Pyrrolidine carboxamido derivatives and methods for preparing and using the same

Abstract

Pyrrolidine carboxamido derivatives, optical isomers thereof, and salts thereof that are able to prevent, improve, and/or treat inflammatory conditions, including inflammatory bowel disease, and methods for preparing and using the same are provided.

1 . A compound represented by the following Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof. 
       
         
           
           
               
               
           
         
         wherein: 
         n is 0, 1, or 2; 
         A is -a 1 -, which is an amino acid independently selected from the group consisting of alanine, (Ala, A), arginine (Arg, R), asparagine (Asn, N), aspartic acid (Asp, D), cysteine (Cys, C), glutamic acid (Glu, E), glutamine (Gln, Q), glycine (Gly, G), histidine (His, H), isoleucine (Ile, I), leucine (Leu, L), lysine (Lys, K), methionine (Met, M), phenylalanine (Phe, F), proline (Pro, P), serine (Ser, S), threonine (Thr, T), tryptophan (Trp, W), tyrosine (Tyr, Y), and valine (Val, V), both terminal ends of the amino acid being coupled to a carbonyl group or an amine group by an amide bond; and 
         R 1  is a straight chain or branched chain C 1-36  alkyl, a straight chain or branched chain C 2-36  alkenyl including at least one double bond, or a straight chain or branched chain C 2-36  alkynyl including at least one triple bond. 
       
     
     
         2 . The compound of  claim 1 , wherein:
 n is 0, 1, or 2;     a   1  is   
       
         
           
           
               
               
           
         
       
       both terminal ends of which is coupled to a carbonyl group or amide group thereof by an amide bond; and
 R 1  is a straight chain or branched chain C 1-36  alkyl. 
 
     
     
         3 . The compound of  claim 1  selected from the group consisting of the following compounds. 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         4 . A method for preparing the compound of  claim 1  represented by Formula 1, which comprises, as represented by the following Reaction Scheme 1:
 reacting a compound 2 with a compound 3 to prepare a compound 4; 
 hydrolyzing the compound 4 in the presence of a base to prepare a compound 5; 
 reacting the compound 5 with a compound 6 to prepare a compound 7; 
 hydrolyzing the compound 7 in the presence of a base to prepare a compound 8; 
 reacting the compound 8 with a compound 9 to prepare a compound 10; 
 hydrolyzing the compound 10 in the presence of a base to prepare the compound of  claim 1 . 
 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         wherein A, R 1  and n are the same as defined in  claim 1  and R 2  is a straight chain or branched chain C 1-5  alkyl. 
       
     
     
         5 . A composition for preventing, improving, or treating inflammatory bowel disease, which comprises, as an active component, the compound, the optical isomer, or the salt of  claim 1 . 
     
     
         6 . The composition of  claim 5 , which inhibits formation of an inflammatory signal transduction complex mediated by MyD88, inhibits formation of an inflammatory signal transduction complex mediated by Pellino-1, inhibits formation of an inflammatory signal transduction complex mediated by Rip1, suppresses expression of at least one protein selected from the group consisting of G-CSF, IL-2, SCF, VEGF, CX3CL1, IGFBP5, IGFBP6, IL-1α, IL-1β, IL-6, IL-9, MCP-1, MIP-3α, IL12p40/70, MIG, TNF-α, and VCAM-1, or suppresses activity of NF-κB. 
     
     
         7 . The composition of  claim 5 , wherein the inflammatory bowel disease includes ulcerative colitis, Behcet's disease, and Crohn's disease. 
     
     
         8 . A method for preventing, improving, or treating inflammatory bowel disease, which comprises administering to a subject in need a composition containing, as an active component, the compound, the optical isomer, or the salt of  claim 1 . 
     
     
         9 . The method of  claim 8 , wherein the composition is administered via oral, nasal, pulmonary, rectal, buccal, vaginal, ocular and transdermal routes. 
     
     
         10 . The method of  claim 8 , wherein the inflammatory bowel disease includes ulcerative colitis, Behcet's disease, and Crohn's disease. 
     
     
         11 . The method of  claim 8 , wherein the composition, wherein the composition inhibits formation of an inflammatory signal transduction complex mediated by MyD88, inhibits formation of an inflammatory signal transduction complex mediated by Pellino-1, inhibits formation of an inflammatory signal transduction complex mediated by Rip1, suppresses expression of at least one protein selected from the group consisting of G-CSF, IL-2, SCF, VEGF, CX3CL1, IGFBP5, IGFBP6, IL-1α, IL-1β, IL-6, IL-9, MCP-1, MIP-3α, ID 2p40/70, MIG, TNF-α, and VCAM-1, or suppresses activity of NF-κB. 
     
     
         12 . A method for preventing, improving, or treating disease or syndrome, which comprises administering to a subject in need a composition containing, as an active component, the compound, the optical isomer, or the salt of  claim 1 , wherein the disease or syndrome involves formation of a Pellino-1 induced inflammatory signal transduction complex containing MyD88, RIP1, or both. 
     
     
         13 . The method of  claim 12 , wherein the disease or syndrome is inflammatory bowel disease. 
     
     
         14 . The method of  claim 13 , wherein the inflammatory bowel disease includes ulcerative colitis, Behcet's disease, and Crohn's disease. 
     
     
         15 . The method of  claim 12 , wherein the disease or syndrome includes multiple sclerosis, psoriasis, sepsis, geographic atrophy, wet age-related macular disease, dry age-related macular disease, diabetic retinopathy, infectious lung diseases, bacterial pneumonia, viral pneumonia, diffuse large B-cell lymphoma, viral infection, autoimmune disease, blood cancer including lymphoma, and tumors in internal organs. 
     
     
         16 . A composition for preventing, improving, or treating disease or syndrome, which comprises, as an active component, the compound, the optical isomer, or the salt of  claim 1 , wherein the disease or syndrome includes geographic atrophy, wet age-related macular disease, dry age-related macular disease, and diabetic retinopathy. 
     
     
         17 . The composition of  claim 16 , wherein the compound, the optimal isomer, or the salt of  claim 1  has a pharmaceutical effect on retinal pigment epithelium cells. 
     
     
         18 . The composition of  claim 16 , wherein the compound, the optimal isomer, or the salt of  claim 1  inhibits expression, in retinal pigment epithelium cells, of at least one protein selected from the group consisting of Nox-4, VEGF, VEGFR1, VEGFR2, Ang2, EPO and EPOR. 
     
     
         19 . The composition of  claim 16 , wherein the compound, the optimal isomer, or the salt of  claim 1  increases expression, in retinal pigment epithelium cells, of Ang 1, Tie2, or both. 
     
     
         20 . A composition for preventing, improving, or treating disease or syndrome, which comprises, as an active component, the compound, the optical isomer, or the salt of claim  1 , wherein the disease or syndrome includes sepsis and multiple sclerosis. 
     
     
         21 . A composition for preventing, improving, or treating alopecia, which comprises, as an active component, the compound, the optical isomer, or the salt of  claim 1 , wherein the active component inhibits expression of IL-6 in scalp and hair follicles. 
     
     
         22 . A composition for preventing, improving, or treating disease or syndrome, which comprises, as an active component, the compound, the optical isomer, or the salt of  claim 1 , wherein the disease or syndrome involves formation of a Pellino-1 induced inflammatory signal transduction complex containing MyD88, RIP1, or both. 
     
     
         23 . The composition of  claim 22 , wherein the disease or syndrome is inflammatory bowel disease. 
     
     
         24 . The composition of  claim 23 , wherein the inflammatory bowel disease includes ulcerative colitis, Behcet's disease, and Crohn's disease. 
     
     
         25 . The composition of  claim 22 , wherein the disease or syndrome includes multiple sclerosis, psoriasis, sepsis, geographic atrophy, wet age-related macular disease, dry age-related macular disease, diabetic retinopathy, infectious lung diseases, bacterial pneumonia, viral pneumonia, diffuse large B-cell lymphoma, viral infection, autoimmune disease, blood cancer including lymphoma, and tumors in internal organs. 
     
     
         26 . A method for suppressing expression of cytokines and/or chemokines, which comprises administering to a subject in need a composition containing, as an active component, the compound, the optical isomer, or the salt of  claim 1 .