidine ). Purity is determined by RPLC / MS (86%). ESI / MS m / e 478 (M ⁺ + H, C ₂₄ H ₃₂ N ₃ O ₃ S)
[991] [Examples 1621-1627]
[992] The compounds used in the present invention are synthesized according to the method of Example 1620, using the corresponding starting materials and reactants, respectively. ESI / MS data, yield, and yield are summarized in Table 30. &lt; tb &gt; &lt; TABLE &gt;
[993] [Table 30]
[994]
[995] Example 1628: Synthesis of 1- (4-chlorobenzyl) -4 - [[2- (3- (4-trifluoromethylphenyl) ureido) acetylamino) methyl] piperidine (Compound No. 852)
[996] To a chloroform (2 mL) solution of 1- (4-chlorobenzyl) -4 - [(glycylamino) methyl] piperidine (14.8 mg, 0.05 mmol) / g) and 3- (trifluoromethyl) phenyl isocyanate (1.3 equivalents), and the mixture was stirred at 25 占 폚 for 16 hours. (Aminomethyl) polystyrene resin is added and stirred at 25 DEG C for 16 hours to capture the residual isocyanate. Methyl] piperidine (Compound No. 852) (19 mg) was obtained by filtration and concentration under reduced pressure to obtain 1- (4-chlorobenzyl) -4- [ , 78%). Purity is determined by RPLC / MS (92%). ESI / MS m / e 483 (M ⁺ + H, C ₂₃ H ₂₆ ClF ₃ N ₄ O ₂ )
[997] [Examples 169-1641]
[998] The compound used in the present invention is synthesized according to the method of Example 1628 using the corresponding starting materials and reactants, respectively. ESI / MS data, yield and yield are summarized in Table 31.
[999] [Table 31]
[1000]
[1001] * Yield of trifluoroacetic acid salt
[1002] Example 1642: Synthesis of l- (4-chlorobenzyl) -4 - [[N- (3-ethoxybenzoyl) -D-phenylalaninyl] aminomethyl] piperidine (Compound No. 2091)
[1003] To a chloroform (3 mL) solution of 1- (4-chlorobenzyl) -4- (aminomethyl) piperidine (100 mg) was added triethylamine (0.090 mL) and N- (tert- butoxycarbonyl) (Phenylalanine) (122 mg), EDCI (89 mg) and HOBt (62 mg), and the mixture was stirred at room temperature for 17 hours. The reaction mixture was washed with a 1 M aqueous NaOH solution (2 mL x 2) and brine (2 mL), and the organic layer was dried and concentrated to obtain 1- (4-chlorobenzyl) -4- {[N- (tert-butoxycarbonyl) Phenylalanyl] aminomethyl] piperidine is obtained.
[1004] The resulting 1- (4-chlorobenzyl) -4 - [[N- (tert-butoxycarbonyl) -D-phenylalaninyl] aminomethyl] piperidine was dissolved in methanol (5 mL) Add the solution. The solution is stirred at room temperature for 19 hours and concentrated.
[1005] Triethylamine (0.090 mL), EDCI (90 mg) and HOBt (68 mg) were added to a chloroform solution (3 mL) of the resulting residue and 3-ethoxybenzoic acid (80 mg, 0.48 mmol) do. The reaction mixture was washed with 1 M aqueous NaOH solution (1.5 mL x 2) and brine (1.5 mL), and the organic layer was dried and concentrated. Column chromatography (SiO _2, dichloromethane / methanol = 95: 5) to 1- (4-chlorobenzyl) -4 - [[N- -D- phenyl alanyl] amino-methyl (3-ethoxy-benzoyl) - P Pyridine (Compound No. 2091) (183.5 mg, 82%). The purity is determined by RPLC / MS (99%). ESI / MS m / e 534.0 (M ⁺ + H, C ₃₁ H ₃₆ ClN ₃ O ₃ )
[1006] [Examples 1643-1657]
[1007] The compounds used in the present invention are synthesized according to the method of Example 1642 using the corresponding starting materials and reactants, respectively. The ESI / MS data, yield and yield are summarized in Table 32.
[1008] [Table 32]
[1009]
[1010] [Referential Example 29] Synthesis of 1- (tert-butoxycarbonyl) -4 - [[N- (3- (trifluoromethyl) benzoyl) glycyl] aminomethyl] piperidine
[1011] (4.25 g, 22.1 mmol), 1-hydroxybenzotriazole hydrate (2.99 g, 22.1 mmol), and triethyl (2-ethylbenzyl) Amine (1.72 g) is added to a dry dichloromethane (200 mL) solution of 1- (tert-butoxycarbonyl) -4- (aminomethyl) piperidine (4.03 g). The reaction mixture was stirred at 25 占 폚 for 20 hours, then H ₂ O (100 mL) was added and extracted with dichloromethane (50 mL × 2). The combined extracts were washed with H ₂ O (50 mL × 2) and brine (50 mL), dried (MgSO 4) and concentrated to give a yellow oil. This was purified by column chromatography (SiO ₂ , 70% ethyl acetate-hexane) to give 1- (tert-butoxycarbonyl) -4 - [[N- (3- (trifluoromethyl) benzoyl) glycyl] amino Methyl] piperidine as a white solid (6.39 g, 85%):
[1012]
[1013] ; Purity is determined by RPLC / MS (97%). ESI / MS m / e 444.3 (M ⁺ + H, C ₂₁ H ₂₆ N ₃ O ₄ )
[1014] [Referential Example 30] Synthesis of 4 - [[N- (3- (trifluoromethyl) benzoyl) glycyl] aminomethyl] piperidine
[1015] A solution of 2.29 g (5.16 mmol) of 1- (tert-butoxycarbonyl) -4 - [[N- (3- (trifluoromethyl) benzoyl) glycyl] aminomethyl] piperidine 1M HCl-Et ₂ O (55 mL) was added to the mixture, and the mixture was stirred at 25 ° C for 15 hours, and then the solvent was removed under reduced pressure. 2 M aqueous NaOH solution (100 mL) was added and extracted with ethyl acetate (100 mL x 3). The combined extracts were washed with brine (50 mL), dried (K ₂ CO ₃ ) and concentrated to give a white solid. This was purified by column chromatography (SiO _2, methanol / dichloromethane / triethylamine = 7: 6: 1) to give 4 - [[N- (3- (trifluoromethyl) benzoyl) glycyl] aminomethyl] P (1.27 g, 72%) as a white solid. Purity is determined by RPLC / MS (98%). ESI / MS m / e 344.1 (M ⁺ + H, C ₁₆ H ₂₀ N ₃ O ₂ )
[1016] Example 1658: Synthesis of 1- [3- (trifluoromethoxy) benzyl] -4 - [(N- (3- (trifluoromethyl) benzoyl) glycyl] aminomethyl] piperidine ) Synthesis of
[1017] (Piperidinomethyl) benzyl) glycyl] aminomethyl] piperidine (19.9 mg, 0.058 mmol) in acetonitrile (1.0 mL) and a solution of (piperidinomethyl) Was added to a solution of 3- (trifluoromethoxy) benzyl bromide (12.3 mg, 0.048 mmol) in acetonitrile (1.0 mL), and the mixture was stirred at 60 ° C for 2.5 hours. Phenyl isocyanate (6.9 mg, 0.048 mmol) is added to the cooled reaction mixture and stirred at 25 ° C for 1 hour, then the reaction mixture is placed on a Varian ^™ SCX column and rinsed with methanol (20 mL). The product was eluted with a methanol solution of 2M NH ₃ and concentrated to give 1- [3- (trifluoromethoxy) benzyl] -4 - [(N- (3- (trifluoromethyl) benzoyl) glycyl] aminomethyl] ESI / MS m / e 518.1 (M ⁺ + H, C ₂₄ H ₂₅ (M + H)) was obtained as a pale yellow oil (22.8 mg, 91% F ₆ N ₃ O ₃ )
[1018] [Examples 1659-1710]
[1019] The compounds used in the present invention are synthesized according to the method of Example 1658 using the corresponding starting materials and reactants, respectively. ESI / MS data, yield and yield are summarized in Table 33.
[1020] [Table 33a]
[1021]
[1022] [Table 33b]
[1023]
[1024] Example 1711: Synthesis of 1- [4- (dimethylamino) benzyl] -4 - [[N- (3- (trifluoromethyl) benzoyl) glycyl] aminomethyl] piperidine (Compound No. 937)
[1025] (1.0 mL) of NaBH ₃ CN (16.5 mg) and a solution of 4 - [[N- (3-trifluoromethyl) benzoyl) glycyl] aminomethyl] piperidine (20.0 mg, Was added to a 5% acetic acid solution (1.0 mL) of (dimethylamino) benzaldehyde (30.4 mg, 0.204 mmol) and the mixture was stirred at 60 ° C for 19 hours. The solvent is distilled off to obtain a solid. Acetonitrile (2.0 mL) and phenyl isocyanate (6.9 mg, 0.048 mmol) were added, and the mixture was stirred at 25 ° C for 1 hour. The reaction mixture is placed on a Varian ^占 SCX column and rinsed with methanol (20 mL). The product was eluted and concentrated using 2M NH ₃ -methanol (6 mL) to give 1- [4- (dimethylamino) benzyl] -4 - [(N- (3- (trifluoromethyl) benzoyl) glycyl] amino MS (ESI / MS m / e 477.3 (M ⁺ + H, C ₂₅ H NMR (CDCl 3) H ₃₁ F ₃ N ₄ O ₂ )
[1026] [Examples 1712-1729]
[1027] The compound used in the present invention is synthesized according to the method of Example 1711 using the corresponding starting materials and reactants, respectively. If necessary, purified by preparative TLC (SiO ₂ ) to obtain the desired product. ESI / MS data, yield and yield are summarized in Table 34.
[1028] [Table 34]
[1029]
[1030] Example 1730: Synthesis of 1- [3-hydroxy-4-methoxybenzyl-4 - [[N- (3- (trifluoromethyl) benzoyl) glycyl] aminomethyl] piperidine (Compound No. 1452) Synthesis of
[1031] 5% of 3-hydroxy-4-methoxybenzaldehyde (33 mg) was added to a solution of 4 - [[N- (3- (trifluoromethyl) benzoyl) glycyl] aminomethylpiperidine (20.0 mg, 0.058 mmol) Acetic acid / methanol (1.0 mL) was added to a 5% acetic acid / methanol (1.0 mL) solution of NaBH ₃ CN (16.5 mg) and the mixture was stirred at 60 ° C for 15 hours. The reaction mixture is placed on a Varian ^占 SCX column and rinsed with methanol (15 mL). The product was eluted and concentrated using 2M NH ₃ -methanol (5 mL) to give 1- [3-hydroxy-4-methoxybenzyl] -4 - [[(N- (3- (trifluoromethyl) to obtain a glycyl] aminomethyl] piperidine (compound No. 1452) (25.8㎎, 92%) . the purity was determined by RPLC / MS (91%). ESI / MS m / e 480 (m + + H, C 24 H ₂₈ F ₃ N ₃ O ₄ )
[1032] [Examples 1731-1733]
[1033] The compounds used in the present invention are synthesized according to the method of Example 1730, using the corresponding starting materials and reactants, respectively. If necessary, purified by preparative TLC to give the desired compound. ESI / MS data, yield and yield are summarized in Table 35.
[1034] [Table 35]
[1035]
[1036] Example 1734: Synthesis of 1- (4-benzylbenzyl) -4 - [[N- (3- (trifluoromethyl) benzoyl) glycyl] aminomethyl] piperidine (Compound No. 926)
[1037] 4- (benzyl) benzyl alcohol (8.7 mg, 0.07 mmol) was added to a chloroform (1.0 mL) solution of methanesulfonyl chloride (4.2 mg, 0.037 mmol) and (piperidinomethyl) polystyrene 0.044 mmol) in chloroform (1.0 mL), and the mixture was stirred at 25 占 폚 for 15 hours. (15.1 mg, 0.044 mmol) and KI (2 mg) were added to the reaction mixture, and the mixture was again stirred at 65 [deg.] C Lt; 0 &gt; C for 5 hours. Phenyl isocyanate (5.2 mg) is added to the cooled reaction mixture and stirred at 25 &lt; 0 &gt; C for 1 hour, then the reaction mixture is placed on a Varian ^™ SCX column and rinsed with methanol (20 mL). The product was eluted with a 2M NH ₃ in methanol (5 mL) solution and concentrated to give 1- (4-benzylbenzyl) -4 - [[N- (3- (trifluoromethyl) benzoyl) glycyl] aminomethyl] (Compound No. 926) as a pale yellow oil (5.6 mg, 29%). Purity is determined by RPLC / MS (94%). ESI / MS m / e 524.1 (M ⁺ + H, C ₃₀ H ₃₂ F ₃ N ₃ O ₂ )
[1038] Referential Example 31 Synthesis of 4 - [[(N- (benzyloxycarbonyl) glycyl) amino] methyl- 1- (tert-butoxycarbonyl) piperidine
[1039] To a solution of 4- (aminomethyl) -1- (tert-butoxycarbonyl) piperidine (3.54 g, 16.5 mmol) in chloroform (80 mL) was added triethylamine (2.8 mL, 20 mmol) (3.77 g, 18 mmol), EDCI (3.45 g, 18 mmol) and HOBt (2.43 g, 18 mmol) were added thereto. The mixture was stirred at room temperature for 15 hours and then 2M aqueous NaOH solution (100 mL) was added. The organic layer was separated, and the aqueous layer was extracted with dichloromethane (100 mL x 3). The organic layers are combined, dried over anhydrous sodium sulfate, filtered, and concentrated. Amino] methyl] -1- (tert-butoxycarbonyl) piperidine as an amorphous (meth) acrylate was obtained by column chromatography (SiO ₂ , ethyl acetate) Obtained as a solid (6.27 g, 94%).
[1040] [Referential Example 32] Synthesis of 4 - [(glycylamino) methyl] -1- (tert-butoxycarbonyl) piperidine
[1041] A methanol (100 mL) solution of 6.25 g (15.4 mmol) of 4 - [[(N- (benzyloxycarbonyl) glycyl) amino] methyl] -1- (tert-butoxycarbonyl) (620 mg) at room temperature for 7 hours. After the catalyst was removed by celite filtration, the filtrate was concentrated to obtain 4 - [(glycylamino) methyl] -1- (tert-butoxycarbonyl) piperidine as a solid (3.84 g, 92%).
[1042] Referential Example 33 Synthesis of 4 - [[(N- (2-amino-5-chlorobenzoyl) glycyl) amino] methyl] -1- (tert-butoxycarbonyl) piperidine
[1043] (0.75 mL, 5.4 mmol), 2 (trimethylsilyl) amide, and 2 (dimethylamino) pyridine were added to a chloroform (25 mL) solution of 4- (tert-butoxycarbonyl) (940 mg, 4.9 mmol) and HOBt (660 mg, 4.9 mmol) were added. After stirring at room temperature for 3 hours, 2M aqueous NaOH solution (20 mL) . The organic layer was separated, and the aqueous layer was extracted with dichloromethane (20 mL x 3). The organic layers are combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (SiO ₂ , ethyl acetate) to obtain 4 - [[(N- (2-amino- Dean is obtained as a solid (1.63 g, 78%).
[1044] [Referential Example 34] Synthesis of 4 - [[(N- (2-amino-5-chlorobenzoyl) glycyl) amino] methyl] piperidine
[1045] To a solution of 1.63 g (3.84 mmol) of 4 - [[(N- (2-amino-5-chlorobenzoyl) glycyl) amino] methyl] -1- (tert-butoxycarbonyl) To the solution was added a 4M HCl solution of dioxane (9.5 mL) and the mixture was stirred at room temperature for 6 hours. The reaction mixture is concentrated, 2M aqueous NaOH solution (20 mL) is added and extracted with dichloromethane (20 mL x 3). The organic layers are combined, dried over anhydrous sodium sulfate, filtered, and concentrated to give 1.19 g (95%) of 4 - [[(N- (2-amino-5-chlorobenzoyl) glycyl) amino] methyl] piperidine:
[1046]
[1047] ; ESI / MS m / e 325.2 (M ⁺ + H, C ₁₅ H ₂₃ ClN ₄ O ₂ )
[1048] Also, 4 - [[(N- (2-amino-5-bromobenzoyl) glycyl) amino] methyl] piperidine is synthesized according to Referential Examples 33 and 34 using the corresponding starting materials and reactants. 951 mg, 64% (2 steps); ESI / MS m / e 369.2 (M ⁺ + H, C ₁₅ H ₂₁ BrN ₄ O ₂ )
[1049] Example 1735: Synthesis of 4 - [[(N- (2- (tert-butoxycarbonylamino) -4,5-difluorobenzoyl) glycyl) amino] methyl] Synthesis of piperidine
[1050] To a dichloromethane (20 mL) solution of 1- (4-chlorobenzyl) -4- [glycylamino) methyl] piperidine dihydrochloride (738 mg, 2 mmol), triethylamine (1.1 mL, (607 mg, 2.2 mmol), EDCI (422 mg, 2.2 mmol) and HOBt (337 mg, 2.2 mmol) were added at room temperature to a solution of 14 After stirring for a time, 0.6 M aqueous NaOH solution (50 mL) was added and extracted with dichloromethane (3 times). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated to give 4 - [[(N- (2- (tert- butoxycarbonylamino) -4,5-difluorobenzoyl) glycyl) amino] - (4-chlorobenzyl) piperidine (1.01 g, 92%). ESI / MS m / e 551.3 (M ⁺ + H, C ₂₇ H ₃₃ ClF ₂ N ₄ O ₄ )
[1051] In addition, the compound represented by the formula (I) can also be obtained by reacting 4 - [[(N- (2- (tert-butoxycarbonylamino) -5- trifluoromethylbenzoyl) glycyl) amino] The synthesis is carried out according to the above-mentioned method using the corresponding raw materials and reactants. 3.03 g, 82%; ESI / MS m / e 583.2 ( M + + H, C 28 H 34 ClF 3 N 4 O 4)
[1052] [Referential Example 35] Synthesis of 4 - [[(N- (2-amino-5-trifluoromethylbenzoyl) glycyl) amino] methyl] piperidine
[1053] Amino] methyl] piperidine (447 mg, 0.93 mmol) and Pd (OH) (4-chlorobenzyl) -4 - [[ ) ₂ (60 mg, 0.23 mmol) in 5% formic acid / methanol (10 mL) was stirred at 50 占 폚 for 14 hours. The palladium catalyst is removed by celite filtration and the filtrate is concentrated. To the residue was added 1 M aqueous NaOH (15 mL) and extracted with ethyl formate (30 mL x 3). The organic layers are combined, dried over anhydrous sodium sulfate, filtered, and concentrated. Column chromatography (SiO _2, ethyl acetate / methanol / triethylamine = 70: 25: 5) to give 4 - [[(N- (2-methylbenzoyl-amino-5-trifluoromethyl) glycyl) amino] Methyl] piperidine (284 mg, 86%). ESI / MS m / e 359.0 (M ⁺ + H, C ₁₆ H ₂₁ F ₃ N ₄ O ₂ )
[1054] In addition, 4 - [[(N- (2-amino-4,5-difluorobenzoyl) glycyl) amino] methyl] piperidine, 4- [ Amino) -5- trifluoromethoxybenzoyl) glycyl) aminomethyl] piperidine and 4 - [[(N- (2- (tert- butoxycarbonylamino) -5-trifluoromethoxybenzoyl) Amino] methyl] piperidine are also synthesized according to the method described above using the corresponding raw materials and reactants, respectively.
[1055] 4 - [[(N- (2-amino-4,5-difluorobenzoyl) glycyl) amino] methyl] piperidine: 564 mg, 89%; ESI / MS m / e 327.2 (M ⁺ + H, C ₁₅ H ₂₀ F ₂ N ₄ O ₂ )
[1056] 4 - [[(N- (2- (tert-butoxycarbonylamino) -5-trifluoromethoxybenzoyl) glycyl] aminomethyl] piperidine: quantitative;
[1057]
[1058] 4 - [[(N- (2- (tert-butoxycarbonylamino) -4,5-difluorobenzoyl) glycyl) amino] methyl] piperidine: 310 mg, 40%; ESI / MS m / e 427.3 (M ⁺ + H, C ₂₀ H ₂₈ F ₂ N ₄ O ₄ )
[1059] 57.1%, ESI / MS m / z &lt; 1 &gt; H NMR (400 MHz, CDCl 3) e 459.3 (M ⁺ + H, C ₂₁ H ₂₉ F ₃ N ₄ O ₄ )
[1060] [Example 1736] 4-ethoxybenzyl) piperidine (Compound No. 1429) and 1- (4-methoxybenzyl) Amino] methyl] piperidine (Compound No. 1433) was synthesized in the same manner as in Synthesis Example 1, except that the title compound was obtained as a pale yellow amorphous solid.
[1061] (0.10 mmol) of 4 - [[(N- (2-amino-5-chlorobenzoyl) glycyl] aminomethyl] piperidine was added to a solution of sodium cyanoborohydride (140 mmol) Was added to a mixture of ethoxybenzaldehyde (0.10 mmol), acetic acid (0.050 mL) and methanol (1.6 mL) and stirred for 14 h at 60 C. The reaction mixture was placed on a Varian ^占 SCX column and rinsed with methanol (20 mL). the product was eluted with methanol and concentrated to a solution of 2M NH ₃ preparative TLC (SiO _2, ethyl acetate / methanol) to 4 -. [[N- (2- amino-5-chlorobenzoyl) glycyl] aminomethyl] -1 - (4-ethoxybenzyl) piperidine (Compound No. 1429) and 1- (4-ethoxybenzyl) -4- Glycyl] aminomethyl] piperidine (Compound No. 1434) was obtained.
[1062] Compound No. 1429: 4.5 mg, 20%; Purity is determined by RPLC / MS (95%). ESI / MS m / e 459.2 (M ⁺ + H, C ₂₄ H ₃₁ ClN ₄ O ₃ )
[1063] Compound No. 1433: 8.4 mg, 28%; Purity is determined by RPLC / MS (98%). ESI / MS m / e 593.2 (M ⁺ + H, C ₃₃ H ₄₁ ClN ₄ O ₄ )
[1064] [Examples 1737-1779]
[1065] The compounds used in the present invention are synthesized according to the method of Example 1736 using the corresponding starting materials and reactants, respectively. ESI / MS data, yield and yield are summarized in Table 36.
[1066] [Table 36a]
[1067]
[1068] [Table 36b]
[1069]
[1070] Example 1780: Synthesis of 4 - [[N- (2-amino-5-trifluoromethoxybenzoyl) glycyl] aminomethyl] -1- (4-isopropylbenzyl) piperidine (Compound No. 1903)
[1071] Aminomethyl] piperidine (0.050 mmol), 4-isopropylbenzaldehyde (0.060 mmol) and 4-isopropylbenzaldehyde ), NaH ₃ CN (0.15 mmol) and methanol (1.3 mL) was added acetic acid (10 mL) and stirred for 8 hours at 60 ° C. After cooling to room temperature, the mixture was placed on a Varian ^™ SCX column and methanol (10 mL) The product was eluted with a 2M NH ₃ in methanol (5 mL) solution and concentrated. To the residue was added a dioxane solution (2 mL) of 4M HCl and stirred overnight at room temperature. After concentration and purification by preparative TLC (Compound No. 1903) (6.6 mg, 26%) was obtained as colorless crystals from 4- (4-fluorophenyl) %). The purity was determined by RPLC / MS (93%). ESI / MS m / e 507 (M ⁺ + H, C ₂₆ H ₃₃ F ₃ N ₄ O ₃ )
[1072] [Examples 1781-1783]
[1073] The compounds used in the present invention are synthesized according to the method of Example 1780 using the corresponding starting materials and reactants, respectively. Table 37 summarizes ESI / MS data, yield and yield.
[1074] [Table 37]
[1075]
[1076] [Example 1784] 4 - {[N- (2-amino-4,5-difluorobenzoyl) glycyl] aminomethyl] -1- (5-bromo-2-ethoxybenzyl) piperidine Compound No. 2052)
[1077] Aminomethyl] piperidine (0.050 mmol), 5-bromo-2- (4-fluorobenzyl) ethoxy-benzaldehyde (0.15 mmol), in methanol by the addition of NaBH ₃ CN (0.25 mmol) to a mixture of (1.2mL) and acetic acid (0.030mL) was stirred at 50 ℃ 13 hours. cool to room temperature up to Varian ^TM SCX column Place washed with methanol (5mL × 3). the product eluted with 2M NH ₃ and concentrated to a methanol (5mL) solution. to the residue in dichloromethane (1mL) at room temperature and tri-fluoro acetic acid (0.50mL) was added to and the mixture was stirred for 10 minutes then the reaction mixture was concentrated and the residue was dissolved in methanol and placed on a Varian ^TM SCX column, eluted, and concentrated and washed with methanol (5mL). the product in methanol (5mL) solution of 2M NH _3. Separation TLC (SiO _2, ethyl acetate / methanol = 10: 1) to give 4 - [[N- (2-benzoyl amino-4,5-difluorophenyl) (10.2 mg, 38%). The purity is determined by RPLC / MS (96%). ESI / MS m / e 539.2 (M ⁺ + H, C ₂₄ H ₂₉ BrF ₂ N ₄ O ₃ )
[1078] [Examples 1785-1792]
[1079] The compounds used in the present invention are synthesized according to the method of Example 1784 using the corresponding starting materials and reactants, respectively. ESI / MS data, yield and yield are summarized in Table 38.
[1080] [Table 38]
[1081]
[1082] Example 1793: Synthesis of 4 - [[N- (2-amino-4,5-difluorobenzoyl) glycyl] aminomethyl] -1- (3,4-diethoxybenzyl) piperidine ) Synthesis of
[1083] (0.050 mmol) of 4 - [[N- (2- (tert-butoxycarbonylamino) -4,5- (difluorobenzoyl) glycyl] aminomethyl] piperidine, 3,4-diethoxybenzaldehyde (0.15 mmol), methanol (1.2 mL) and acetic acid (0.050 mL) was added NaBH ₃ CN (0.25 mmol) and stirred overnight at 50 ° C. The reaction mixture was cooled to room temperature and placed on a Varian ^™ SCX column, washed with × 2). the product eluted with 2M NH ₃ in methanol and concentrate in (5mL) solution. to the residue was added dichloromethane (2mL) and phenyl isocyanate (0.10mL) was stirred at room temperature for 1 hour and Varian ^TM Place a SCX column, washed with methanol (5mL). the product was eluted and concentrated with methanol (5mL) solution of 2M NH _3. the residue was dissolved in methanol (0.25mL) and 4M HCl in dioxane (0.125mL) And the mixture is stirred at room temperature overnight and concentrated. The residue is dissolved in methanol and diluted with Varian ^占 S CX column and washed with methanol (5 mL x 2). The product was eluted with a 2M NH ₃ in methanol (5 mL) solution and concentrated to give 4 - [[N- (2-amino-4,5-difluorobenzoyl The purity is determined by RPLC / MS (97%). ESI &lt; RTI ID = 0.0 &gt; / MS m / e 505.2 (M ⁺ + H, C ₂₆ H ₃₄ F ₂ N ₄ O ₄ )
[1084] [Examples 174-1808]
[1085] The compounds used in the present invention are synthesized according to the method of Example 1793 using the corresponding starting materials and reactants, respectively. Table 39 summarizes ESI / MS data, yield and yield.
[1086] [Table 39]
[1087]
[1088] Example 1809: Synthesis of 4 - {[N- (2-amino-4,5-difluorobenzoyl) glycyl] aminomethyl] -1- (2-hydroxy-3-methylbenzyl) piperidine No. 2106)
[1089] Aminomethyl] piperidine (0.050 mmol), 2-hydroxy-3- (4-fluorobenzyl) methyl-benzaldehyde (0.25 mmol), methanol (1.0mL) and acetic acid to the mixture of (0.040mL) was added NaBH ₃ CN (0.40 mmol) and stirred overnight at 50 ℃. left to cool to room temperature and put on Varian ^TM SCX column, methanol (5 mL x 2) The product was eluted with a 2 M NH ₃ in methanol (5 mL) solution and concentrated. The residue was dissolved in ethyl acetate / methanol = 5: 1 (1 mL) and placed on a Varian ^™ SCX column Elution with ethyl acetate / methanol = 5: 1 (5 mL) and concentration The residue is dissolved in methanol (2 mL) and a solution of 4M HCl in dioxane (0.50 mL) is added and stirred at room temperature overnight and concentrated. The residue is dissolved in methanol and placed on a Varian ^占 SCX column and washed with methanol (5 mL x 2). M NH ₃ in methanol to elute and concentrate in (5mL) solution of preparative TLC with 4 -. [[N- (2-aminobenzoyl a 4,5-difluorophenyl) glycyl] aminomethyl] -1- (2- MS m / e 447.0 (M ⁺ + H, C ₂₃ H ₂₈ F ₂ N (M + H) ₄ O ₃ )
[1090] [Examples 1810-1823]
[1091] The compound used in the present invention is synthesized according to the method of Example 1809 using the corresponding raw materials and reactants, respectively. ESI / MS data, yield and yield are summarized in Table 40.
[1092] [Table 40]
[1093]
[1094] ND: Uncertain
[1095] Example 1824: Synthesis of 4 - [[N- (2-amino-4,5-difluorobenzoyl) glycyl] aminomethyl] -1- 2114)
[1096] Aminomethyl] piperidine (0.050 mmol), 4-methyl-3-nitro (4-methylpiperazin-1-yl) benzaldehyde (0.25 mmol), methanol (1.2mL) and the addition of NaBH ₃ CN (0.50 mmol) in a mixture of acetic acid (0.050mL) and the mixture was stirred overnight at 50 ℃. left to cool to room temperature and put on Varian ^TM SCX column in methanol ( . washed with 5mL × 2) and the product eluted and concentrated with methanol (5mL) solution of 2M NH ₃ of the residue with ethyl acetate / methanol = 2: dissolved in 1 (2mL) and place on Varian ^TM Si column, ethyl The residue is dissolved in methanol (1 mL) and a solution of 4M HCl in dioxane (0.50 mL) is added, stirred at room temperature over night, and concentrated. The water was dissolved in methanol and placed on a Varian ( ^TM) SCX column, washed with methanol (5 mL x 2), washed with 2M NH ₃ in methane (5 mL) solution. By concentration, 4 - [[N- (2-amino-4,5-difluorobenzoyl) glycyl] aminomethyl] -1- ) Piperidine.
[1097] To a solution of the obtained 4 - [[N- (2-amino-4,5-difluorobenzoyl) glycyl] aminomethyl] -1- Mg) and methanol (2 mL) was stirred at room temperature for 4 hours under a hydrogen atmosphere. The palladium catalyst is removed by celite filtration and the filtrate is concentrated. Preparative TLC (SiO _2, ethyl acetate / methanol = 3: 1) with 4 - [[N- (2-benzoyl-a-Amino-4, 5-deployment) glycyl] aminomethyl] -1- (3-amino- 4-methylbenzyl) piperidine (Compound No. 2114) (2.9 mg, 13%). Purity is determined by RPLC / MS (100%). ESI / MS m / e 446.1 (M ⁺ + H, C ₂₃ H ₂₉ F ₂ N ₅ O ₂ )
[1098] Example 1825: Synthesis of 4 - [[N- (2-amino-4,5-difluorobenzoyl) glycyl] aminomethyl] -1- (3-amino-4-methoxybenzyl) piperidine No. 2113)
[1099] (Compound No. 2113) The title compound was obtained as a white amorphous solid from 4- [[N- (2-amino-4,5-difluorobenzoyl) glycyl] aminomethyl] Is synthesized according to the method of Example 1824 using the corresponding starting materials and reactants. 4.6 mg, 20% yield; ESI / MS m / e 462.2 (M ⁺ + H, C ₂₃ H ₂₉ F ₂ N ₅ O ₃ )
[1100] [Example 1826] 1- (3-Amino-4-hydroxybenzyl) -4- [[N- (2- (tert- butoxycarbonylamino) -4,5- difluorobenzoyl) glycyl] Aminomethyl] piperidine
[1101] Glycyl] aminomethyl] piperidine (0.35 mmol), 4-hydroxy-3-nitrobenzoyl chloride benzaldehyde (1.22mmol), in methanol (3.2 mL) solution of NaBH ₃ CN (1.58mmol) in a mixture of methanol (3.8mL) and acetic acid (0.175 mL) was added and the mixture was stirred overnight at 50 ℃. Cool to room temperature and place on a Varian ^™ SCX column and rinse with methanol (5 mL x 2). The product was eluted and concentrated with methanol (5mL) solution of 2M NH _3. The residue was ethyl acetate / methanol = 5: 1 was dissolved in a Varian ^TM Si column in place of ethyl acetate / methanol = 5: elution using 1 (10mL) and concentrated by 4 - [[N- (2- ( tert -Butoxycarbonylamino) -4,5-difluorobenzoyl) glycyl] aminomethyl] -1- (4-hydroxy-3-nitrobenzyl) piperidine was obtained (175 mg, 87%).
[1102] The obtained 4 - [[N- (2- (tert-butoxycarbonylamino) -4,5-difluorobenzoyl) glycyl] aminomethyl] -1- A mixture of feridine, 10% palladium carbon (45 mg) and methanol (5 mL) was stirred at room temperature for 4 hours under a hydrogen atmosphere. The palladium catalyst was removed by filtration and the filtrate was concentrated to obtain 1- (3-amino-4-hydroxybenzyl) -4 - [[N- (2- (tert- butoxycarbonylamino) Fluorobenzoyl) glycyl] aminomethyl] piperidine (100 mg, 60%).
[1103] [Example 1827] Synthesis of 4 - [[N- (2-amino-4,5-difluorobenzoyl) glycyl] aminomethyl] -1- (3-amino-4-hydroxybenzyl) piperidine No. 2141)
[1104] (3-amino-4-hydroxybenzyl) -4 - [[N- (2- (tert- butoxycarbonylamino) -4,5-difluorobenzoyl) glycyl] aminomethyl] (20.0 mg, 0.035 mmol) in methanol (1 mL) was added 4M HCl in dioxane (0.50 mL), and the mixture was stirred at room temperature overnight. After concentration, the residue is dissolved in methanol and loaded on a Varian ^™ SCX column, washed with methanol (5 mL x 2) and eluted with a 2 M NH ₃ in methanol (5 mL) solution. By concentrating, 4 - [[N- (2-amino-4,5-difluorobenzoyl) glycyl] aminomethyl] -1- (3-amino-4-hydroxybenzyl) piperidine ) (17.6 mg, quantitative). Purity is determined by RPLC / MS (85%). ESI / MS m / e 448.3 ( M + + H, C 22 H 27 F 2 N 5 O 3).
[1105] [Examples 1828-1831]
[1106] The compounds used in the present invention are synthesized according to the methods of Examples 1826 and 1827, respectively, using corresponding starting materials and reactants. If necessary, purified by preparative TLC to obtain the desired product. The ESI / MS data and the yields and yields of the final processes are summarized in Table 41.
[1107] [Table 41]
[1108]
[1109] Example 1832: Synthesis of 1- (3-amino-4-chlorobenzyl) -4 - [[N- (2- (tert- butoxycarbonylamino) -4,5- difluorobenzoyl) glycyl] amino Methyl] piperidine &lt; / RTI &gt;
[1110] (0.14 mmol), 4-chloro-3-nitrobenzaldehyde (0.14 mmol), and 4-chloro-3-nitrobenzaldehyde (0.50mmol), and methanol (1.3mL) solution of NaBH ₃ CN (0.63mmol) in a mixture of methanol (1.5mL) and acetic acid (0.070mL) was added and the mixture was stirred overnight at 50 ℃. Cool to room temperature and place on a Varian ^™ SCX column and rinse with methanol. The product is eluted with 2M NH ₃ in methanol and concentrated. The residue was ethyl acetate / methanol = 5: 1 was dissolved in a Varian ^TM Si column in place of ethyl acetate / methanol = 5: elution using 1 (6mL) and concentrated by 4 - [[N- (2- ( tert -Butoxycarbonylamino) -4,5-difluorobenzoyl) glycyl] aminomethyl] -1- (4-chloro-3-nitrobenzyl) piperidine was obtained (44 mg, 53%). ESI / MS m / e 596.3 (M &lt; ⁺ & gt ^; + H)
[1111] 4- [[N- (2- (tert-butoxycarbonylamino) -4,5-difluorobenzoyl) glycyl] aminomethyl] -1- (4-chloro-3-nitrobenzyl) piperidine (121 mg, 0.20 mmol), 10% palladium carbon (85 mg), ethyl acetate (10 mL) and methanol (1 mL) was stirred at room temperature for 19 hours under a hydrogen atmosphere. The palladium catalyst was removed by filtration and the filtrate was concentrated to obtain 1- (3-amino-4-chlorobenzyl) -4 - [[N- (2- (tert-butoxycarbonylamino) Rovenoyl) glycyl] amino methyl] piperidine (78 mg, 68%).
[1112] Example 1833: Synthesis of 1- (3-amino-4-chlorobenzyl) -4 - [[N- (2-amino-4,5- difluorobenzoyl) glycyl] aminomethyl] piperidine 2142)
[1113] (Compound No. 2142) was obtained as a pale-yellow amorphous solid from 1- (3-amino-4-chlorobenzyl) -4- The synthesis is carried out according to the method of Example 1827 using the corresponding starting materials and reactants. 13.7 mg, 98%; Purity is determined by RPLC / MS (83%). ESI / MS m / e 466.2 ( M + + H, C 22 H 26 ClF 2 N 5 O 2).
[1114] Example 1834: Synthesis of 1- (3-acetylamino-4-hydroxybenzyl) -4 - [[N- (2- (amino4,5- difluorobenzoyl) glycyl] aminomethyl] piperidine (Compound No. 2148) Synthesis of
[1115] (3-amino-4-hydroxybenzyl) -4 - [[N- (2- (tert- butoxycarbonylamino) -4,5-difluorobenzoyl) glycyl] aminomethyl] Dichloromethane (0.12 mL) of acetic anhydride (0.12 mmol) was added to a mixture of di (27 mg, 0.049 mmol), (piperidinomethyl) polystyrene (2.7 mmol / g, 60 mg, 0.15 mmol) and dichloromethane (2 mL) And the mixture was stirred at room temperature for 3 hours. The mixture is placed on a Varian ^占 SCX column and rinsed with methanol. The product is eluted with 2M NH ₃ in methanol and concentrated. The residue was ethyl acetate / methanol = 5: 1 was dissolved in a Varian ^TM Si column in place of ethyl acetate / methanol = 5: elution using 1 (6mL) and concentrated by 1- (3-acetylamino-4-hydroxy Hydroxybenzyl) -4 - [[N- (2- (tert-butoxycarbonylamino) -4,5-difluorobenzoyl) glycyl] aminomethyl] piperidine (30 mg, quantitative). ESI / MS m / e 590.4 (M &lt; ⁺ & gt ^; + H, C ₂₉ H ₃₇ N ₅ O ₆ ).
[1116] The obtained 1- (3-acetylamino-4-hydroxybenzyl) -4- [[N- (2- (tert- butoxycarbonylamino) -4,5- difluorobenzoyl) glycyl] amino Methyl] piperidine in methanol (1 mL) was added a dioxane solution of 4M HCl (0.50 mL), and the solution was stirred at room temperature overnight. After concentration, the residue is dissolved in methanol and loaded on a Varian ( ^TM) SCX column, washed with methanol (5 mL x 2) and eluted with 2 M NH ₃ in methanol (5 mL). The residue was purified by preparative TLC (SiO ₂ , ethyl acetate / methanol = 3: 2) to give 1- (3-acetylamino-4-hydroxybenzyl) -4- (98%). ESI / MS m / e &lt; RTI ID = 0.0 &gt; (M + H) &lt; / RTI & ^{490.3 (M + + H, C} 24 H 29 F 2 N 5 O 4).
[1117] [Examples 1835 to 1839]
[1118] The compounds used in the present invention are synthesized according to the methods of Examples 1826 and 1834, respectively, using corresponding starting materials and reactants. The ESI / MS data and the yields and yields of the final process are summarized in Table 42.
[1119] [Table 42]
[1120]
[1121] Example 1840: Synthesis of 4 - [[N- (2-amino-4,5-difluorobenzoyl) glycyl] aminomethyl] -1- (3-methylamino-4-hydroxybenzyl) piperidine Compound No. 2160)
[1122] 4- [[N- (2- (tert-butoxycarbonylamino) -4,5-difluorobenzoyl) glycyl] aminomethyl] -1- (3-amino-4-hydroxy) piperidine add methanol (0.2mL) solution of (20.4㎎, 0.037mmol), 37% HCHO solution (3.0㎎, 0.037mmol), acetic acid (0.1mL) and methanol _{(1.3mL) NaBH 3 CN (7.0㎎} ) to a mixture of And stirred overnight at 60 ° C. Cool to room temperature and place on a Varian ( ^TM) SCX column and rinse with methanol (5 mL x 2). The product was eluted with a 2M NH ₃ solution in methanol (8 mL) and concentrated to give 4 - [[N- (2-tert-butoxycarbonylamino) -4,5-difluorobenzoyl) glycyl] aminomethyl] 1- (3-methylamino-4-hydroxybenzyl) piperidine is obtained.
[1123] Glycyl] aminomethyl] -1- (3-methyl-4-hydroxybenzyl) glycyl] aminomethyl] -1,2,3,4-tetrahydroisoquinolin- Piperidine in methanol (1.0 mL) was added 4M HCl in dioxane (1.0 mL), and the mixture was stirred at room temperature for 3 hours. After concentration, the residue is dissolved in methanol (1 mL) and placed on a Varian ^™ SCX column, washed with methanol (5 mL x 2) and eluted with a 2 M NH ₃ in methanol (8 mL) solution. Concentrated and then purified by preparative TLC (SiO ₂ ) to give 4 - [[N- (2-amino-4,5-difluorobenzoyl) glycyl] aminomethyl] -1- Hydroxyphenyl) piperidine (Compound No. 2160) (3.4 g, 20%). Purity is determined by RPLC / MS (96%). ESI / MS m / e 462.4 (M ⁺ + H, C ₂₃ H ₂₉ F ₂ N ₅ O ₃ ).
[1124] [Examples 1841 to 1844]
[1125] The compounds used in the present invention are synthesized according to the methods of Examples 1826 and 1840, respectively, using corresponding starting materials and reactants. The ESI / MS data and yields and yields of the final process are summarized in Table 43.
[1126] [Table 43]
[1127]
[1128] [Example 1845] The title compound was obtained using 4 - {[N- (2-amino-4,5-difluorobenzoyl) glycyl] aminomethyl] -1- (benzo [c] prazan- Compound No. 2130)
[1129] (0.050 mmol), 5- (bromomethyl) benzoyl chloride (0.050 mmol), and the like were added to a solution of 4- [[N- (2- (tert- butoxycarbonylamino) -4,5- difluorobenzoyl) glycyl] aminomethyl] piperidine (2.6-2.8 mmol / g, 60 mg, 0.15 mmol), methanol (0.2 mL), acetonitrile (1.0 mL) and chloroform (0.50 mL) Lt; RTI ID = 0.0 &gt; 50 C &lt; / RTI &gt; overnight. Cool to room temperature, place on a Varian ^™ SCX column and rinse with methanol (5 mL x 2). The product was eluted and concentrated with methanol (5mL) solution of 2M NH _3. The residue was mixed with chloroform (1.5 mL) and phenylisocyanate (0.075 mL), stirred at room temperature for 1 hour, placed on a Varian ^™ SCX column, and washed with methanol (5 mL × 2). The product was eluted and concentrated with methanol (5mL) solution of 2M NH _3. The residue is dissolved in methanol (1 mL) and a solution of 4M HCl in dioxane (0.50 mL) is added, stirred at room temperature over night and concentrated. The residue is dissolved in methanol and loaded on a Varian ^™ SCX column, washed with methanol (5 mL x 2) and eluted with a 2 M NH ₃ in methanol (5 mL) solution. The residue was purified by preparative TLC (SiO ₂ , ethyl acetate / methanol = 5: 1) to give 4 - [[N- (2- (amino- The purity is determined by RPLC / MS (87%). ESI / MS m / e &lt; RTI ID = 0.0 &gt; ^{459.3 (M + + H, C} 22 H 24 F 2 N 6 O 3).
[1130] Example 1846: Synthesis of 4 - [[N - (2-amino-4,5-difluorobenzoyl) glycyl] aminomethyl] -1- (3,5-dimethylisoxazol- (Compound No. 2131) Synthesis of
[1131] The title compound was prepared according to the procedure described in Example 1 except that the title compound was prepared from 4 - [[N- (2-amino-4,5-difluorobenzoyl) glycyl] aminomethyl] 2131) is synthesized according to the method of Example 1845 using the corresponding starting materials and reactants. ESI / MS m / e 436.2 (M ⁺ + H, C ₂₁ H ₂₇ F ₂ N ₅ O ₃ ).
[1132] [Example 1847] Synthesis of 4 - [[N- (2-amino-5-chlorobenzoyl) glycyl] aminomethyl] -1- [4-trifluoromethylthio) benzyl] piperidine synthesis
[1133] (16.2 mg, 0.050 mmol) and 4- (trifluoromethylthio) benzyl chloride (20.3 mg, 0.075 mmol) were added to a solution of 4 - [[N- mmol), acetonitrile (1.0 mL) and chloroform (0.50 mL) was stirred at 60 占 폚 for 15 hours. After cooling, place on a Varian ( ^TM) SCX column and rinse with methanol (15 mL). The product was eluted with a 2M NH ₃ in methanol (5 mL) solution and concentrated to give 4 - [[N- (2-amino-5-chlorobenzoyl) glycyl] aminomethyl] -1- [4- (trifluoromethylthio ) Benzyl] piperidine (Compound No. 1616) (21.9 mg, 85%). Purity is determined by RPLC / MS (96%). ESI / MS m / e 545.2 (M ⁺ + H, C ₂₃ H ₂₆ ClF ₃ N ₄ O ₂ S).
[1134] [Examples 1848-1868]
[1135] The compounds used in the present invention are synthesized according to the method of Example 1847 using the corresponding starting materials and reactants, respectively. If necessary, purified by preparative TLC to obtain the desired product. The ESI / MS data and the yields and yields of the final process are summarized in Table 44.
[1136] [Table 44]
[1137]
[1138] Example 1869: Synthesis of 4 - [[N- (2-amino-5-trifluoromethylbenzoyl) glycyl] aminomethyl] -1- (4-bromobenzyl) piperidine (Compound No. 1910)
[1139] (0.050 mmol) of 4 - [[N- (2-tert-butoxycarbonylamino) -5-trifluoromethoxybenzoyl) glycyl] aminomethyl] piperidine ), Piperidinomethyl polystyrene (60 mg), acetonitrile (0.8 mL) and chloroform (0.5 mL) was stirred at 60 占 폚 for 12 hours. After cooling, it is placed on a Varian ^™ SCX column and rinsed with 50% chloroform / methanol (10 mL) and methanol (10 mL). The product was eluted and concentrated with methanol (5mL) solution of 2M NH _3. To the residue was added a solution of 4M HCl in 1,4-dioxane (2 mL), and the mixture was stirred at room temperature overnight. The residue was purified by preparative TLC to give 4 - [[N- (2-amino-5-trifluoromethoxybenzoyl) glycyl] aminomethyl] -1- (4-bromobenzyl) piperidine 1910) (6.5 mg, 24%). Purity is determined by RPLC / MS (96%). ESI / MS m / e 545 ( M + + H, C 23 H 26 BrF 3 N 4 O 3).
[1140] [Examples 1870-1873]
[1141] The compounds used in the present invention are synthesized according to the method of Example 1869 using the corresponding starting materials and reactants, respectively. Table 45 summarizes the yields and yields of ESI / MS data and the final process.
[1142] [Table 45]
[1143]
[1144] [Example 1874] Synthesis of 4 - [[N- (2-amino-5-trifluoromethylbenzoyl) glycyl] aminomethyl] -1- (benz [d] imidazol-5-yl) piperidine No. 2186)
[1145] (0.060 mmol), 1- (tert-butoxycarbonylamino) -5- trifluoromethylbenzoyl) glycyl] aminomethyl] piperidine A mixture of 3-bromo-6- (bromomethyl) benz [d] imidazole (15.6 mg, 0.050 mmol), (piperidinomethyl) polystyrene (86 mg, 0.15 mmol) and acetonitrile (2 mL) Stir time. After cooling to room temperature, phenyl isocyanate (30 mg) was added, stirred overnight at room temperature, placed on a Varian ^™ SCX column, and washed with methanol (5 mL) and chloroform (5 mL). The product was eluted and concentrated with methanol (5mL) solution of 2M NH _3.
[1146] The obtained material was dissolved in methanol (1 mL), 4M HCl in dioxane (1 mL) was added, and the mixture was stirred at room temperature overnight. Place a Varian ^TM SCX column and washed with methanol (5mL) and dichloromethane (5mL). The product is eluted with 2M NH ₃ in methanol and concentrated. The residue was purified by preparative TLC (SiO ₂ , ethyl acetate / methanol = 3: 1) to obtain 4 - [[N- (2-amino-5-trifluoromethylbenzoyl) glycyl] aminomethyl] -1- (benz [ ] Imidazol-5-yl) piperidine (Compound No. 2186) (1.9 mg, 7.8%). Purity is determined by RPLC / MS (100%). ESI / MS m / e 489.4 (M ⁺ + H, C ₂₄ H ₂₇ F ₃ N ₆ O ₂ ).
[1147] Example 1875: Synthesis of 4 - [[N- (2-amino-4,5-difluorobenzoyl) glycyl] aminomethyl] -1- (benzo [c] thiadiazol- (Compound No. 2184) Synthesis of
[1148] Methanesulfonyl chloride (0.0042 mL) was added to a mixture of 5- (hydroxymethyl) benzo [c] thiadiazole (8.3 mg, 0.050 mmol), (piperidinomethyl) polystyrene (86 mg) and chloroform And the mixture was stirred at room temperature for 1.5 hours. (1 mL) and 4 - [[(N- (2- (tert-butoxycarbonylamino) -4,5-difluorobenzoyl) glycyl] aminomethyl] piperidine were added to the reaction mixture Is stirred for 3 hours at 50 DEG C. After cooling to room temperature, phenyl isocyanate (30 mg) is added, stirred at room temperature for 1 hour, placed on a Varian ( ^TM) SCX column and washed with methanol (5 mL) and chloroform (5 mL). the product was eluted and concentrated with methanol (3mL) solution of 2M NH _3. Purification of the obtained residue was dissolved in methane (1mL) is added to dichloromethane (1mL) solution of 1M chlorotrimethylsilane and 1M phenol 0.5 at room temperature after an hour stirring, placed on Varian ^TM SCX column, washed with methanol and dichloromethane to elute the product in methanol solution of 2M NH ₃ preparative TLC (SiO _2, ethyl acetate / methanol = 3: 1). to give the 4 - [[N- (2-amino-4,5-difluorobenzoyl) glycyl] (1.3 mg, 5.5%). The purity is determined by RPLC / MS (100%). ESI &lt; RTI ID = 0.0 &gt; / MS m / e 475.2 (m + + H, C 22 H 24 F 2 N 6 O 2 S).
[1149] Example 1876: Synthesis of 4 - [[N- (2-amino-5-trifluorobenzoyl) glycyl] aminomethyl] -1- (benzo [c] thiadiazol- No. 2185)
[1150] (Compound No. 2185) was synthesized in the same manner as in Reference Example 1, except that 4-amino-2- (4-fluorophenyl) The synthesis is carried out according to the method of Example 1875 using the corresponding starting materials and reactants. 7.2 mg, 28% yield; ESI / MS m / e 507.4 ( M + + H, C 23 H 25 F 3 N 6 O 2 S).
[1151] Example 1877: Synthesis of 4 - [[N- (2-amino-5-trifluoromethylbenzoyl) glycyl] aminomethyl] -1- ) Synthesis of
[1152] (0.050 mmol), 4-chloro-2-nitrobenzyl chloride (0.050 mmol), piperidine A mixture of dinomethylpolystyrene (60 mg), acetonitrile (1.0 mL) and chloroform (0.7 mL) was stirred at 50 &lt; 0 &gt; C overnight. After cooling, place on a Varian ^™ SCX column and wash with chloroform / methanol (10 mL) and methanol (10 mL). The product was eluted and concentrated with methanol (5mL) solution of 2M NH _3. Ethanol (3 mL) and 10% palladium carbon (15 mg) were added to the obtained residue, and the mixture was stirred at room temperature for 1.5 hours under a hydrogen atmosphere. Filtered, concentrated and purified by preparative TLC to give 4 - [[N- (2-amino-5-trifluoromethylbenzoyl) glycyl] aminomethyl] Pyridine (Compound No. 1919) (5.1 mg, 14%). Purity is determined by RPLC / MS (90%). ;
[1153]
[1154] [Examples 1878-1879]
[1155] The compounds used in the present invention are synthesized according to the method of Example 1877 using the corresponding starting materials and reactants, respectively. The ESI / MS data and the yields and yields of the final process are summarized in Table 46.
[1156] [Table 46]
[1157]
[1158] Example 1880: Synthesis of 4 - [[N- (2-amino-5-trifluoromethylbenzoyl) glycyl] aminomethyl] -1- (benz [d] oxazol-5-yl) piperidine No. 2188)
[1159] (3-amino-4-hydroxybenzyl) -4 - [[N- (2- (tert-butoxycarbonylamino) -5- trifluoromethylbenzoyl) Triethyl orthoformate (0.033 mL, 3.3 eq.) And pyridium p-toluenesulfonate (2 mg, 0.4 eq.) Were added to a THF (2 mL) solution of And the mixture is stirred under reflux overnight. After cooling to room temperature, the mixture is concentrated. Eluted with 1 and concentrated: The residue was dissolved in ethyl acetate was placed on a BondElut ^TM Si column, ethyl acetate / methanol = 4.
[1160] The resulting residue is dissolved in ethyl acetate (1.5 mL) and a dioxane solution of 4M HCl (0.5 mL) is added. After stirring overnight at room temperature, the pH was adjusted to 10 with 5 M aqueous NaOH and extracted with ethyl acetate. The extract was concentrated and purified by preparative TLC (SiO ₂ , ethyl acetate / methanol = 4: 1) to give 4 - [[N- (2-amino-5-trifluoromethylbenzoyl) glycyl] aminomethyl] (Benz [d] oxazol-5-yl) piperidine (Compound No. 2188) (1.6 mg, 5%). Purity is determined by RPLC / MS (94%). ESI / MS m / e 490.3 (M ⁺ + H, C ₂₄ H ₂₆ F ₃ N ₅ O ₃ ).
[1161] [Example 1881] 4 - {[N- (2-Amino-4,5-difluorobenzoyl) glycyl] aminomethyl] -1- (2-oxo-2,3-dihydro- Benzoxazol-5-yl) piperidine (Compound No. 2190) Synthesis of
[1162] (3-amino-4-hydroxy) -4 - [[N- (2-tert-butoxycarbonylamino) -4,5-difluorobenzoyl) glycyl] aminomethyl] piperidine Phenyl chloroformate (0.040 mL) was added to a mixture of methanol (20 mL, 0.040 mmol), NaHCO ₃ (0.040 mmol), water (0.7 mL) and methanol (1.5 mL) and the mixture was stirred at room temperature for 3 hours. 1 M NaOH solution (0.040 mL) was added and the mixture was stirred for 1.5 hours. The mixture was extracted with ethyl acetate and the extract was concentrated. The residue is dissolved in methanol and placed on a Varian ^占 SCX column and rinsed with methanol (5 mL x 2). The product was eluted and concentrated with methanol (5mL) solution of 2M NH _3. To the resulting residue is added a solution of 1 M chlorotrimethylsilane and 1 M phenol in dichloromethane (2 mL). After stirring at room temperature for 2 hours and concentration, the residue is dissolved in methanol and placed on a Varian ^™ SCX column and rinsed with methanol (5 mL x 2). The product was eluted and concentrated with methanol (5mL) solution of 2M NH _3. Preparative TLC (SiO _2, ethyl acetate / methanol = 5: 2) to give 4 - [[N- (2-amino-4, 5-trifluoro-benzoyl) glycyl] aminomethyl] -1- (2- Oxo-2,3-dihydro-1,3-benzoxazol-5-yl) piperidine (Compound No. 2190) (4.1 mg, 22%). Purity is determined by RPLC / MS (100%). ESI / MS m / e 474.2 ( M + + H, C 23 H 25 F 2 N 5 O 4).
[1163] [Examples 1882-1884]
[1164] The compounds used in the present invention are synthesized according to the method of Example 1881 by using the corresponding starting materials and reactants, respectively (the synthesis of Compound Nos. 2192 and 2193 uses phenyl chloroformate in place of phenyl chloroformate). The ESI / MS data and the yields and yields of the final process are summarized in Table 47.
[1165] [Table 47]
[1166]
[1167] [Referential Example 36] 4 - [[N- (1- (9-fluorenylmethoxycarbonyl) piperidin-4-ylmethyl) carbamoylmethyl] aminomethyl] -3- methoxyphenyloxymethyl- polystyrene
[1168] To a DMF (65 mL) solution of 1- (9-fluorenylmethoxycarbonyl) -4- (glycylaminomethyl) piperidine hydrochloride (10 mmol) was added acetic acid (0.3 mL), sodium triacetoxy borohydride 1.92 g) and 4-formyl-3- (methoxyphenyloxymethyl) -polystyrene (1 mmol / g, 200 g) were added and shaken for 2 hours and filtered. The resin is washed with methanol, DMF, dichloromethane and methanol, and dried to obtain the target material.
[1169] [Example 1885-2000] Solid phase synthesis of 4-aminomethylpiperidine
[1170] Diisopropylethylamine (3.6 mmol) is added to a mixture of the corresponding carboxylic acid (1.6 mmol), HBTU (1.6 mmol) and DMF (6 mL) and shaken for 2 min. (0.4 mmol) of 4 - [[N- (1- (9-fluorenylmethoxycarbonyl) piperidin- And the mixture is shaken for 1 hour and filtered. The resin is washed with DMF and dichloromethane and dried.
[1171] To the obtained resin (0.05 mmol) was added a mixture of NaBH (OAc) ₃ (0.25 mmol), acetic acid (0.025 mmol) and DMF and the corresponding aldehyde (2.5 mmol) was further added thereto. The mixture was shaken for 2 hours, filtered, , 10% diisopropylethylamine in DMF, DMF, dichloromethane and methanol. The resin, a mixture of water (0.050 mL) and trifluoroacetic acid (0.95 mL) is shaken for 1 hour, filtered and the resin is washed with dichloromethane and methanol. The filtrate and the washing solution are combined and concentrated. The residue is placed on a Varian ^占 SCX column and rinsed with methanol (15 mL). The product was eluted and concentrated with methanol (5mL) solution of 2M NH _3. If desired, purified by preparative TLC or HPLC to give the desired product. Table 48 summarizes ESI / MS data, yield and yield.
[1172] [Table 48a]
[1173]
[1174] [Table 48b]
[1175]
[1176] [Table 48c]
[1177]
[1178] [Table 48d]
[1179]
[1180] * Yield of trifluoroacetic acid salt
[1181] Example 2001 Synthesis of 1- (3-carbamoylbenzyl) -4 - [[N- (3-trifluoromethyl) benzoyl) glycyl] aminomethyl] piperidine (Compound No. 924)
[1182] EDCI (10.7 mg), 1-hydroxybenzotriazole hydrate (7.5 mg), triethylamine (15.4 mg), dioxane solution of 0.5 M NH ₃ (0.1 mL, 0.05 mmol) and DMF A solution of the chloroform solution (2.5 mL) of 1- (3-carboxybenzoyl) -4 - [[N- (3-trifluoromethyl) benzoyl) glycyl] aminomethyl] piperidine (19.4 mg, 0.041 mmol) , Shaken at 25 ° C for 20 hours, and washed with 2M aqueous NaOH solution (2 x 2 mL) and brine (1 mL). After filtration through a PTFE membrane filter, the solvent was removed under reduced pressure to give 1- (3-carbamoylbenzyl) -4 - [[N- (3-trifluoromethyl) benzoyl) glycyl] aminomethyl] piperidine (Compound No. 924) as a yellowish-white solid (17.9 mg, 92%). Purity is determined by RPLC / MS (89%). ESI / MS m / e 447.3 (M ⁺ + H, C ₂₄ H ₂₇ F ₃ N ₄ O ₃ ).
[1183] [Example 2002] Synthesis of 1- (4-carbamoylbenzyl) -4 - [[N- (3-trifluoromethyl) benzoyl) glycyl] aminomethyl] piperidine (Compound No. 925)
[1184] Compound No. 925 is synthesized according to the method of Example 2001 using the corresponding starting materials and reactants. 14.2 mg, 72%. Purity is determined by RPLC / MS (86%). ESI / MS m / e 447 (M ⁺ + H, C ₂₄ H ₂₇ F ₃ N ₄ O ₃ ).
[1185] Example 2003 Synthesis of 1- (4-aminobenzyl) -4 - [[N- (3-trifluoromethyl) benzoyl) glycyl] aminomethyl] piperidine (Compound No. 516)
[1186] (3 mL) solution of 1- (4-nitrobenzyl) -4 - [[N- (3-trifluoromethyl) benzoyl) glycyl] aminomethyl] piperidine (22.4 mg, 0.047 mmol) In the presence of 5% palladium on carbon (10 mg) under a 1 atm hydrogen atmosphere for 1 hour. The catalyst was removed by filtration and washed with ethanol (5 mL). The filtrate was combined and concentrated to obtain 1- (4-aminobenzyl) -4 - [[N- (3-trifluoromethyl) benzoyl) glycyl] aminomethyl] piperidine (Compound No. 516) as a yellowish white solid (20.1 mg, 96%). Purity is determined by RPLC / MS (99%). ESI / MS m / e 449.1 (M ⁺ + H, C ₂₃ H ₂₇ F ₃ N ₄ O ₂ ).
[1187] [Example 2004-2005]
[1188] Compound Nos. 517 and 518 were synthesized according to the method of Example 2003 using the corresponding starting materials and reactants, respectively. The ESI / MS data and the yields and yields of the final process are summarized in Table 49.
[1189] [Table 49]
[1190]
[1191] Example 2006 Synthesis of 1- [4- (benzoylamino) benzyl) -4 - [[N- (3-trifluoromethyl) benzoyl) glycyl] aminomethyl] piperidine (Compound No. 519)
[1192] (4- (aminobenzyl) -4 - [[N- (2-pyrrolidin-1-ylmethoxy) benzyl] (3-trifluoromethyl) benzoyl) glycyl] aminomethyl] piperidine (10.1 mg, 0.023 mmol) in dichloromethane (2.5 mL) and the mixture was stirred at 25 ° C for 16 hours. The reaction mixture was washed with 2M NaOH aqueous solution (2 mL x 2) and brine (1 mL), filtered through a PTFE membrane filter, and the solvent was distilled off under reduced pressure to obtain a yellow oil. This preparative TLC (SiO _2, 10% methanol / dichloromethane) to give 1- [4- (benzoylamino) benzyl) -4- [methyl [N- (3- trifluoromethyl) benzoyl) glycyl] aminomethyl ] Piperidine (Compound No. 519) as a colorless oil (4.6 mg, 36%). Purity is determined by RPLC / MS (99%). ESI / MS m / e 553.2 (M ⁺ + H, C ₃₀ H ₃₁ F ₃ N ₄ O ₃ ).
[1193] [Example 2007] Synthesis of 1- [4- (piperidinocarbonyl) benzyl) -4 - [[N- (3- (trifluoromethyl) benzoyl) glycyl] aminomethyl] piperidine ) Synthesis of
[1194] A DMF solution of piperidine (0.048 mg), diisopropylcarbodiimide (0.45 mmol) in DMF (0.15 mL) and 1-hydroxybenzotriazole hydrate (0.45 mmol) was added to a solution of 1- (4- ) Was added to a DMF (1.0 mL) solution of 4 - [[N- (3-trifluoromethyl) benzoyl) glycyl] aminomethyl] piperidine (0.040 mmol) ^{Place on a TM} SCX column and wash with chloroform / methanol = 1: 1 (5 mL) and methanol (5 mL). The product was eluted with a 2M NH ₃ in methanol (5 mL) solution and concentrated to give 1- [4- (piperidinocarbonyl) benzyl) -4 - [[N- (3- (trifluoromethyl) benzoyl) glycyl ] Aminomethyl] piperidine (Compound No. 1572) (14.3 mg, 66%). Purity is determined by RPLC / MS (99%). ESI / MS m / e 545 (M ⁺ + H, C ₂₉ H ₃₅ F ₃ N ₄ O ₃ ).
[1195] [Example 2008-2015]
[1196] The compounds used in the present invention are synthesized according to the method of Example 2007 using the corresponding raw materials and reactants, respectively. The ESI / MS data and the yields and yields of the final process are summarized in Table 50.
[1197] [Table 50]
[1198]
[1199] Example 2016: Synthesis of 1- [4- (chloroformyl) benzyl] -4 - [[N- (3- (trifluoromethyl) benzoyl) glycyl] aminomethyl] piperidine
[1200] A mixture of 1- (4-carboxybenzyl) -4 - [[N- (3-trifluoromethyl) benzoyl) glycyl] aminomethyl] piperidine (240 mg) and thionyl chloride After stirring for 12 hours, thionyl chloride was removed under reduced pressure to obtain 1- [4- (chloroformyl) benzyl] -4- [[N- (3- (trifluoromethyl) benzoyl) glycyl] amino Methyl] piperidine. This acid chloride is used without further purification.
[1201] Example 2017: Synthesis of 1- [4- [N- (2-methoxyethyl) carbamoyl] benzyl] -4 - [[N- (3- (trifluoromethyl) benzoyl) glycyl] aminomethyl] Synthesis of piperidine (Compound No. 1612)
[1202] (0.042 mmol) of 1 - [4- (chloroformyl) benzyl] -4 - [[N- (3- trifluoromethyl) benzoyl) glycyl] aminomethyl] piperidine 3.8 mg, 0.050 mmol), piperidinomethyl polystyrene (46 mg) and dichloromethane (1.5 mL) was stirred at room temperature for 17 hours. Water (0.020 mL) is added and the mixture is stirred for 30 minutes, then methanol (1 mL) is added and the mixture is placed on a Varian ( ^TM) SCX column and washed with methanol (10 mL). The product by elution with methanol and concentrated to a solution of _{2M NH 3 1- [4- [N-} (2- methoxyethyl) carbamoyl] benzyl] -4- [methyl [N- (3- (trifluoromethyl) Benzoyl) glycyl] aminomethyl] piperidine (Compound No. 1612) (26.7 mg, 100%). Purity is determined by RPLC / MS (92%). ESI / MS m / e 535.2 (M ⁺ + H, C ₂₇ H ₃₃ F ₃ N ₄ O ₄ ).
[1203] [Example 2018-2020]
[1204] The compounds used in the present invention are synthesized according to the method of Example 2017 using the corresponding raw materials and reactants, respectively. If necessary, purified by preparative TLC to obtain the desired product. ESI / MS data, yield and yield are summarized in Table 51.
[1205] [Table 51]
[1206]
[1207] Example 2021: Synthesis of 4- [N- [5-bromo-2- (methylamino) benzoyl] glycyl] aminomethyl-1- (4-chlorobenzyl) piperidine
[1208] A mixture of triethyl orthoformate (50 mg, 0.10 mmol) and 4- (trifluoromethyl) benzoic acid was added to a solution of 4- [N- (2-amino-5-bromobenzoyl) glycyl] aminomethyl- (6.5 mL) was stirred at 150 占 폚 for 17 hours. Concentration gives a yellow solid. Sodium borohydride (7.6 mg, 0.2 mmol) was added to a solution of this yellow solid in ethanol (3 mL), and the mixture was stirred at room temperature for 14 hours. The white precipitate obtained is dissolved in dichloromethane and the solution is washed with 1M aqueous NaOH (2 mL). The organic layer is separated, dried over K ₂ CO ₃ , filtered and concentrated. Column chromatography to give the (SiO _2, 20% methanol / chloroform) 4- [N- [5- bromo-2- (methylamino) benzoyl] glycyl] amino-1- (4-Chloro-benzyl) Pyridine (Compound No. 1427) (40 mg, 80%). Purity is determined by RPLC / MS (100%). ESI / MS m / e 505 (M ⁺ + H, C ₂₃ H ₂₈ BrClF ₆ N ₄ O ₂ ).
[1209] [Example 2022] Synthesis of 4- [N- [5-bromo-2- (dimethylamino) benzoyl] glycyl] aminomethyl-1- (4-chlorobenzyl) piperidine
[1210] (26 mg, 0.42 mmol) and acetic acid (14 L) were added to a solution of 4- [N- (2-amino-5-bromobenzoyl) glycyl] aminomethyl-1- (4-chlorobenzyl) piperidine (67 mg, 0.14 mmol), 37% formaldehyde solution (0.112 mL, 1.4 mmol), acetonitrile (2 mL) and methanol (1.5 mL), and the mixture was stirred at 50 ° C for 30 hours Then, a 1 M aqueous NaOH solution and dichloromethane are added. The aqueous layer is separated, and the organic layer is dried over K ₂ CO ₃ , filtered and concentrated. Column chromatography to give the (SiO _2, 20% methanol / ethyl acetate) 4- [N- [5- bromo-2- (dimethylamino) benzoyl] glycyl] amino-1- (4-chlorobenzyl) Piperidine (Compound No. 1428) (60 mg, 82%). Purity is determined by RPLC / MS (100%). ESI / MS m / e 523 (M ⁺ + H, C ₂₄ H ₃₀ BrClF ₆ N ₄ O ₂ ).
[1211] Example 2023 Synthesis of 4 - [[N- [5-bromo-2- (methylsulfonylamino) benzoyl] glycyl] aminomethyl] -1- (4- chlorobenzyl) piperidine (Compound No. 1581) Synthesis of
[1212] (4-chlorobenzyl) piperidine (25 mg, 0.05 mmol), methanesulfonyl chloride (0.0045 g, mL), triethylamine (0.026 mL) and dichloromethane (2 mL) was stirred at room temperature for 17 hours. The reaction mixture is purified by column chromatography (SiO ₂ ), loaded on a Varian ^™ SCX column and washed with methanol (5 mL). The product was eluted with a solution of 0.1 M HCl in methanol (5 mL) and concentrated to give 4 - [[N- [5-bromo-2- (methylsulfonylamino) benzoyl] glycyl] aminomethyl] Chlorobenzyl) piperidine (Compound No. 1581) (5.4 mg, 19%). ESI / MS m / e 573.0 ( M + + H, C 23 H 28 BrClN 4 O 4 S).
[1213] Example 2024 Synthesis of 4 - [[N- [5-bromo-2- (bis (methylsulfonyl) amino) benzoyl) glycyl] aminomethyl] -1- (4- chlorobenzyl) piperidine No. 1582)
[1214] Aminomethyl] piperidine (57 mg, 0.10 mmol), methanesulfonyl chloride (0.018 g, 0.10 mmol) was added to a solution of 1- (4-chlorobenzyl) -4- mL, 0.024 mL), triethylamine (0.068 mL) and dichloromethane (2 mL) was stirred at room temperature for 8 hours. Add 1 M NaOH aqueous solution (1 mL) and extract with dichloromethane (2 mL x 3). The combined extracts are dried with K ₂ CO ₃ , filtered and concentrated. Purification by column chromatography _{(SiO 2) 4 - [[} N- [5- bromo-2- (bis (methylsulfonyl) amino) benzoyl) glycyl] aminomethyl] -1- (4-chlorobenzyl) Piperidine (Compound No. 1582) (40 mg, 62%). ESI / MS m / e 651 (M ⁺ + H, C ₂₄ H ₃₀ BrClN ₄ O ₆ S ₂ ).
[1215] Example 2025 Synthesis of iodosized 1- (4-chlorobenzyl) -1-methyl-4 - [[N- (3-trifluoromethyl) benzoyl) glycyl] aminomethyl] Methylammonium salt)
[1216] A solution of (piperidinomethyl) polystyrene (80 mg) in acetonitrile (1.0 mL) was added to a solution of 4 - [[N- [3- trifluoromethyl) benzoyl) glycyl] aminomethyl] piperidine Mg, 2.7 mmol base / g resin) was added to a chloroform (1.0 mL) solution of 4-chlorobenzyl chloride (11.7 mg, 0.073 mmol) and the mixture was stirred at 60 캜 for 2 hours. Phenyl isocyanate (10.4 mg, 0.087 mmol) was added to the reaction mixture cooled to room temperature, stirred at 25 ° C for 1 hour, placed on a Varian ^™ SCX column and washed with methanol (20 mL). The product was eluted with a 2M NH ₃ solution in methanol (6 mL) and concentrated to give 1- (4-chlorobenzyl) -4- [[N- (3- (trifluoromethyl) benzoyl) glycyl] aminomethyl] piperidine As a colorless oil.
[1217] Methyl iodide (28 mg, 0.20 mmol) was dissolved in acetonitrile (2.0 mL) of 1- (4-chlorobenzyl) -4 - [[ ) Solution and the reaction mixture was stirred at 70 ° C for 4 hours. The solvent was removed under reduced pressure to obtain 1- (4-chlorobenzyl) -1-methyl-4 - [[N- (3- (trifluoromethyl) benzoyl) glycyl] aminomethyl] piperid iodide as a yellow oil (31.7 mg, 71%). Purity is determined by PRLC / MS (99%). ESI / MS m / e 482.1 (M ⁺ + H, C ₂₄ H ₂₈ ClF ₃ N ₃ O ₂ ).
[1218] [Example 2026] 1- (4-Chlorobenzyl) -4- [N-methyl-N- [N- (3- (trifluoromethyl) benzoyl) glycyl] aminomethyl] piperidine ) Synthesis of
[1219] (108 mg, 1.33 mmol, 37 wt%) was added to a 10% aqueous solution of 1- (4-chlorobenzyl) -4- (aminomethyl) piperidine (318 mg, 1.33 mmol) and NaBH ₃ CN (668 mg) Acetic acid / methanol (3 mL), and the mixture was stirred at 25 占 폚 for 1 hour. The reaction mixture was placed on a Dowex 50Wx2 column ^TM (10mL) and washed with methanol (20mL). The product was eluted with 2M NH ₃ in methanol (6 mL) and concentrated to give 1- (4-chlorobenzyl) -4 - [(methylamino) methyl] piperidine as a colorless oil which was used without purification.
[1220] Hydroxybenzotriazole hydrate (60 mg) was dissolved in dichloromethane (1 ml) of 1- (4-chlorobenzyl) -4 - [(methylamino) methyl] piperidine (111 mg, 0.44 mmol) Methane (4 mL), stirred at 25 ° C. for 1 hour, and then washed with 2 M aqueous NaOH (2 mL × 2). After filtration through a PTFE membrane filter, the solvent was removed under reduced pressure to obtain a yellow oil which was purified by preparative TLC to give 1- (4-chlorobenzyl) -4- [N-methyl-N- [N- (Trifluoromethyl) benzoyl) glycyl] aminomethyl] piperidine (Compound No. 520) as a yellowish white oil (14.0 mg, 3.4%). Purity is determined by PRLC / MS (99%). ESI / MS m / e 482.1 (M ⁺ + H, C ₂₄ H ₂₇ ClF ₃ N ₃ O ₂ ).
[1221] [Referential Example 37] Synthesis of 3-amino-homopiperidine
[1222] 1 M BH ₃ -THF solution (80 mL) was added to a solution of DL- [alpha] -amino- [epsilon] -caprolactam (2 g, 16 mmol) in THF (70 mL) and refluxed for 3 hours. 2 M Hydrochloric acid (50 mL) is added and the reaction is heated to reflux for another 1 h and then cooled to 25 &lt; 0 &gt; C. The reaction is made alkaline (pH 10) with 4M NaOH solution and extracted with ethyl acetate (200 mL x 3). The combined organic layers were washed with saturated aqueous NaHCO ₃ , dried (MgSO ₄ ) and concentrated to obtain the desired product (990 mg, 54%). This is used without further purification.
[1223] [Referential Example 38] Synthesis of 3-amino-1- (4-chlorobenzyl) homopiperidine
[1224] P-Chlorobenzyl chloride (463 mg, 2.9 mmol) and K ₂ CO ₃ (828 g, 6 mmol) were added to a solution of 3-amino hophopiperidine (1.71 g, 15 mmol) in acetonitrile (45 mL) The mixture is stirred under heating for 9 hours. Cool to 25 &lt; 0 &gt; C and concentrate to obtain a yellow solid. The residue was partitioned between H ₂ O (5 mL) and ethyl acetate (50 mL) and extracted with ethyl acetate (50 mL × 2). The combined organic layers were washed with brine (20 mL), dried (MgSO ₄ ) and concentrated. Purification of the yellow oil obtained was chromatographed (SiO _2, 5-20% methanol / dichloromethane gradient elution) to give the desired product as yellow oil body (639㎎, 93%).
[1225] [Example 2027] synthesis of 1- (4-chlorobenzyl) -3 - [(4-benzoylbutyryl) amino] homopiperidine (Compound No. 994)
[1226] To a solution of 3-amino-1- (4-chlorobenzyl) homopiperidine (24 mg, 0.10 mmol) and 4-benzoylbutyric acid (1.2 equivalents) in chloroform (1 mL) was added EDCI (23 mg) and HOBt ) And triethylamine (15.2 μL), and the mixture was stirred at 25 ° C for 16 hours. The reaction mixture was diluted with dichloromethane (0.5 mL), filtered through a PTFE membrane and concentrated to give 1- (4-chlorobenzyl) -3- [(4-benzoylbutyryl) amino] homopiperidine (Compound No. 994) (43 mg, 99%). Purity is determined by RPLC / MS (98%). ESI / MS m / e 413 (M ⁺ H, C ₂₄ H ₂₉ ClN ₂ O ₂ )
[1227] [Example 2028-2042]
[1228] The compounds used in the present invention are synthesized according to Example 2027 using the corresponding raw materials and reactants, respectively. If necessary, the product is purified by chromatography (HPLC-C ₁₈ ) to obtain the desired product as a TFA salt. ESI / MS data, yields and yields are summarized in Table 52.
[1229] [Table 52]
[1230]
[1231] * Yield of trifluoroacetic acid salt
[1232] [Example 2043] Measurement of the inhibitory effect of test compounds on MIP-1 Binding to THP-1 cells
[1233] THP-1 cells as human leukemia cells were adjusted to pH 7.4 by adding 0.1% BSA and 25 mM HEPES to an assay buffer (RPMI-1640 (manufactured by Gibco-BRL)) at a concentration of 1 × 10 ⁷ cells / ) To give a cell suspension. A solution of the test compound diluted with assay buffer is used as a test compound solution. A solution diluted with assay buffer to give 250 nCi / mL of iodine labeled MIP-1 alpha (DuPont NEN) is used as the labeled ligand solution. (25 μL of the test compound, 25 μL of the labeled ligand solution and 50 μL of the cell suspension) per well in a 96-well filter plate (manufactured by Millipore) and stirred (100 μL of the reaction solution), followed by incubation at 18 ° C. for 1 hour.
[1234] After completion of the reaction, the reaction solution was filtered, and the filter was washed twice with 200 μL of cold PBS (filtered after adding 200 μL of cold PBS). After the filter is dried in the air, the liquid scintillator is added at 25 μL per well, and the radioactivity at which the cells on the filter are maintained is measured with a saw count (manufactured by Packard Co.).
[1235] The count obtained when 100 ng of the unlabeled human MIP-1 alpha (manufactured by Peprotech Co., Ltd.) was added instead of the test compound was subtracted as nonspecific adsorption, and the count when the test compound was not added was 100% -1 &lt; / RTI &gt; cells.
[1236] Inhibition rate (%) = [1- (A-B) / (C-B)] 100
[1237] (A: count when the test compound is added, B: count when adding 100 ng of unlabeled human MIP-1 alpha, C: count when only ¹²⁵ I labeled human MIP-1 is added)
[1238] As a result of measuring the inhibitory activity of the cyclic amine derivative as an active ingredient of the present invention, for example, the following compounds exhibit 20% -50%, 50% -80%, and> 80% inhibition at 2 μM or 10 μM concentration, respectively.
[1239] Compound exhibiting an inhibitory effect of 20% -50% at a concentration of 10 μM:
[1240]
[1241] Compound exhibiting 50% -80% inhibition at a concentration of 10 [mu] M:
[1242]
[1243] &Lt; RTI ID = 0.0 &gt; 80% &lt; / RTI &gt;
[1244]
[1245] Compound exhibiting an inhibitory effect of 20% -50% at a concentration of 2 μM:
[1246]
[1247] Compound exhibiting an inhibitory effect of 50% -80% at a concentration of 2 μM:
[1248] Compound No. 1190, 1414, 1600, 2091, 2094, 2095
[1249] &Lt; RTI ID = 0.0 &gt; 80% &lt; / RTI &gt;
[1250] Compound No. 2093, 2097, 2099, 2103, 2104
[1251] [Example 2044] Measurement of inhibitory effect on binding of MCP-1 to THP-1 cells
[1252] 1. Production of recombinant baculovirus containing human MCP-1 gene
[1253] Two types of DNA synthesis primers (5'-CACTCTAGACTCCAGCATGA (SEQ ID NO: 1)) were prepared by adding a restriction enzyme recognition site on the basis of a known human MCP-1 gene sequence (for example, see Yoshimura, T. et al., Febs Letters 1989, 244, 487-493, 3 'and 5'-TAGCTGCAGATTCTTGGGTTG-3'), cDNA derived from human vascular endothelial cells (purchased from Kurabo Industries Co., Ltd.) was amplified by PCR method and restriction enzymes (PstI and XbaI) were cut and then transferred vector pVL1393 Ltd.). These vectors and infectious baculovirus are then subjected to contrac- tion in Sf-9 insect cells, and the human MCP-1 gene recombinant baculovirus is isolated from the supernatant by plaque assay.
[1254] 2. [ ¹²⁵I] Acquisition of human MCP-1 expressing the marker baculovirus
[1255] According to a method other than ISHII, K. (see Biochemical and Biophysical Research Communications 1995, 206, 955-961), 5 x 10 ⁶ Sf-9 insect cells were transfected with 5 x 10 ⁷ PFU of human MCP-1 recombinant baculovirus (Plaque forming unit), and cultured in EX-CELL 401 medium for 7 days. Affinity purification was performed using a heparin Sepharose column (manufactured by Pharmacia), followed by reverse phase HPLC (Vydac C18 column) Human MCP-1 is obtained. For the obtained purified human MCP-1, a protein labeled with [ ¹²⁵ I] labeled baculovirus expressed in Bolton-Hunter method (MCP-1 inactivated: 2000 Ci / mmol) was obtained do.
[1256] 3-1. [ ¹²⁵I] Inhibition of Bacillus virus expression in human MCP-1 binding to THP-1 cells (Method 1)
[1257] THP-1 cells as leukemia cells derived from human sheath warts were adjusted to pH 7.4 by adding 0.1% BSA and 25 mM HEPES to assay buffer (RPMI-1640 (manufactured by Gibco-BRL)) at a concentration of 1 × 10 ⁷ cells / ) To prepare a cell suspension. A solution of the test compound diluted with assay buffer is used as a test compound solution. The above-described [ ¹²⁵ I] labeled baculovirus-expressing human MCP-1 is diluted with assay buffer to 1 μCi / mL as a labeled ligand solution. 25 μL of the test compound solution, 25 μL of the labeled ligand solution and 50 μL of the cell suspension are dispensed into a 96-well filter plate (manufactured by Millipore Corporation) per well and stirred (100 μL of the reaction solution), followed by incubation at 18 ° C. for 1 hour.
[1258] After completion of the reaction, the reaction solution was filtered, and the filter was washed twice with 200 μL of cold PBS (filtered after adding 200 μL of cold PBS). After the filter is dried in the air, the liquid scintillator is added at 25 μL per well, and the radioactivity at which the cells on the filter are maintained is measured with a saw count (manufactured by Packard Co.).
[1259] The count obtained when 100 ng of the above-mentioned baculovirus human MCP-1 (non-labeled) was added in place of the test compound was subtracted as nonspecific adsorption, and the count when the test compound was not added at all was 100% &Lt; / RTI &gt; to the THP-1 cells.
[1260] Inhibition rate (%) = {1- (A-B) / (C-B)} 100
[1261] (A: Count when the test compound is added, B: Count when 100 ng of unlabeled human MCP-1 is added, and C: Count when only ¹²⁵ I labeled human MCP-1 is added)
[1262] As a result of measuring the inhibitory activity of the cyclic amine derivative as an active ingredient of the present invention, for example, the following compounds exhibit 20% -50%, 50% -80%, and> 80% inhibition at 1 μM, 10 μM or 100 μM concentration, respectively.
[1263] Compound exhibiting an inhibition of 20% -50% at a concentration of 100 μM:
[1264]
[1265] Compound exhibiting 50% -80% inhibition at a concentration of 100 μM:
[1266]
[1267] &Lt; RTI ID = 0.0 &gt; 80% &lt; / RTI &gt;
[1268]
[1269] Compound exhibiting an inhibitory effect of 20% -50% at a concentration of 10 μM:
[1270]
[1271] Compound exhibiting 50% -80% inhibition at a concentration of 10 [mu] M:
[1272]
[1273] &Lt; RTI ID = 0.0 &gt; 80% &lt; / RTI &gt;
[1274]
[1275] Compound exhibiting an inhibitory effect of 20% -50% at a concentration of 1 μM:
[1276] Compound No. 1118, 1121, 1136, 1143, 1146, 1158, 1159, 1167, 1170, 1359, 1361, 1362, 1363
[1277] Compound exhibiting an inhibition of 50% -80% at a concentration of 1 μM:
[1278] Compound No. 1133, 1134, 1137, 1141, 1156, 1161, 1162, 1163, 1164, 1166
[1279] Compound exhibiting &gt; 80% inhibition at a concentration of 1 [mu] M:
[1280] Compound No. 1147
[1281] 3-2. [ ¹²⁵I] Inhibition of Bacillus Virus Expression of Human MCP-1 in THP-1 Cells (Method 2)
[1282] THP-1 cells, which are leukemia cells derived from human sheath warts, were suspended in assay buffer (50 mM HEPES, pH 7.4, 1.0 mM CaCl ₂ , 5.0 mM MgCl ₂ , 0.5% BSA) at a concentration of 1 × 10 ⁷ cells / . A solution of the test compound diluted with assay buffer is used as a test compound solution. The above-described [ ¹²⁵ I] labeled baculovirus-expressing human MCP-1 is diluted with assay buffer to 1 μCi / mL as a labeled ligand solution. 25 μL of the test compound, 25 μL of the labeled ligand solution and 50 μL of the cell suspension are dispensed in a 96-well filter plate (manufactured by Millipore Corporation) per well and stirred (100 μL of the reaction solution), followed by incubation at 18 ° C. for 1 hour.
[1283] After completion of the reaction, the reaction solution was filtered, and the filter was washed twice with 200 μL of cold PBS (filtered after adding 200 μL of cold PBS). After the filter is dried in the air, the liquid scintillator is added at 25 μL per well, and the radioactivity at which the cells on the filter are maintained is measured with a saw count (manufactured by Packard Co.). The count obtained when 100 ng of the above-mentioned baculovirus human MCP-1 (unlabeled) was added in place of the test compound was subtracted as nonspecific adsorption, and the count when the test compound was not added at all was 100% &Lt; / RTI &gt; to the THP-1 cells.
[1284] Inhibition rate (%) = {1- (A-B) / (C-B)} 100
[1285] (A: count when the test compound is added, B: count when 100 ng of unlabeled human MCP-1 is added, and C: count when only ¹²⁵ I labeled human MCP-1 is added)
[1286] As a result of measuring the inhibitory activity of the cyclic amine derivative as an active ingredient of the present invention, for example, the following compounds exhibit 20% -50%, 50% -80%, and> 80% inhibition at 0.2 μM, 1 μM or 10 μM concentration, respectively.
[1287] Compound exhibiting an inhibitory effect of 20% -50% at a concentration of 10 μM:
[1288] Compound No. 1560
[1289] Compound exhibiting 50% -80% inhibition at a concentration of 10 [mu] M:
[1290] Compound No. 1550
[1291] &Lt; RTI ID = 0.0 &gt; 80% &lt; / RTI &gt;
[1292] Compound No. 541, 1042, 1043, 1559
[1293] Compound exhibiting an inhibitory effect of 20% -50% at a concentration of 1 μM:
[1294]
[1295] Compound exhibiting an inhibition of 50% -80% at a concentration of 1 μM:
[1296]
[1297] Compound exhibiting &gt; 80% inhibition at a concentration of 1 [mu] M:
[1298]
[1299] Compound exhibiting an inhibitory effect of 20% -50% at a concentration of 0.2 μM:
[1300]
[1301] Compound exhibiting 50% -80% inhibition at a concentration of 0.2 [mu] M:
[1302]
[1303] Compound exhibiting &gt; 80% inhibition at a concentration of 0.2 [mu] M:
[1304] Compound No. 1696, 1892
[1305] [Example 2045] Measurement of the inhibitory effect on binding of MCP-1 to MCP-1 receptor expressing cells ( evaluation using [ ¹²⁵ I] labeled human MCP-1)
[1306] 1. Acquisition of MCP-1 receptor expressing cells
[1307] A plasmid obtained by ligating the MCP-1 receptor cDNA fragment (see Biochemical and Biophysical Research Communications 1994, 202, 1156-1162) obtained by YAMAGAMI, S. et al. To the NotI site of the expression plasmid pCEP-4 (Invitrogen) was ligated with a Lipofectamine reagent (Gibco-BRL) to 293-EBNA cells derived from human kidney epithelium, cultured in the presence of a selective agent (hygromycin), and then a stable expression strain is obtained. Expression of the receptor is confirmed by the binding of [ ¹²⁵ I] labeled human MCP-1.
[1308] 2. [ ¹²⁵I] Inhibition of Bacillus Viral Expression Human MCP-1 was assayed for binding to MCP-1 receptor expressing cells
[1309] The MCP-1 receptor expressing cells on the culture chamber were peeled off with a cell scraper, and 0.1% BSA and 25 mM HEPES were added to an assay buffer (D-MEM (Gibco-BRL)) at a concentration of 6 × 10 ⁶ cells / 7.4) to prepare a cell suspension. Subsequent operations are carried out in the same manner as in Example 2044.
[1310] As a result of measuring the low-performance of the cyclic amine derivative as the active ingredient of the present invention, the low-performance of the representative compound in this example is almost equivalent to the low-performance shown in Example 2044.
[1311] [Example 2046] Measurement of cytolytic activity
[1312] In order to investigate the cytolytic activity of the compound according to the present invention, cytoprotection caused by the monocyte migration factor MCP-1 was measured using human sheath-derived leukemia cell THP-1 as a host cell, J. Immunol. Methods. 1980, 33, 239-247). That is, THP-1 cells were suspended in 2 × 10 ⁶ / mL (RPMI-1640 (manufactured by Flow Laboratories) + 10% FCS) in a chamber loss (200 μL) of a 96-well microchemotaxis chamber (Neuroprobe) ML) was diluted with the same solution to a final concentration of 20 ng / mL, and a polycarbonate filter (PVP-free) was placed between the two chambers. , Neuroprobe; registered trademark) to be fixed incubated for 2 hours under 5% CO ₂ present in 37 ℃ bait.
[1313] After removing the filter and filtering with a Diff Quick solution (manufactured by Kokusa Kogyo Co., Ltd.), immigrant cells were fixedly stained and then measured at a measurement wavelength of 550 nm with a plate reader (Molecular Device) It shall be an index of number. At this time, the test compound is added to the supernatant with various concentrations of THP-1 cells to determine cell lysis inhibitory activity (inhibition degree: IC ₅₀ (μM)). (The number of cells migrated by MCP-1 when the test compound was not added to the supernatant) - (the number of cells migrated when MCP-1 was not added) = 100%} and the 50% Is referred to as &quot; IC _{50 &} quot ;.
[1314] As a result of measuring the low-performance of the cyclic amine derivative as an active ingredient of the present invention, for example, the IC ₅₀ value of the following compounds is 0.1 μM or less.
[1315] Examples of compounds having an IC ₅₀ value of 0.1 μM or less:
[1316]
[1317] The results in Examples 2043, 2044, 2045 and 2046 clearly show that the compounds of the present invention have an activity of inhibiting the action of chemokines on target cells as receptor antagonists of chemokines such as MIP-1 alpha and / or MCP-1 .
[1318] [Example 2047] Examination of inhibitory effect on mouse collagen arthritis
[1319] Mouse collagen arthritis is produced according to the method of Kato et al. (Arthritis in mice induced by a single immunization with collagen. Ann. Rheum. Dis., 55, 535-539, 1996).
[1320] 1. Method
[1321] Type II collagen derived from small joints (Collagen Technology Workshop) is mixed with an equivalent amount of ProNeed Immunobiologicals to produce a homogeneous emulsion. Ultrasonic homogenizer (Titech Co., Ltd.) is used for emulsion preparation. 0.15 mg / 0.1 mL / body of the emulsion is administered into the root muscle of the tail of DBA / 1 mouse (Nihon Charles River Co., Ltd.) using a glass syringe for tuberculin and a 27G needle.
[1322] The test compound is suspended or suspended in an aqueous solution of 0.5% sodium carboxymethyl cellulose (CMC, Wako Pure Yaku Kogyo Co., Ltd.), orally administered from the day after the administration of the emulsion by adjusting the predetermined amount of the overdose.
[1323] The control group was a group administered with 0.5% CMC (hereinafter referred to as a control) and three groups administered with 30 or 100 mg / kg of the test compound. The solvent or the test compound is administered once a day. The number of animals in each group shall be 16.
[1324] 2. Evaluation of arthritis
[1325] After 12 weeks of emulsion administration, the degree of joint swelling is scored for each of the limb fingers by Abbe's method (immunotherapy for arthritis models, inflammation 12, 417-422, 1992). Each limb is scored in 4 steps of score 0-3 and the maximum is 12 points.
[1326] 3. Effect of synovial proliferation, destruction of articular cartilage and bone destruction of cartilage
[1327] After observing arthritis score, take the right fuzzy. After paraffin embedding, a section cut with a thin knee joint was prepared and subjected to hematoxylin and eosin staining to evaluate the action of synovial membrane proliferation, destruction of articular cartilage, and osteoclastic bone destruction by a conventional method do. Scores are scored in five steps of 0-4 for each item.
[1328] 4. Evaluation Results
[1329] A categorical Dunnett test was performed on the control group and it is assumed that there is a significant difference when the p value is 0.05 or less. The following charts are expressed as mean ± standard deviation (SD). Fig. 1 shows the results of arthritis when Compound No. 1583 was orally administered for 12 weeks. The group administered with Compound No. 1583 significantly inhibited the arthritis score as compared with the control group.
[1330] The results for the proliferation of synovial membrane, destruction of articular cartilage, and osteolysis of cartilage bone of Compound No. 1583 are shown in FIGS. 2-4, respectively. Compound 1583 is significantly inhibited for any evaluation item.
[1331] [Example 2048] Examination of inhibitory effect on rat collagen arthritis
[1332] Rat collagen arthritis is produced as follows, based on the method of Trentham et al. (Autoimmunity to type II collagen: an experimental model of arthritis, J. Exp. Med., 146, 857-68 (1977)).
[1333] 1. Method
[1334] Type II collagen (collagen technology training institute) derived from small joints and muramyldipeptide (CHEMICON International) were mixed with PRONDE incomplete adjuvant (CHEMICON International) to a final concentration of 0.08% and 0.02%, respectively, to obtain a homogeneous emulsion And make them. The emulsion is prepared by vigorously stirring in two glass syringes bonded with a connector at 4 占 폚. The emulsion was immersed in 10 portions of 1 mL using a glass syringe for tuberculin and a 26G injection needle at the abdominal endothelium of Lewis female rats (Nippon Charles River; 6 weeks after birth). After one week, the emulsion prepared in the same manner as above was further immunized (boosted) with 0.1 mL in the tail muscle root.
[1335] The test compound is suspended in an aqueous solution of 0.5% carboxymethylcellulose sodium (CMC, Wako Pure Chemical Industries, Ltd.) as a trigger, and a predetermined dose of the test compound is prepared and orally administered daily for 3 weeks from the first emulsion administration.
[1336] The control group was the untreated group (hereinafter referred to as Inertik group), the 0.5% CMC group (control group) and the compound group 1245 (300 mg / kg). The solvent or the test compound is administered once a day. The number of animals in each group shall be eight.
[1337] 2. Evaluation of arthritis
[1338] The swelling of the leg joint of Fuji is evaluated by measuring the volume change. The foot volume of the left and right rats of the rat was measured using a rat fujiposo edema volume measuring device (TK-105, UNICON) over a total of 7 times on the day of boosting and 2, 5, 7, 9, 12 and 14 days after the administration. The result is expressed as a percentage of increase in the foot volume of the boosted day as 100%. The average of all the left and right Fuji volumes in each group is taken as the average value of the group.
[1339] 3. Evaluation Method
[1340] Fig. 5 shows the results of arthritis when Compound No. 1245 was orally administered daily for 3 weeks. The values in the figure are mean values ± SE. . Student's t-test or Wilcoxon test was performed on the control group, and it is assumed that the p-value is 0.05 or less. The group to which Compound No. 1245 was administered showed significant (5, 7 and 14 days after P <0.01, 9 and 12 days after P <0.01, P <0.01) for the control group at each time point after 5, 7, 9, 12, 0.001) to suppress joint swelling.
[1341] The results of Examples 2047 and 2048 show that the medicament of the present invention can be effectively used for the treatment or prevention of diseases accompanied by cartilage destruction or bone destruction such as arthritis, chronic arthritis rheumatism, deformed arthropathy, traumatic joint destruction, osteoporosis, It can be seen that it has an effect.
[1342] [Example 2049] Examination of inhibitory action in a model of WKY-rat ginseng nephritis
[1343] 1. Method (Common for experiments 1 and 2)
[1344] An anti glomerular basement membrane serum obtained by immunizing a rabbit with a trypsin digest of a rat kidney cortex is intravenously administered to female WKY rats (Charles River Co., Ltd.) at a ratio of 2.5 mL / kg body weight for 4 weeks to cause glomerulonephritis.
[1345] After the administration of the antiserum, the urine of each animal was collected for 24 hours with a metabolic cage (Nippon Kurea) for rats on days 1, 4, 7, 10 and 14 and the amount of urine was measured by urine weight. Protein concentration is measured using a protein measurement kit (Tonein TP-II, Otsuka Pharmaceutical) in a urine solution, and the amount of excreted protein in urine per day is determined.
[1346] On the 15th day after the administration of the antiserum, the serum of the animal used in the experiment was sampled and the creatinine in the blood was measured with a Hitachi Model 7070 autoanalyzer using a creatinine measurement kit (Otosera CRE, Daicigakaku Co., Ltd.).
[1347] The test compound was administered at a dose of 100 mg / kg body weight twice daily (1 hour before and after 6:00 am in Experiment 1, around 10:00 am and 5:00 am in Experiment 2) from the day of administration of the anti-glomerular basement membrane serum, . In the control group, only the vehicle solution (0.5% aqueous solution of carboxymethylcellulose) is orally administered. The dosage should be 10 mL / kg body weight. The N number of animals is 10.
[1348] 2. Results and Discussion
[1349] On the 4th day after the sera of the anti glomerular basement membrane, the urine protein starts to be detected in each experimental group, and the amount of urine protein is increased by the passage of time to the 14th day, resulting in nephritis. In the group administered with Compound No. 1583, 26% of the inhibition tendency of urinary protein was observed on the 7th day after the administration of the antiserum, and on the 10th and 14th days, 51 and 54% (p <0.01, Mann -Whitney &lt; / RTI &gt; U test) protein content (Fig. 6).
[1350] The serum creatinine level on the 15th day after the serum of the anti-glomerular basement membrane was measured. As a result, a decrease of 20% (p <0.01, Mann-Whitney U test) was observed in the compound No. 1583 administration group compared to the control group (Table 53).
[1351] Therefore, it can be seen that Compound No. 1583 alleviated the glomerular injury and deterioration of the renal function of the rat, thereby suppressing the nephritis.
[1352] [Table 53]
[1353] Serum creatinine inhibitory effect
[1354] The serum creatinine value (mg / dl)
[1355] PlaceboCompound No. 1583 0.49 + 0.060.39 ± 0.03 ^**
[1356] 2-2. Experiment 2
[1357] From the 4th day after serotonin administration of anti-glomerular basement membrane, urine protein starts to be detected in each experimental group, and until then to the 14th day, the amount of urine protein is increased with time to cause nephritis. (P <0.001, Mann-Whitney U test) urine protein content was significantly higher in the group administered with Compound No. 1245 than that of the control group on days 4, 7, 10 and 14 after the administration of the antiserum (Fig. 7). The serum creatinine level on the 15th day after the sera of the anti-glomerular basement membrane was measured, and a decrease of 10% (p <0.05, Student's t-test) was observed in the compound A administration group as compared with the control group (Table 54).
[1358] Therefore, Compound No. 1245 shows that the glomerular injury and deterioration of the renal function of the rat are alleviated and the nephritis is suppressed.
[1359] [Table 54]
[1360] Serum creatinine inhibitory effect
[1361] Compound No. 1245 Serum creatinine value (mg / dl)
[1362] controlCompound No. 1245 0.53 ± 0.050.48 0.04 ^**
[1363] From the above results, it can be seen that the compound of the present invention has an effective therapeutic or preventive effect on nephritis or nephritis such as glomerulonephritis, interstitial nephritis or nepheline syndrome.
[1364] [Example 2050] Chronic mouse recurrence experiment 검토 Examination of inhibitory effect in animal model of allergic encephalomyelitis
[1365] 1. Method
[1366] An animal model of chronic recurrent allergic encephalomyelitis is prepared according to the method described in Okuda et al. (Okuda Y., et al., J. Neuroimmunol. 81, 201-210 (1998)).
[1367] Incomplete adjuvant (Difco) containing 500 μg of Rabbit myelin basic protein (Sigma) and 500 μg of Mycobacterium tuberculosis H37Ra (Difco) in the abdomen of 8-week-old female SJL / J × PL / J F1 mice 100 μL of a physiological saline = 1: 1 (volume ratio) emulsion is subcutaneously injected. After 24 hours, 100 μL of physiological saline containing 400 ng of Brodetella pertussis toxin (Sigma) is intraperitoneally administered to induce chronic recurrent allergic encephalomyelitis. The number of samples is 10.
[1368] The test compound is suspended in an aqueous solution of 0.5% (w / v) sodium carboxymethyl cellulose (Wako Pure Chemical Industries, Ltd.) as a trigger, and a predetermined solution is prepared and orally administered from the day of administration of the emulsion.
[1369] Clinical manifestations of chronic recurrent allergic encephalomyelitis were assessed by observing each animal once a day using the method described by Tavira et al. (&Quot; Immunization Experimental Procedure &quot; p.1178-1181, Nanko Doo (1995) do. That is, score 0 = normal; Score 1 = Tightness of the tail (1 imp tail); Score 2 = over light walking; Score 3 = pronounced Fuji depletion; Score 4 = Fuji pair paralysis; Score 5 = Blood death or death.
[1370] 2. Results and discussion
[1371] 2-1. Experiment 1: Effect of Compound No. 1583
[1372] The results up to 41 days after emulsion administration are shown in Table 55 and FIG.
[1373] Symptom trends are expressed as the mean value of each experimental group at each observation day. In the maximum symptom score of Table 55, the maximum value of the symptom score that each animal showed during the observation period is adopted as the representative value of the example. The statistical analysis method uses a nonparametric test of multiple groups with no response to the control group for symptom scores. For other weighing values, use multiple comparisons (Dunnett's multiple comparisons) to the control.
[1374] In comparison with the control group, in the group administered with 100 mg / kg body weight in the compound No. 1583 group, the delayed onset date (no significant difference), symptomatic suppression (p <0.05) and shortening of the onset period (p <0.05) . In the 30 mg / kg body weight group of compound No. 1583, there is no definite effect on these items, but the tendency of dose-dependent effects can be seen. 8, "Compound 1" means a compound of Compound No. 1583, not Compound No. 1 in the present invention.
[1375] [Table 55]
[1376] Experimental groupControl groupCompound No. 158330 mg / kg body weightCompound No. 1583100 mg / kg body weight First onset Date of onset12.6 ± 1.912.3 ± 1.913.6 ± 2.0 Maximum symptom score3.9 ± 0.63.5 ± 0.92.4 ± 1.3 * Duration of onset8.8 ± 2.59.8 ± 3.35.7 ± 3.8 * Second onset (recurrence) Date of onset26.8 ± 7.526.3 ± 3.428.5 ± 4.7 * Maximum symptom score3.8 ± 0.83.7 ± 0.63.0 ± 0.9 * Duration of onsetNot calculatedNot calculatedNot calculated *: P &lt; 0.05
[1377] 2-2. Experiment 2: Effect of Compound No. 1245
[1378] The results up to 21 days after emulsion administration are shown in Table 56 and FIG.
[1379] Symptom trends are expressed as the mean value of each experimental group at each observation day. In the maximum symptom score in Table 56, the maximum value of the symptom score that each animal showed during the observation period is adopted as the representative value of the example. Statistical analysis uses a nonparametric test of the two groups for symptom scores with no response to the control group. For other weighing values, use a Student's t-test for the control group.
[1380] In comparison with the control group, the delayed onset date (p <0.05) and symptom suppression tendency (no significant difference) were observed in the 300 mg / kg body weight of the compound No. 1245.
[1381] [Table 56]
[1382] Experimental groupControl groupCompound No. 1245300 mg / kg body weight Frequency of onset (number of animals exposed / number of animals immunized)34/3917/19 Date of onset11.2 ± 2.013.2 + 2.4 * Maximum symptom score3.0 ± 0.92.5 ± 1.5 Duration of onset5.5 ± 1.75.4 ± 2.4 *: P &lt; 0.05
[1383] From the above results, it can be seen that the compound of the present invention has an effective therapeutic or preventive effect on dehydration diseases such as multiple sclerosis.
[1384] The results shown in Examples 2043 to 2050 also show that the compounds of the present invention are useful as chemokine receptor antagonists for the treatment of atherosclerosis, chronic arthritis, psoriasis, asthma, ulcerative colitis, nephritis (nephritis), multiple sclerosis, Such as MIP-1 alpha and / or MCP-1, including pancreatitis, sarcoidosis, Crohn's disease, endometriosis, congestive heart failure, viral meningitis, cerebral infarction, neuropathy, Kawasaki disease, sepsis, allergic rhinitis and allergic dermatitis Indicating that chemokines may be therapeutic or preventive agents for various diseases considered to be involved.
[1385] Example 2051: Preparation of tablets
[1386] A tablet containing 30 mg of Compound No. 1583 is prepared by the following formulation.
[1387] Compound No. 1583 30 mg
[1388] Lactose 87 mg
[1389] Starch 30 mg
[1390] Magnesium stearate 3 mg
[1391] Example 2052 Preparation of injection
[1392] A solution for injection containing 0.3 mg of the hydrochloride of Compound No. 1583 in 1 mL is prepared by the following prescription.
[1393] Compound No. 1583 (hydrochloride) 30 mg
[1394] Sodium salt 900 mg
[1395] 100 mL distilled water for injection
[1396] The cyclic amine compound, a pharmaceutically acceptable acid addition product thereof, or a pharmaceutically acceptable C ₁ -C ₆ alkyl adduct thereof used in the present invention may be a chemokine receptor antagonist such as MIP-1α and / or MCP-1 Since the action of the same chemokine inhibits the action on the target cells, the infiltration of leukocyte tissues such as monocytes and lymphocytes plays an important role in the progression and maintenance of the disease, arteriosclerosis, pulmonary embolism, cardiomyopathy, hepatitis, pancreatitis Or prophylactic agents for diseases such as sarcoidosis, Crohn's disease, endometriosis, congestive heart failure, viral meningitis, cerebral infarction, neuropathy, Kawasaki disease, sepsis, allergic rhinitis and allergic dermatitis.

权利要求:
Claims (11)
[1" claim-type="Currently amended] A therapeutic or preventive agent for a disease involving a chemokine or chemokine receptor comprising a compound represented by the following formula (I), a pharmaceutically acceptable acid addition product thereof or a pharmaceutically acceptable C ₁ -C ₆ alkyl adduct thereof as an active ingredient:
(I)

[Wherein, R ¹ is a phenyl group, C ₃ -C ₈ cycloalkyl group or a hetero atom represents an aromatic heterocyclic ring having 1-3 oxygen atoms, sulfur atoms and / or nitrogen atoms, a phenyl group or an aromatic heterocyclic ring in the above R ¹ group to a benzene ring or a hetero atom condensed aromatic heterocyclic group having 1-3 oxygen atoms, sulfur atoms and / or nitrogen atom and may form a condensed ring, and a phenyl group, C ₃ -C ₈ cycloalkyl group represented by the R ¹ , an aromatic heterocyclic group, or condensed ring is any number of a halogen atom, a hydroxy group, a cyano group, a nitro group, a carboxyl group, a carbamoyl group, C ₁ -C ₆ alkyl, C ₃ -C ₈ cycloalkyl, C ₂ -C ₆ alkenyl group, C ₁ -C ₆ alkoxy group, C ₁ -C ₆ alkylthio, C ₃ -C ₅ alkylene group, C ₂ -C ₄ alkylene group, a C ₁ -C ₃ alkylenedioxy group, a phenyl group, a phenoxy A phenylthio group, a benzyl group, a benzyloxy group, a benzoylamino group, a C ₂ -C ₇ alkane Noilgi, C ₂ -C ₇ alkoxycarbonyl group, C ₂ -C ₇ alkanoyloxy group, C ₂ -C ₇ alkanoylamino group, C ₂ -C ₇ N- alkyl carbamoyl, C ₄ -C ₉ cycloalkyl N- A carbamoyl group, a C ₁ -C ₆ alkylsulfonyl group, a C ₃ -C ₈ (alkoxycarbonyl) methyl group, an N-phenylcarbamoyl group, a piperidinocarbonyl group, a morpholinocarbonyl group, : -NH (C = O) represented by the top 2 O-, formula: -NH (C = S) to the top 2 represented by O-, amino groups, mono (C ₁ -C ₆ alkyl) amino groups or di (C ₁ -C ₆ being optionally substituted by alkyl) amino group, those of phenyl, C ₃ -C ₈ cycloalkyl group, the substituent of the aromatic heterocyclic group or condensed ring is a methyl group in any number of a halogen atom, a hydroxy group, an amino group, a trifluoro of, A C ₁ -C ₆ alkyl group or a C ₁ -C ₆ alkoxy group.
R ² represents a hydrogen atom, a C ₁ -C ₆ alkyl group, a C ₂ -C ₇ alkoxycarbonyl group, a hydroxy group or a phenyl group, and the C ₁ -C ₆ alkyl group or phenyl group of R ² represents any number of halogen atoms, ₁ -C ₆ alkyl group or is optionally substituted with C ₁ -C ₆ alkoxy. However, when j = 0, R ² is not a hydroxy group.
j represents an integer of 0-2.
k represents an integer of 0-2.
m represents an integer of 2-4.
n represents 0 or 1;
R ³ represents a hydrogen atom or C (which may be substituted with the same or different arbitrary number of halogen atoms, a hydroxy group, a C ₁ -C ₆ alkyl group or one or two phenyl groups which may be substituted with a C ₁ -C ₆ alkoxy group) Represents a C ₁ -C ₆ alkyl group.
R ⁴ and R ⁵ are the same or different a hydrogen atom, a hydroxy group, a phenyl group or a C ₁ -C ₆ alkyl group represents, wherein R ⁴ and R ⁵ C ₁ -C ₆ alkyl group is any number of a halogen atom, a hydroxy group in, a cyano group, a nitro group, a carboxyl group, a carbamoyl group, a mercapto group, a guanidino group, a C ₃ -C ₈ cycloalkyl, C ₁ -C ₆ alkoxy group, C ₁ -C ₆ alkylthio import, (any number of A phenyl group which may be substituted with a halogen atom, a hydroxy group, a C ₁ -C ₆ alkyl group, a C ₁ -C ₆ alkoxy group or a benzyloxy group), a phenoxy group, a benzyloxy group, a benzyloxycarbonyl group, a C ₂ -C ₇ alkanoyl group , C ₂ -C ₇ alkoxycarbonyl group, C ₂ -C ₇ alkanoyloxy group, C ₂ -C ₇ alkanoylamino group, C ₂ -C ₇ N- alkyl carbamoyl, C ₁ -C ₆ alkylsulfonyl group, an amino group , mono (C ₁ -C ₆ alkyl) amino group, di (C ₁ -C ₆ alkyl) amino group or (as a hetero atom 1 an oxygen atom, a sulfur atom and / or nitrogen atom A condensed ring formed by condensation with an aromatic heterocyclic group having three or a benzene ring thereof), or R ⁴ and R ⁵ may all be monosubstituted to form a 3- to 6-membered cyclic hydrocarbon.
p represents 0 or 1;
q represents 0 or 1;
G is _{-CO-, -SO 2 -, -CO-} O-, -NR 7 -CO-, -CO-NR 7 -, -NH-CO-NH-, -NH-CS-NH-, -NR 7 -SO ₂ -, -SO ₂ -NR ⁷ -, -NH-CO-O- or -O-CO-NH-. Here, R ⁷ represents a hydrogen atom or a C ₁ -C ₆ alkyl group, or R ⁷ may be combined with R ⁵ to form a C ₂ -C ₅ alkylene group.
R ⁶ represents a phenyl group, a C ₃ -C ₈ cycloalkyl group, a C ₃ -C ₆ cycloalkenyl group, a benzyl group or an aromatic heterocyclic group having 1 to 3 oxygen atoms, a sulfur atom and / or a nitrogen atom as a hetero atom, The phenyl group, benzyl group or aromatic heterocyclic group in R ⁶ may be condensed with a benzene ring or an aromatic heterocyclic group having 1 to 3 oxygen atoms, a sulfur atom and / or a nitrogen atom as a hetero atom to form a condensed ring, phenyl group in the R ^6, C ₃ -C ₈ cycloalkyl, C ₃ -C ₆ cycloalkenyl group, a benzyl group, an aromatic heterocyclic group, or condensed ring is any number of a halogen atom, a hydroxy group, a mercapto group, a cyano group, A nitro group, a thiocyanato group, a carboxyl group, a carbamoyl group, a trifluoromethyl group, a C ₁ -C ₆ alkyl group, a C ₃ -C ₈ cycloalkyl group, a C ₂ -C ₆ alkenyl group, a C ₁ -C ₆ alkoxy group, C ₃ -C ₈ cycloalkyloxy groups, C ₁ -C ₆ alkyl group Group, a C ₁ -C ₃ alkylenedioxy group, a phenyl group, a phenoxy group, a phenyl group, a benzyl group, a benzoyl group, phenyl sulfinyl group, phenylsulfonyl group, a 3-phenyl-ureido group, C ₂ -C ₇ alkanoyl group, C ₂ -C ₇ alkoxycarbonyl group, C ₂ -C ₇ alkanoyloxy group, C ₂ -C ₇ alkanoylamino group, C ₂ -C ₇ N- alkyl carbamoyl, C ₁ -C ₆ alkylsulfonyl group, phenyl carbamoyl group, N, N- di (C ₁ -C ₆ alkyl) sulfamoyl group, an amino group, a mono (C ₁ -C ₆ alkyl) amino group, di (C ₁ -C ₆ alkyl) amino group, a benzyl group, a C ₂ -C ₇ (alkoxycarbonyl) amino groups, C ₁ -C ₆ (alkylsulfonyl) amino groups or bis (C ₁ -C ₆ alkylsulfonyl) group optionally substituted with an amino group is, those of the phenyl group, C ₃ -C ₈ cycloalkyl group, C ₃ -C ₈ cycloalkenyl group, the benzyl group, the substituent of the aromatic heterocyclic ring group or a condensed ring group of a halogen atom, a cyano group, a hydroxy group, an amino group, a trifluoromethyl any number of, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy group, or may be further substituted with C ₁ -C ₆ alkylthio group, a mono (C ₁ -C ₆ alkyl) amino groups or di (C ₁ -C ₆ alkyl) amino group].
Or a pharmacologically acceptable acid addition product thereof or a pharmaceutically acceptable C ₁ -C ₆ alkyl adduct thereof as an active ingredient, in the preparation of a medicament for preventing or preventing a disease involving a chemokine or chemokine receptor.
[2" claim-type="Currently amended] The therapeutic or preventive agent according to claim 1, wherein the disease is a disease involving cartilage destruction or bone destruction.
[3" claim-type="Currently amended] The therapeutic or preventive agent according to claim 2, wherein the disease accompanying cartilage destruction or bone destruction is arthritis, chronic joint rheumatism, deformed arthropathy, trauma, osteoporosis or swelling.
[4" claim-type="Currently amended] The therapeutic drug or prophylactic agent according to claim 1, wherein the disease is chronic arthritic rheumatism.
[5" claim-type="Currently amended] The therapeutic or preventive agent according to claim 1, wherein the disease is nephritis or kidney.
[6" claim-type="Currently amended] The therapeutic or preventive agent according to claim 5, wherein the disease is glomerulonephritis, interstitial nephritis or nepheline syndrome.
[7" claim-type="Currently amended] The therapeutic agent or prophylactic agent according to claim 1, wherein the disease is a dehydration disease.
[8" claim-type="Currently amended] The therapeutic agent or prophylactic agent according to claim 7, wherein the disease is multiple sclerosis.
[9" claim-type="Currently amended] The therapeutic or prophylactic agent according to claim 1, wherein the chemokine is MIP-1 alpha or MCP-1.
[10" claim-type="Currently amended] The therapeutic or preventive agent according to claim 1, wherein the chemokine receptor is CCR1 or CCR2.
[11" claim-type="Currently amended] A pharmaceutical composition comprising a compound represented by the formula (I), a pharmaceutically acceptable acid addition product thereof or a pharmaceutically acceptable C ₁ -C ₆ alkyl adduct thereof as an active ingredient.

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Pease et al.2009|Chemokine receptor antagonists: Part 1

同族专利:

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公开号 | 公开日

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DK1179341T3|2006-03-27|

---

AU779954B2|2005-02-24|

---

EP1179341A1|2002-02-13|

---

KR100673340B1|2007-02-28|

---

CA2373942A1|2000-11-23|

---

DE60023878D1|2005-12-15|

---

CN1240699C|2006-02-08|

---

NZ515374A|2004-09-24|

---

WO2000069432A1|2000-11-23|

---

NO20015599D0|2001-11-16|

---

NO20015599L|2001-11-16|

---

EP1179341B1|2005-11-09|

---

EP1179341A4|2003-10-29|

---

CN1384743A|2002-12-11|

---

DE60023878T2|2006-07-20|

---

US7390830B1|2008-06-24|

---

AT308985T|2005-11-15|

---

AU4614700A|2000-12-05|

---

ES2250132T3|2006-04-16|

引用文献:

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公开号 | 申请日 | 公开日 | 申请人 | 专利标题

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法律状态:
1999-05-18|Priority to JP17585699

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1999-05-18|Priority to JPJP-P-1999-00175856

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1999-09-06|Priority to JPJP-P-1999-00251464

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1999-09-06|Priority to JP25146499

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2000-05-18|Application filed by 야스이 쇼사꾸, 데이진 가부시키가이샤

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2002-02-27|Publication of KR20020015322A

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2007-02-28|Application granted

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2007-02-28|Publication of KR100673340B1

优先权:

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申请号 | 申请日 | 专利标题

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JP17585699|1999-05-18|

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JPJP-P-1999-00175856|1999-05-18|

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JPJP-P-1999-00251464|1999-09-06|

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JP25146499|1999-09-06|