MX2008010560A - Indole-3-carboxylic acid amide, ester, thioamide and thiol ester compounds bearing aryl or heteroaryl groups having sphingosine-1-phosphate (s1p) receptor antagonist biological activity - Google Patents
Indole-3-carboxylic acid amide, ester, thioamide and thiol ester compounds bearing aryl or heteroaryl groups having sphingosine-1-phosphate (s1p) receptor antagonist biological activityInfo
- Publication number
- MX2008010560A MX2008010560A MXMX/A/2008/010560A MX2008010560A MX2008010560A MX 2008010560 A MX2008010560 A MX 2008010560A MX 2008010560 A MX2008010560 A MX 2008010560A MX 2008010560 A MX2008010560 A MX 2008010560A
- Authority
- MX
- Mexico
- Prior art keywords
- indole
- group
- hydroxy
- carboxylic acid
- methyl
- Prior art date
Links
- 230000000694 effects Effects 0.000 title claims abstract description 22
- 239000002464 receptor antagonist Substances 0.000 title claims description 7
- DUYSYHSSBDVJSM-KRWOKUGFSA-N Sphingosine-1-phosphate Chemical compound CCCCCCCCCCCCC\C=C\[C@@H](O)[C@@H](N)COP(O)(O)=O DUYSYHSSBDVJSM-KRWOKUGFSA-N 0.000 title description 13
- 150000002148 esters Chemical group 0.000 title description 8
- 125000005418 aryl aryl group Chemical group 0.000 title description 4
- 150000007970 thio esters Chemical group 0.000 title description 3
- LSGKMZLPZFPAIN-UHFFFAOYSA-N 1H-indole-3-carboxamide Chemical compound C1=CC=C2C(C(=O)N)=CNC2=C1 LSGKMZLPZFPAIN-UHFFFAOYSA-N 0.000 title description 2
- AEOCXXJPGCBFJA-UHFFFAOYSA-N Ethionamide Chemical group CCC1=CC(C(N)=S)=CC=N1 AEOCXXJPGCBFJA-UHFFFAOYSA-N 0.000 title description 2
- 125000001072 heteroaryl group Chemical group 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 242
- 201000010099 disease Diseases 0.000 claims abstract description 15
- 230000003042 antagnostic Effects 0.000 claims abstract description 9
- 239000005557 antagonist Substances 0.000 claims abstract description 9
- 102000011011 Sphingosine 1-phosphate receptors Human genes 0.000 claims abstract description 6
- 108050001083 Sphingosine 1-phosphate receptors Proteins 0.000 claims abstract description 6
- 230000033115 angiogenesis Effects 0.000 claims abstract description 5
- 230000000271 cardiovascular Effects 0.000 claims abstract description 5
- 206010013774 Dry eye Diseases 0.000 claims abstract description 4
- 208000010412 Glaucoma Diseases 0.000 claims abstract description 4
- 230000029663 wound healing Effects 0.000 claims abstract 3
- 125000003118 aryl group Chemical group 0.000 claims description 47
- -1 nitro, thio Chemical group 0.000 claims description 47
- 125000004432 carbon atoms Chemical group C* 0.000 claims description 40
- QKMOLIRWUQBAIK-UHFFFAOYSA-N 5-hydroxy-2-methyl-1-(thiophen-2-ylmethyl)indole-3-carboxylic acid Chemical compound CC1=C(C(O)=O)C2=CC(O)=CC=C2N1CC1=CC=CS1 QKMOLIRWUQBAIK-UHFFFAOYSA-N 0.000 claims description 39
- 125000000217 alkyl group Chemical group 0.000 claims description 38
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 38
- 229910052739 hydrogen Inorganic materials 0.000 claims description 34
- 239000001257 hydrogen Substances 0.000 claims description 30
- 229910052760 oxygen Inorganic materials 0.000 claims description 30
- 229910052717 sulfur Inorganic materials 0.000 claims description 29
- 125000003342 alkenyl group Chemical group 0.000 claims description 28
- 125000004435 hydrogen atoms Chemical group [H]* 0.000 claims description 28
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 28
- 125000000623 heterocyclic group Chemical group 0.000 claims description 27
- 229910052757 nitrogen Inorganic materials 0.000 claims description 27
- IUCOSMXBCOBPJV-UHFFFAOYSA-N FC=1C=C(C[NH-])C=C(C1)F Chemical compound FC=1C=C(C[NH-])C=C(C1)F IUCOSMXBCOBPJV-UHFFFAOYSA-N 0.000 claims description 26
- 239000001301 oxygen Chemical group 0.000 claims description 26
- MYMOFIZGZYHOMD-UHFFFAOYSA-N oxygen Chemical group O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 claims description 26
- AFJUTWMHDOPIKE-UHFFFAOYSA-N FC=1C=C(C[NH-])C=CC1F Chemical compound FC=1C=C(C[NH-])C=CC1F AFJUTWMHDOPIKE-UHFFFAOYSA-N 0.000 claims description 25
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 24
- NINIDFKCEFEMDL-UHFFFAOYSA-N sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 23
- 239000011593 sulfur Chemical group 0.000 claims description 22
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 20
- 125000003545 alkoxy group Chemical group 0.000 claims description 19
- BQQVDHBVVUHJFH-UHFFFAOYSA-N COC1=CC=CC(C[NH-])=C1 Chemical compound COC1=CC=CC(C[NH-])=C1 BQQVDHBVVUHJFH-UHFFFAOYSA-N 0.000 claims description 18
- 125000000304 alkynyl group Chemical group 0.000 claims description 18
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 18
- 125000004429 atoms Chemical group 0.000 claims description 16
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 16
- 125000002837 carbocyclic group Chemical group 0.000 claims description 15
- 125000005843 halogen group Chemical group 0.000 claims description 14
- ODZYATADCNGTRM-UHFFFAOYSA-N 1-(furan-2-ylmethyl)-5-hydroxy-2-methylindole-3-carboxylic acid Chemical compound CC1=C(C(O)=O)C2=CC(O)=CC=C2N1CC1=CC=CO1 ODZYATADCNGTRM-UHFFFAOYSA-N 0.000 claims description 13
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 13
- 125000005842 heteroatoms Chemical group 0.000 claims description 13
- 150000002430 hydrocarbons Chemical group 0.000 claims description 13
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 12
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 12
- 239000002253 acid Substances 0.000 claims description 11
- 125000004448 alkyl carbonyl group Chemical group 0.000 claims description 11
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 11
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 11
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims description 11
- 125000001188 haloalkyl group Chemical group 0.000 claims description 11
- 125000005740 oxycarbonyl group Chemical group [*:1]OC([*:2])=O 0.000 claims description 11
- QOFHQRSMYGKORN-UHFFFAOYSA-N FC(C1=CC=CC=C1)([NH-])F Chemical compound FC(C1=CC=CC=C1)([NH-])F QOFHQRSMYGKORN-UHFFFAOYSA-N 0.000 claims description 10
- 239000000556 agonist Substances 0.000 claims description 10
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 10
- CXWXQJXEFPUFDZ-UHFFFAOYSA-N Tetralin Chemical compound C1=CC=C2CCCCC2=C1 CXWXQJXEFPUFDZ-UHFFFAOYSA-N 0.000 claims description 9
- 125000005599 alkyl carboxylate group Chemical group 0.000 claims description 9
- 125000000664 diazo group Chemical group [N-]=[N+]=[*] 0.000 claims description 9
- 125000001153 fluoro group Chemical group F* 0.000 claims description 9
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 9
- 125000004962 sulfoxyl group Chemical group 0.000 claims description 9
- 229910052736 halogen Inorganic materials 0.000 claims description 8
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 8
- DFIVRYDUQGHCLZ-UHFFFAOYSA-N 5-hydroxy-2-methyl-1-phenylindole-3-carboxylic acid Chemical compound CC1=C(C(O)=O)C2=CC(O)=CC=C2N1C1=CC=CC=C1 DFIVRYDUQGHCLZ-UHFFFAOYSA-N 0.000 claims description 7
- 229910052799 carbon Inorganic materials 0.000 claims description 7
- 239000003814 drug Substances 0.000 claims description 7
- ZYGHJZDHTFUPRJ-UHFFFAOYSA-N Coumarin Chemical compound C1=CC=C2OC(=O)C=CC2=C1 ZYGHJZDHTFUPRJ-UHFFFAOYSA-N 0.000 claims description 6
- 125000002102 aryl alkyloxo group Chemical group 0.000 claims description 6
- OKTJSMMVPCPJKN-UHFFFAOYSA-N carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 6
- UFWIBTONFRDIAS-UHFFFAOYSA-N naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 claims description 6
- 239000011780 sodium chloride Substances 0.000 claims description 6
- UNJPENVPALIPCT-UHFFFAOYSA-N N-benzyl-5-hydroxy-2-methyl-1-(thiophen-2-ylmethyl)indole-3-carboxamide Chemical compound C12=CC(O)=CC=C2N(CC=2SC=CC=2)C(C)=C1C(=O)NCC1=CC=CC=C1 UNJPENVPALIPCT-UHFFFAOYSA-N 0.000 claims description 5
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 5
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 5
- 238000004519 manufacturing process Methods 0.000 claims description 5
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 5
- 150000003839 salts Chemical class 0.000 claims description 5
- MBHGSQQNBRGGSI-UHFFFAOYSA-N 5-hydroxy-2-methyl-1-pyridin-2-ylindole-3-carboxylic acid Chemical compound CC1=C(C(O)=O)C2=CC(O)=CC=C2N1C1=CC=CC=N1 MBHGSQQNBRGGSI-UHFFFAOYSA-N 0.000 claims description 4
- ODUDBVMYXYVEBO-UHFFFAOYSA-N 5-hydroxy-2-methyl-1-thiophen-2-ylindole-3-carboxylic acid Chemical compound CC1=C(C(O)=O)C2=CC(O)=CC=C2N1C1=CC=CS1 ODUDBVMYXYVEBO-UHFFFAOYSA-N 0.000 claims description 4
- JDSPIHYMGSKWMU-UHFFFAOYSA-N FC=1C=CC=C(C[NH-])C1 Chemical compound FC=1C=CC=C(C[NH-])C1 JDSPIHYMGSKWMU-UHFFFAOYSA-N 0.000 claims description 4
- 125000003277 amino group Chemical group 0.000 claims description 4
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 4
- 150000002829 nitrogen Chemical class 0.000 claims description 4
- 239000010452 phosphate Substances 0.000 claims description 4
- RZFZAUAFDSLZCD-UHFFFAOYSA-N (4-fluorophenyl)methylazanide Chemical compound [NH-]CC1=CC=C(F)C=C1 RZFZAUAFDSLZCD-UHFFFAOYSA-N 0.000 claims description 3
- LBUJPTNKIBCYBY-UHFFFAOYSA-N 1,2,3,4-tetrahydroquinoline Chemical compound C1=CC=C2CCCNC2=C1 LBUJPTNKIBCYBY-UHFFFAOYSA-N 0.000 claims description 3
- IRFSXVIRXMYULF-UHFFFAOYSA-N 1,2-dihydroquinoline Chemical compound C1=CC=C2C=CCNC2=C1 IRFSXVIRXMYULF-UHFFFAOYSA-N 0.000 claims description 3
- YJUFGFXVASPYFQ-UHFFFAOYSA-N 2,3-dihydro-1-benzothiophene Chemical compound C1=CC=C2SCCC2=C1 YJUFGFXVASPYFQ-UHFFFAOYSA-N 0.000 claims description 3
- HBEDSQVIWPRPAY-UHFFFAOYSA-N 2,3-dihydrobenzofuran Chemical compound C1=CC=C2OCCC2=C1 HBEDSQVIWPRPAY-UHFFFAOYSA-N 0.000 claims description 3
- CZPWVGJYEJSRLH-UHFFFAOYSA-N 289-95-2 Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 claims description 3
- WPWNEKFMGCWNPR-UHFFFAOYSA-N 3,4-dihydro-2H-thiochromene Chemical compound C1=CC=C2CCCSC2=C1 WPWNEKFMGCWNPR-UHFFFAOYSA-N 0.000 claims description 3
- IANQTJSKSUMEQM-UHFFFAOYSA-N Benzofuran Chemical compound C1=CC=C2OC=CC2=C1 IANQTJSKSUMEQM-UHFFFAOYSA-N 0.000 claims description 3
- FCEHBMOGCRZNNI-UHFFFAOYSA-N Benzothiophene Chemical compound C1=CC=C2SC=CC2=C1 FCEHBMOGCRZNNI-UHFFFAOYSA-N 0.000 claims description 3
- 125000006539 C12 alkyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 3
- VZWXIQHBIQLMPN-UHFFFAOYSA-N Chromane Chemical compound C1=CC=C2CCCOC2=C1 VZWXIQHBIQLMPN-UHFFFAOYSA-N 0.000 claims description 3
- ZRJGQPAGURUPPS-UHFFFAOYSA-N ClC=1C=C(C[NH-])C=CC1 Chemical compound ClC=1C=C(C[NH-])C=CC1 ZRJGQPAGURUPPS-UHFFFAOYSA-N 0.000 claims description 3
- KEIFWROAQVVDBN-UHFFFAOYSA-N Dialin Chemical compound C1=CC=C2C=CCCC2=C1 KEIFWROAQVVDBN-UHFFFAOYSA-N 0.000 claims description 3
- PQNFLJBBNBOBRQ-UHFFFAOYSA-N Indane Chemical compound C1=CC=C2CCCC2=C1 PQNFLJBBNBOBRQ-UHFFFAOYSA-N 0.000 claims description 3
- YBYIRNPNPLQARY-UHFFFAOYSA-N Indene Chemical compound C1=CC=C2CC=CC2=C1 YBYIRNPNPLQARY-UHFFFAOYSA-N 0.000 claims description 3
- ZLTPDFXIESTBQG-UHFFFAOYSA-N Isothiazole Chemical compound C=1C=NSC=1 ZLTPDFXIESTBQG-UHFFFAOYSA-N 0.000 claims description 3
- CTAPFRYPJLPFDF-UHFFFAOYSA-N Isoxazole Chemical compound C=1C=NOC=1 CTAPFRYPJLPFDF-UHFFFAOYSA-N 0.000 claims description 3
- PBMFSQRYOILNGV-UHFFFAOYSA-N Pyridazine Chemical compound C1=CC=NN=C1 PBMFSQRYOILNGV-UHFFFAOYSA-N 0.000 claims description 3
- OFNWQHNIYUUIKS-UHFFFAOYSA-N [NH-]CC1=CC=C(Cl)C=C1 Chemical compound [NH-]CC1=CC=C(Cl)C=C1 OFNWQHNIYUUIKS-UHFFFAOYSA-N 0.000 claims description 3
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 3
- QZHPTGXQGDFGEN-UHFFFAOYSA-N chromene Chemical compound C1=CC=C2C=C[CH]OC2=C1 QZHPTGXQGDFGEN-UHFFFAOYSA-N 0.000 claims description 3
- 229960000956 coumarin Drugs 0.000 claims description 3
- 235000001671 coumarin Nutrition 0.000 claims description 3
- WCPAKWJPBJAGKN-UHFFFAOYSA-N oxadiazole Chemical compound C1=CON=N1 WCPAKWJPBJAGKN-UHFFFAOYSA-N 0.000 claims description 3
- ZCQWOFVYLHDMMC-UHFFFAOYSA-N oxazole Chemical compound C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 claims description 3
- QVGXLLKOCUKJST-UHFFFAOYSA-N oxygen atom Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 3
- KYQCOXFCLRTKLS-UHFFFAOYSA-N pyrazine Chemical compound C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 claims description 3
- SMWDFEZZVXVKRB-UHFFFAOYSA-N quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 claims description 3
- FZWLAAWBMGSTSO-UHFFFAOYSA-N thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 claims description 3
- YTPLMLYBLZKORZ-UHFFFAOYSA-N thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 claims description 3
- BSUNTQCMCCQSQH-UHFFFAOYSA-N triazine Chemical compound C1=CN=NN=C1.C1=CN=NN=C1 BSUNTQCMCCQSQH-UHFFFAOYSA-N 0.000 claims description 3
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 2
- 208000008787 Cardiovascular Disease Diseases 0.000 claims description 2
- 125000006379 fluoropyridyl group Chemical group 0.000 claims description 2
- 125000004076 pyridyl group Chemical group 0.000 claims 5
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims 4
- IHESMYVYGRSRPU-UHFFFAOYSA-N CC1=CC=C(C[NH-])C=C1 Chemical compound CC1=CC=C(C[NH-])C=C1 IHESMYVYGRSRPU-UHFFFAOYSA-N 0.000 claims 2
- 125000005037 alkyl phenyl group Chemical group 0.000 claims 2
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 claims 2
- QJIWQTQZVBIUTA-UHFFFAOYSA-N furan;1,3-thiazole Chemical compound C=1C=COC=1.C1=CSC=N1 QJIWQTQZVBIUTA-UHFFFAOYSA-N 0.000 claims 2
- 125000002541 furyl group Chemical group 0.000 claims 2
- KYQCOXFCLRTKLS-UHFFFAOYSA-O hydron;pyrazine Chemical compound C1=C[NH+]=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-O 0.000 claims 2
- RAXXELZNTBOGNW-UHFFFAOYSA-O imidazolium Chemical compound C1=C[NH+]=CN1 RAXXELZNTBOGNW-UHFFFAOYSA-O 0.000 claims 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims 2
- 125000002971 oxazolyl group Chemical group 0.000 claims 2
- 125000000714 pyrimidinyl group Chemical group 0.000 claims 2
- 125000004434 sulfur atoms Chemical group 0.000 claims 2
- 125000000335 thiazolyl group Chemical group 0.000 claims 2
- 125000001544 thienyl group Chemical group 0.000 claims 2
- UGUHFDPGDQDVGX-UHFFFAOYSA-N 1,2,3-thiadiazole Chemical compound C1=CSN=N1 UGUHFDPGDQDVGX-UHFFFAOYSA-N 0.000 claims 1
- DDAINDMVKSETGF-UHFFFAOYSA-N 2,3-difluorobenzamide Chemical compound NC(=O)C1=CC=CC(F)=C1F DDAINDMVKSETGF-UHFFFAOYSA-N 0.000 claims 1
- CMWOHNIHUBDEAG-UHFFFAOYSA-N 3,4-difluorobenzamide Chemical compound NC(=O)C1=CC=C(F)C(F)=C1 CMWOHNIHUBDEAG-UHFFFAOYSA-N 0.000 claims 1
- FHSZQYNWIIHBAX-UHFFFAOYSA-N 5-hydroxy-2-methyl-1H-indole-3-carboxylic acid Chemical compound C1=C(O)C=C2C(C(O)=O)=C(C)NC2=C1 FHSZQYNWIIHBAX-UHFFFAOYSA-N 0.000 claims 1
- CXWSQDJFZDLNGI-UHFFFAOYSA-N ON1C(=C(C2=CC=CC=C12)C(=O)O)C Chemical compound ON1C(=C(C2=CC=CC=C12)C(=O)O)C CXWSQDJFZDLNGI-UHFFFAOYSA-N 0.000 claims 1
- 125000003373 pyrazinyl group Chemical group 0.000 claims 1
- 239000000018 receptor agonist Substances 0.000 abstract description 2
- 238000000034 method Methods 0.000 description 48
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 42
- XEKOWRVHYACXOJ-UHFFFAOYSA-N acetic acid ethyl ester Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 42
- 238000006243 chemical reaction Methods 0.000 description 42
- NCHGPLXPTROIAW-UHFFFAOYSA-N 1-benzyl-N-[(3,4-difluorophenyl)methyl]-6-hydroxy-2-propan-2-ylindole-3-carboxamide Chemical compound C12=CC=C(O)C=C2N(CC=2C=CC=CC=2)C(C(C)C)=C1C(=O)NCC1=CC=C(F)C(F)=C1 NCHGPLXPTROIAW-UHFFFAOYSA-N 0.000 description 38
- 101710037523 ACAT1 Proteins 0.000 description 35
- 102100014089 S1PR3 Human genes 0.000 description 35
- HEDRZPFGACZZDS-MICDWDOJSA-N cdcl3 Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 32
- 239000007787 solid Substances 0.000 description 28
- OKKJLVBELUTLKV-MZCSYVLQSA-N cd3od Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 26
- 239000000243 solution Substances 0.000 description 26
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 22
- 229910000027 potassium carbonate Inorganic materials 0.000 description 20
- 235000019439 ethyl acetate Nutrition 0.000 description 19
- 210000004027 cells Anatomy 0.000 description 18
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 17
- 239000012267 brine Substances 0.000 description 16
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 16
- 239000000203 mixture Substances 0.000 description 16
- 239000000741 silica gel Substances 0.000 description 14
- 229910002027 silica gel Inorganic materials 0.000 description 14
- 206010020772 Hypertension Diseases 0.000 description 12
- XKRFYHLGVUSROY-UHFFFAOYSA-N argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 12
- 230000002829 reduced Effects 0.000 description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- 208000005333 Pulmonary Edema Diseases 0.000 description 11
- 206010037423 Pulmonary oedema Diseases 0.000 description 11
- 235000015320 potassium carbonate Nutrition 0.000 description 11
- 125000001424 substituent group Chemical group 0.000 description 11
- CVTLAVSKDNBJEJ-UHFFFAOYSA-N 2-methyl-1-phenyl-5-phenylmethoxyindole-3-carboxylic acid Chemical compound C=1C=C2N(C=3C=CC=CC=3)C(C)=C(C(O)=O)C2=CC=1OCC1=CC=CC=C1 CVTLAVSKDNBJEJ-UHFFFAOYSA-N 0.000 description 10
- WWUZIQQURGPMPG-KRWOKUGFSA-N Sphingosine Chemical compound CCCCCCCCCCCCC\C=C\[C@@H](O)[C@@H](N)CO WWUZIQQURGPMPG-KRWOKUGFSA-N 0.000 description 10
- 230000000747 cardiac effect Effects 0.000 description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 10
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 10
- 230000002685 pulmonary Effects 0.000 description 10
- 102000005962 receptors Human genes 0.000 description 10
- 108020003175 receptors Proteins 0.000 description 10
- 150000003408 sphingolipids Chemical class 0.000 description 10
- 208000006218 Bradycardia Diseases 0.000 description 9
- 150000001412 amines Chemical class 0.000 description 9
- 230000036471 bradycardia Effects 0.000 description 9
- KMAKOBLIOCQGJP-UHFFFAOYSA-N indole-3-carboxylic acid Chemical compound C1=CC=C2C(C(=O)O)=CNC2=C1 KMAKOBLIOCQGJP-UHFFFAOYSA-N 0.000 description 9
- AGEZXYOZHKGVCM-UHFFFAOYSA-N Benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 description 8
- XHXFXVLFKHQFAL-UHFFFAOYSA-N Phosphoryl chloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 8
- 125000002877 alkyl aryl group Chemical group 0.000 description 8
- UIIMBOGNXHQVGW-UHFFFAOYSA-M buffer Substances [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 8
- 239000008079 hexane Substances 0.000 description 8
- 229910052938 sodium sulfate Inorganic materials 0.000 description 8
- 235000011152 sodium sulphate Nutrition 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- UESVMEVJQRUYRR-UHFFFAOYSA-N 5-amino-1-benzyl-2-methylindole-3-carboxylic acid Chemical compound CC1=C(C(O)=O)C2=CC(N)=CC=C2N1CC1=CC=CC=C1 UESVMEVJQRUYRR-UHFFFAOYSA-N 0.000 description 7
- 206010001052 Acute respiratory distress syndrome Diseases 0.000 description 7
- 208000006673 Asthma Diseases 0.000 description 7
- 101700067048 CDC13 Proteins 0.000 description 7
- 206010007559 Cardiac failure congestive Diseases 0.000 description 7
- KKGQTZUTZRNORY-UHFFFAOYSA-N Fingolimod Chemical class CCCCCCCCC1=CC=C(CCC(N)(CO)CO)C=C1 KKGQTZUTZRNORY-UHFFFAOYSA-N 0.000 description 7
- 208000003067 Myocardial Ischemia Diseases 0.000 description 7
- 239000007832 Na2SO4 Substances 0.000 description 7
- 208000001871 Tachycardia Diseases 0.000 description 7
- 230000004913 activation Effects 0.000 description 7
- 201000000028 adult respiratory distress syndrome Diseases 0.000 description 7
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 7
- OUNXBJISJUHARV-UHFFFAOYSA-N ethyl 2-methyl-1-phenyl-5-phenylmethoxyindole-3-carboxylate Chemical compound C12=CC=C(OCC=3C=CC=CC=3)C=C2C(C(=O)OCC)=C(C)N1C1=CC=CC=C1 OUNXBJISJUHARV-UHFFFAOYSA-N 0.000 description 7
- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 7
- 229960000556 fingolimod Drugs 0.000 description 7
- VIJARGFIJBYEDM-UHFFFAOYSA-N 1-butyl-5-hydroxy-2-methylindole-3-carboxylic acid Chemical compound OC1=CC=C2N(CCCC)C(C)=C(C(O)=O)C2=C1 VIJARGFIJBYEDM-UHFFFAOYSA-N 0.000 description 6
- RJUBRYYKCHYVEP-UHFFFAOYSA-N 5-methoxy-1,2-dimethylindole-3-carboxylic acid Chemical compound COC1=CC=C2N(C)C(C)=C(C(O)=O)C2=C1 RJUBRYYKCHYVEP-UHFFFAOYSA-N 0.000 description 6
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- 230000001154 acute Effects 0.000 description 6
- 229910052786 argon Inorganic materials 0.000 description 6
- 230000027455 binding Effects 0.000 description 6
- 201000006233 congestive heart failure Diseases 0.000 description 6
- DGTIEXDBQRVGSQ-UHFFFAOYSA-N ethyl 1-benzyl-5-hydroxy-2-methylindole-3-carboxylate Chemical compound C12=CC=C(O)C=C2C(C(=O)OCC)=C(C)N1CC1=CC=CC=C1 DGTIEXDBQRVGSQ-UHFFFAOYSA-N 0.000 description 6
- 238000003818 flash chromatography Methods 0.000 description 6
- 150000002367 halogens Chemical group 0.000 description 6
- 239000003446 ligand Substances 0.000 description 6
- 150000003410 sphingosines Chemical class 0.000 description 6
- 239000000126 substance Substances 0.000 description 6
- DKGAVHZHDRPRBM-UHFFFAOYSA-N t-BuOH Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 6
- QEMRCWRJRWGSHY-UHFFFAOYSA-N 1-benzyl-N-[(3,4-difluorophenyl)methyl]-6-methoxy-2-propan-2-ylindole-3-carboxamide Chemical compound CC(C)C=1N(CC=2C=CC=CC=2)C2=CC(OC)=CC=C2C=1C(=O)NCC1=CC=C(F)C(F)=C1 QEMRCWRJRWGSHY-UHFFFAOYSA-N 0.000 description 5
- 206010007554 Cardiac failure Diseases 0.000 description 5
- CSCPPACGZOOCGX-WFGJKAKNSA-N Deuterated acetone Chemical compound [2H]C([2H])([2H])C(=O)C([2H])([2H])[2H] CSCPPACGZOOCGX-WFGJKAKNSA-N 0.000 description 5
- JKMHFZQWWAIEOD-UHFFFAOYSA-N HEPES Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 5
- 206010019280 Heart failure Diseases 0.000 description 5
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Natural products C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 5
- 206010022114 Injury Diseases 0.000 description 5
- 230000033228 biological regulation Effects 0.000 description 5
- OTZRXYXBNSZGMY-UHFFFAOYSA-N ethyl 2-methyl-5-phenylmethoxy-1H-indole-3-carboxylate Chemical compound C1=C2C(C(=O)OCC)=C(C)NC2=CC=C1OCC1=CC=CC=C1 OTZRXYXBNSZGMY-UHFFFAOYSA-N 0.000 description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N hydrogen Chemical group [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 5
- 239000002207 metabolite Substances 0.000 description 5
- 239000012044 organic layer Substances 0.000 description 5
- 239000001184 potassium carbonate Substances 0.000 description 5
- 230000004044 response Effects 0.000 description 5
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 4
- QTEXJMCOTHHQFZ-UHFFFAOYSA-N 5-acetamido-1-benzyl-2-methylindole-3-carboxylic acid Chemical compound CC1=C(C(O)=O)C2=CC(NC(=O)C)=CC=C2N1CC1=CC=CC=C1 QTEXJMCOTHHQFZ-UHFFFAOYSA-N 0.000 description 4
- 206010059512 Apoptosis Diseases 0.000 description 4
- 210000001772 Blood Platelets Anatomy 0.000 description 4
- ILAHWRKJUDSMFH-UHFFFAOYSA-N Boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 description 4
- 102000004190 Enzymes Human genes 0.000 description 4
- 108090000790 Enzymes Proteins 0.000 description 4
- 102000015779 HDL Lipoproteins Human genes 0.000 description 4
- 108010010234 HDL Lipoproteins Proteins 0.000 description 4
- 239000012593 Hanks’ Balanced Salt Solution Substances 0.000 description 4
- 206010061218 Inflammation Diseases 0.000 description 4
- 206010061255 Ischaemia Diseases 0.000 description 4
- 208000010125 Myocardial Infarction Diseases 0.000 description 4
- 210000000329 Myocytes, Smooth Muscle Anatomy 0.000 description 4
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 4
- 206010035664 Pneumonia Diseases 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 4
- 230000006907 apoptotic process Effects 0.000 description 4
- 238000004587 chromatography analysis Methods 0.000 description 4
- 230000034994 death Effects 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- 229940079593 drugs Drugs 0.000 description 4
- VRZMECYOQWGKFT-UHFFFAOYSA-N ethyl 1-benzyl-2-methylindole-3-carboxylate Chemical compound C12=CC=CC=C2C(C(=O)OCC)=C(C)N1CC1=CC=CC=C1 VRZMECYOQWGKFT-UHFFFAOYSA-N 0.000 description 4
- 230000004054 inflammatory process Effects 0.000 description 4
- 150000002632 lipids Chemical class 0.000 description 4
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 4
- 210000000663 muscle cells Anatomy 0.000 description 4
- 230000002107 myocardial Effects 0.000 description 4
- 210000000107 myocyte Anatomy 0.000 description 4
- 230000002633 protecting Effects 0.000 description 4
- 230000011664 signaling Effects 0.000 description 4
- 239000011734 sodium Substances 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 150000003573 thiols Chemical class 0.000 description 4
- YXFVVABEGXRONW-UHFFFAOYSA-N toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 4
- PHLZUDXEBCQHKM-UHFFFAOYSA-N (3,4-difluorophenyl)methanamine Chemical compound NCC1=CC=C(F)C(F)=C1 PHLZUDXEBCQHKM-UHFFFAOYSA-N 0.000 description 3
- UJUPJZYUKBFHHO-UHFFFAOYSA-N 1-benzyl-N-[(3,4-difluorophenyl)methyl]-2-propan-2-yl-6-propan-2-yloxyindole-3-carboxamide Chemical compound CC(C)C=1N(CC=2C=CC=CC=2)C2=CC(OC(C)C)=CC=C2C=1C(=O)NCC1=CC=C(F)C(F)=C1 UJUPJZYUKBFHHO-UHFFFAOYSA-N 0.000 description 3
- AFDUGVKJXKJJMO-UHFFFAOYSA-N 1-benzyl-N-[(3,4-difluorophenyl)methyl]-2-propan-2-yl-6-propoxyindole-3-carboxamide Chemical compound CC(C)C=1N(CC=2C=CC=CC=2)C2=CC(OCCC)=CC=C2C=1C(=O)NCC1=CC=C(F)C(F)=C1 AFDUGVKJXKJJMO-UHFFFAOYSA-N 0.000 description 3
- GOYJNCFLJXZTMT-UHFFFAOYSA-N 1-benzyl-N-[(3,4-difluorophenyl)methyl]-6-(2-methoxyethoxy)-2-propan-2-ylindole-3-carboxamide Chemical compound CC(C)C=1N(CC=2C=CC=CC=2)C2=CC(OCCOC)=CC=C2C=1C(=O)NCC1=CC=C(F)C(F)=C1 GOYJNCFLJXZTMT-UHFFFAOYSA-N 0.000 description 3
- FSYKYZHUYGSKDF-UHFFFAOYSA-N 1-benzyl-N-[(3,4-difluorophenyl)methyl]-6-(2-methylpropoxy)-2-propan-2-ylindole-3-carboxamide Chemical compound CC(C)C=1N(CC=2C=CC=CC=2)C2=CC(OCC(C)C)=CC=C2C=1C(=O)NCC1=CC=C(F)C(F)=C1 FSYKYZHUYGSKDF-UHFFFAOYSA-N 0.000 description 3
- DYBAWQPNTCVILP-UHFFFAOYSA-N 1-benzyl-N-[(3,4-difluorophenyl)methyl]-6-(2-oxooxolan-3-yl)oxy-2-propan-2-ylindole-3-carboxamide Chemical compound C12=CC=C(OC3C(OCC3)=O)C=C2N(CC=2C=CC=CC=2)C(C(C)C)=C1C(=O)NCC1=CC=C(F)C(F)=C1 DYBAWQPNTCVILP-UHFFFAOYSA-N 0.000 description 3
- QDPYMLOAXYQPAY-UHFFFAOYSA-N 1-benzyl-N-[(3,4-difluorophenyl)methyl]-6-(methoxymethoxy)-2-propan-2-ylindole-3-carboxamide Chemical compound CC(C)C=1N(CC=2C=CC=CC=2)C2=CC(OCOC)=CC=C2C=1C(=O)NCC1=CC=C(F)C(F)=C1 QDPYMLOAXYQPAY-UHFFFAOYSA-N 0.000 description 3
- FRGLCXJTNHCBSP-UHFFFAOYSA-N 1-benzyl-N-[(3,4-difluorophenyl)methyl]-6-(oxolan-2-yloxy)-2-propan-2-ylindole-3-carboxamide Chemical compound C12=CC=C(OC3OCCC3)C=C2N(CC=2C=CC=CC=2)C(C(C)C)=C1C(=O)NCC1=CC=C(F)C(F)=C1 FRGLCXJTNHCBSP-UHFFFAOYSA-N 0.000 description 3
- QJSCMTWCKLQHFW-UHFFFAOYSA-N 1-benzyl-N-[(3,4-difluorophenyl)methyl]-6-(oxolan-3-yloxy)-2-propan-2-ylindole-3-carboxamide Chemical compound C12=CC=C(OC3COCC3)C=C2N(CC=2C=CC=CC=2)C(C(C)C)=C1C(=O)NCC1=CC=C(F)C(F)=C1 QJSCMTWCKLQHFW-UHFFFAOYSA-N 0.000 description 3
- CFBLBYAIWLIWFQ-UHFFFAOYSA-N 1-benzyl-N-[(3,4-difluorophenyl)methyl]-6-[2-(dimethylamino)ethoxy]-2-propan-2-ylindole-3-carboxamide Chemical compound C12=CC=C(OCCN(C)C)C=C2N(CC=2C=CC=CC=2)C(C(C)C)=C1C(=O)NCC1=CC=C(F)C(F)=C1 CFBLBYAIWLIWFQ-UHFFFAOYSA-N 0.000 description 3
- LGZFQQBSHRVYOY-UHFFFAOYSA-N 1-benzyl-N-[(3,4-difluorophenyl)methyl]-6-hexoxy-2-propan-2-ylindole-3-carboxamide Chemical compound CC(C)C=1N(CC=2C=CC=CC=2)C2=CC(OCCCCCC)=CC=C2C=1C(=O)NCC1=CC=C(F)C(F)=C1 LGZFQQBSHRVYOY-UHFFFAOYSA-N 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- QZOBOLDDGXPTBP-UHFFFAOYSA-N 2-(bromomethyl)thiophene Chemical compound BrCC1=CC=CS1 QZOBOLDDGXPTBP-UHFFFAOYSA-N 0.000 description 3
- BKOOMYPCSUNDGP-UHFFFAOYSA-N 2-Methyl-2-butene Chemical compound CC=C(C)C BKOOMYPCSUNDGP-UHFFFAOYSA-N 0.000 description 3
- LZVXPAFUYYBKEC-UHFFFAOYSA-N 2-methyl-5-phenylmethoxy-1-pyridin-2-ylindole-3-carboxylic acid Chemical compound C=1C=C2N(C=3N=CC=CC=3)C(C)=C(C(O)=O)C2=CC=1OCC1=CC=CC=C1 LZVXPAFUYYBKEC-UHFFFAOYSA-N 0.000 description 3
- BKIQORJIKOPRCG-UHFFFAOYSA-N 3-iodooxolane Chemical compound IC1CCOC1 BKIQORJIKOPRCG-UHFFFAOYSA-N 0.000 description 3
- MUBWGBJYKGNJKN-UHFFFAOYSA-N 5-hydroxy-N-[(3-methoxyphenyl)methyl]-2-methyl-1-(thiophen-2-ylmethyl)indole-3-carboxamide Chemical compound COC1=CC=CC(CNC(=O)C=2C3=CC(O)=CC=C3N(CC=3SC=CC=3)C=2C)=C1 MUBWGBJYKGNJKN-UHFFFAOYSA-N 0.000 description 3
- ZIPZPELKAMHRTM-UHFFFAOYSA-N 5-methoxy-2-methyl-1-phenylindole-3-carboxylic acid Chemical compound CC1=C(C(O)=O)C2=CC(OC)=CC=C2N1C1=CC=CC=C1 ZIPZPELKAMHRTM-UHFFFAOYSA-N 0.000 description 3
- 241000196324 Embryophyta Species 0.000 description 3
- 210000002889 Endothelial Cells Anatomy 0.000 description 3
- 210000003989 Endothelium, Vascular Anatomy 0.000 description 3
- XYIBRDXRRQCHLP-UHFFFAOYSA-N Ethyl acetoacetate Chemical compound CCOC(=O)CC(C)=O XYIBRDXRRQCHLP-UHFFFAOYSA-N 0.000 description 3
- 206010061216 Infarction Diseases 0.000 description 3
- 206010024119 Left ventricular failure Diseases 0.000 description 3
- 208000009856 Lung Disease Diseases 0.000 description 3
- INQOMBQAUSQDDS-UHFFFAOYSA-N Methyl iodide Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 3
- 210000003097 Mucus Anatomy 0.000 description 3
- 210000004413 Myocytes, Cardiac Anatomy 0.000 description 3
- QOSSAOTZNIDXMA-UHFFFAOYSA-N N,N′-Dicyclohexylcarbodiimide Substances C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 3
- VODZWWMEJITOND-OWWNRXNESA-N N-Stearoylsphingosine Chemical compound CCCCCCCCCCCCCCCCCC(=O)NC(CO)C(O)\C=C\CCCCCCCCCCCCC VODZWWMEJITOND-OWWNRXNESA-N 0.000 description 3
- LYGJENNIWJXYER-UHFFFAOYSA-N Nitromethane Chemical compound C[N+]([O-])=O LYGJENNIWJXYER-UHFFFAOYSA-N 0.000 description 3
- 241000700159 Rattus Species 0.000 description 3
- 206010063837 Reperfusion injury Diseases 0.000 description 3
- 230000036772 blood pressure Effects 0.000 description 3
- 201000011510 cancer Diseases 0.000 description 3
- 230000003197 catalytic Effects 0.000 description 3
- 230000010261 cell growth Effects 0.000 description 3
- 230000001413 cellular Effects 0.000 description 3
- 125000004122 cyclic group Chemical group 0.000 description 3
- 238000011161 development Methods 0.000 description 3
- 230000018109 developmental process Effects 0.000 description 3
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 230000002401 inhibitory effect Effects 0.000 description 3
- 235000019796 monopotassium phosphate Nutrition 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- 230000000241 respiratory Effects 0.000 description 3
- 230000019491 signal transduction Effects 0.000 description 3
- BZKBCQXYZZXSCO-UHFFFAOYSA-N sodium hydride Chemical compound [H-].[Na+] BZKBCQXYZZXSCO-UHFFFAOYSA-N 0.000 description 3
- 230000000638 stimulation Effects 0.000 description 3
- 230000001225 therapeutic Effects 0.000 description 3
- 210000001519 tissues Anatomy 0.000 description 3
- 231100000419 toxicity Toxicity 0.000 description 3
- 230000001988 toxicity Effects 0.000 description 3
- VJNGGOMRUHYAMC-UHFFFAOYSA-N (3,5-difluorophenyl)methanamine Chemical compound NCC1=CC(F)=CC(F)=C1 VJNGGOMRUHYAMC-UHFFFAOYSA-N 0.000 description 2
- HVYWMOMLDIMFJA-DPAQBDIFSA-N (3β)-Cholest-5-en-3-ol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 2
- AZQWKYJCGOJGHM-UHFFFAOYSA-N 1,4-Benzoquinone Chemical compound O=C1C=CC(=O)C=C1 AZQWKYJCGOJGHM-UHFFFAOYSA-N 0.000 description 2
- 229940005561 1,4-benzoquinone Drugs 0.000 description 2
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 2
- WRGQSWVCFNIUNZ-GDCKJWNLSA-N 1-oleoyl-sn-glycerol 3-phosphate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@@H](O)COP(O)(O)=O WRGQSWVCFNIUNZ-GDCKJWNLSA-N 0.000 description 2
- JVSFQJZRHXAUGT-UHFFFAOYSA-N 2,2-dimethylpropanoyl chloride Chemical compound CC(C)(C)C(Cl)=O JVSFQJZRHXAUGT-UHFFFAOYSA-N 0.000 description 2
- CCZWSTFVHJPCEM-UHFFFAOYSA-N 2-iodopyridine Chemical compound IC1=CC=CC=N1 CCZWSTFVHJPCEM-UHFFFAOYSA-N 0.000 description 2
- ROIMNSWDOJCBFR-UHFFFAOYSA-N 2-iodothiophene Chemical compound IC1=CC=CS1 ROIMNSWDOJCBFR-UHFFFAOYSA-N 0.000 description 2
- FBLATEKZFXMRDX-UHFFFAOYSA-N 2-methyl-1-(thiophen-2-ylmethyl)indole-3-carboxylic acid Chemical compound CC1=C(C(O)=O)C2=CC=CC=C2N1CC1=CC=CS1 FBLATEKZFXMRDX-UHFFFAOYSA-N 0.000 description 2
- IKBFYOQMSYXGBI-UHFFFAOYSA-N 2-methyl-5-nitro-1H-indole-3-carbaldehyde Chemical compound C1=C([N+]([O-])=O)C=C2C(C=O)=C(C)NC2=C1 IKBFYOQMSYXGBI-UHFFFAOYSA-N 0.000 description 2
- JVVRCYWZTJLJSG-UHFFFAOYSA-N 4-Dimethylaminophenol Substances CN(C)C1=CC=C(O)C=C1 JVVRCYWZTJLJSG-UHFFFAOYSA-N 0.000 description 2
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-Toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 2
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 2
- DJGNUBADRQIDNQ-UHFFFAOYSA-N 5-phenylmethoxy-1H-indole-3-carbaldehyde Chemical compound C1=C2C(C=O)=CNC2=CC=C1OCC1=CC=CC=C1 DJGNUBADRQIDNQ-UHFFFAOYSA-N 0.000 description 2
- AVSZDJCFFGQKHD-UHFFFAOYSA-N 6-methoxy-1H-indole-3-carboxamide Chemical class COC1=CC=C2C(C(N)=O)=CNC2=C1 AVSZDJCFFGQKHD-UHFFFAOYSA-N 0.000 description 2
- 241000349731 Afzelia bipindensis Species 0.000 description 2
- WGQKYBSKWIADBV-UHFFFAOYSA-N Benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 2
- 210000004369 Blood Anatomy 0.000 description 2
- 101710024147 CYP716A53v2 Proteins 0.000 description 2
- 239000004215 Carbon black (E152) Substances 0.000 description 2
- 210000000170 Cell Membrane Anatomy 0.000 description 2
- 229940106189 Ceramides Drugs 0.000 description 2
- 210000004351 Coronary Vessels Anatomy 0.000 description 2
- 102000036655 EDG receptors Human genes 0.000 description 2
- 108091007067 EDG receptors Proteins 0.000 description 2
- 210000003038 Endothelium Anatomy 0.000 description 2
- 241000233866 Fungi Species 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 210000004072 Lung Anatomy 0.000 description 2
- 210000004698 Lymphocytes Anatomy 0.000 description 2
- 230000036740 Metabolism Effects 0.000 description 2
- GNSKLFRGEWLPPA-UHFFFAOYSA-M Monopotassium phosphate Chemical compound [K+].OP(O)([O-])=O GNSKLFRGEWLPPA-UHFFFAOYSA-M 0.000 description 2
- 210000004165 Myocardium Anatomy 0.000 description 2
- 208000009157 Neurocirculatory Asthenia Diseases 0.000 description 2
- 206010030113 Oedema Diseases 0.000 description 2
- 229910019213 POCl3 Inorganic materials 0.000 description 2
- ZDYVRSLAEXCVBX-UHFFFAOYSA-N Pyridinium p-toluenesulfonate Chemical compound C1=CC=[NH+]C=C1.CC1=CC=C(S([O-])(=O)=O)C=C1 ZDYVRSLAEXCVBX-UHFFFAOYSA-N 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-N Salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- UKLNMMHNWFDKNT-UHFFFAOYSA-M Sodium chlorite Chemical compound [Na+].[O-]Cl=O UKLNMMHNWFDKNT-UHFFFAOYSA-M 0.000 description 2
- SUKJFIGYRHOWBL-UHFFFAOYSA-N Sodium hypochlorite Chemical compound [Na+].Cl[O-] SUKJFIGYRHOWBL-UHFFFAOYSA-N 0.000 description 2
- 239000005708 Sodium hypochlorite Substances 0.000 description 2
- 206010041321 Somatoform disorder cardiovascular Diseases 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- LWIHDJKSTIGBAC-UHFFFAOYSA-K Tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 2
- LRFKWQGGENFBFO-IBGZPJMESA-N [(2S)-2-amino-2-(hydroxymethyl)-4-(4-octylphenyl)butyl] dihydrogen phosphate Chemical compound CCCCCCCCC1=CC=C(CC[C@](N)(CO)COP(O)(O)=O)C=C1 LRFKWQGGENFBFO-IBGZPJMESA-N 0.000 description 2
- WFDIJRYMOXRFFG-UHFFFAOYSA-N acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 2
- 239000012190 activator Substances 0.000 description 2
- 230000001058 adult Effects 0.000 description 2
- 150000001299 aldehydes Chemical class 0.000 description 2
- 150000001408 amides Chemical class 0.000 description 2
- UHOVQNZJYSORNB-UHFFFAOYSA-N benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 2
- 230000000975 bioactive Effects 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 239000011575 calcium Substances 0.000 description 2
- 230000003913 calcium metabolism Effects 0.000 description 2
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 2
- 210000002317 cardiac myocyte Anatomy 0.000 description 2
- 210000000748 cardiovascular system Anatomy 0.000 description 2
- 230000015556 catabolic process Effects 0.000 description 2
- 230000035569 catabolism Effects 0.000 description 2
- 101700018328 ccdB Proteins 0.000 description 2
- 150000001783 ceramides Chemical class 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 238000010276 construction Methods 0.000 description 2
- GBRBMTNGQBKBQE-UHFFFAOYSA-L copper;diiodide Chemical compound I[Cu]I GBRBMTNGQBKBQE-UHFFFAOYSA-L 0.000 description 2
- 239000010779 crude oil Substances 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 230000002950 deficient Effects 0.000 description 2
- 238000007872 degassing Methods 0.000 description 2
- 230000003511 endothelial Effects 0.000 description 2
- 210000002919 epithelial cells Anatomy 0.000 description 2
- BSNHKSUAAMJXBB-UHFFFAOYSA-N ethyl 5-hydroxy-2-methyl-1H-indole-3-carboxylate Chemical compound C1=C(O)C=C2C(C(=O)OCC)=C(C)NC2=C1 BSNHKSUAAMJXBB-UHFFFAOYSA-N 0.000 description 2
- 239000012091 fetal bovine serum Substances 0.000 description 2
- 238000005755 formation reaction Methods 0.000 description 2
- 230000036541 health Effects 0.000 description 2
- 125000001183 hydrocarbyl group Chemical group 0.000 description 2
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxyl anion Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 2
- 230000036039 immunity Effects 0.000 description 2
- 230000001861 immunosuppresant Effects 0.000 description 2
- 239000003018 immunosuppressive agent Substances 0.000 description 2
- 230000001771 impaired Effects 0.000 description 2
- 150000002475 indoles Chemical class 0.000 description 2
- 230000002757 inflammatory Effects 0.000 description 2
- PCEBAZIVZVIQEO-UHFFFAOYSA-N iodocyclopentane Chemical compound IC1CCCC1 PCEBAZIVZVIQEO-UHFFFAOYSA-N 0.000 description 2
- 230000000670 limiting Effects 0.000 description 2
- IHLVCKWPAMTVTG-UHFFFAOYSA-N lithium;carbanide Chemical compound [Li+].[CH3-] IHLVCKWPAMTVTG-UHFFFAOYSA-N 0.000 description 2
- 238000011068 load Methods 0.000 description 2
- 230000004060 metabolic process Effects 0.000 description 2
- 230000035786 metabolism Effects 0.000 description 2
- AWIJRPNMLHPLNC-UHFFFAOYSA-N methanethioic S-acid Chemical compound SC=O AWIJRPNMLHPLNC-UHFFFAOYSA-N 0.000 description 2
- OPUUCOLVBDQWEY-UHFFFAOYSA-N methyl 6-methoxy-1H-indole-2-carboxylate Chemical compound C1=C(OC)C=C2NC(C(=O)OC)=CC2=C1 OPUUCOLVBDQWEY-UHFFFAOYSA-N 0.000 description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N methylene dichloride Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 2
- 230000005012 migration Effects 0.000 description 2
- 230000003680 myocardial damage Effects 0.000 description 2
- MWUXSHHQAYIFBG-UHFFFAOYSA-N nitric oxide Chemical compound O=[N] MWUXSHHQAYIFBG-UHFFFAOYSA-N 0.000 description 2
- 239000003921 oil Substances 0.000 description 2
- 235000019198 oils Nutrition 0.000 description 2
- KJIFKLIQANRMOU-UHFFFAOYSA-N oxidanium;4-methylbenzenesulfonate Chemical compound O.CC1=CC=C(S(O)(=O)=O)C=C1 KJIFKLIQANRMOU-UHFFFAOYSA-N 0.000 description 2
- 230000003647 oxidation Effects 0.000 description 2
- 238000007254 oxidation reaction Methods 0.000 description 2
- 150000002923 oximes Chemical class 0.000 description 2
- 229910052763 palladium Inorganic materials 0.000 description 2
- 230000002093 peripheral Effects 0.000 description 2
- 230000035699 permeability Effects 0.000 description 2
- 239000008194 pharmaceutical composition Substances 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 229910052698 phosphorus Inorganic materials 0.000 description 2
- 230000003389 potentiating Effects 0.000 description 2
- OZAIFHULBGXAKX-UHFFFAOYSA-N precursor Substances N#CC(C)(C)N=NC(C)(C)C#N OZAIFHULBGXAKX-UHFFFAOYSA-N 0.000 description 2
- 230000000770 pro-inflamatory Effects 0.000 description 2
- 230000004088 pulmonary circulation Effects 0.000 description 2
- 230000001105 regulatory Effects 0.000 description 2
- 210000002345 respiratory system Anatomy 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 229960002218 sodium chlorite Drugs 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 230000001629 suppression Effects 0.000 description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- 150000003568 thioethers Chemical class 0.000 description 2
- FKKJJPMGAWGYPN-UHFFFAOYSA-N thiophen-2-ylmethanamine Chemical compound NCC1=CC=CS1 FKKJJPMGAWGYPN-UHFFFAOYSA-N 0.000 description 2
- 238000002054 transplantation Methods 0.000 description 2
- GDFBHCMFIUBEQT-UHFFFAOYSA-N (2,5-difluorophenyl)methanamine Chemical compound NCC1=CC(F)=CC=C1F GDFBHCMFIUBEQT-UHFFFAOYSA-N 0.000 description 1
- LRFWYBZWRQWZIM-UHFFFAOYSA-N (2-fluorophenyl)methanamine Chemical compound NCC1=CC=CC=C1F LRFWYBZWRQWZIM-UHFFFAOYSA-N 0.000 description 1
- PXJACNDVRNAFHD-UHFFFAOYSA-N (2-methoxyphenyl)methanamine Chemical compound COC1=CC=CC=C1CN PXJACNDVRNAFHD-UHFFFAOYSA-N 0.000 description 1
- BRZYSWJRSDMWLG-DJWUNRQOSA-N (2R,3R,4R,5R)-2-[(1S,2S,3R,4S,6R)-4,6-diamino-3-[(2S,3R,4R,5S,6R)-3-amino-4,5-dihydroxy-6-[(1R)-1-hydroxyethyl]oxan-2-yl]oxy-2-hydroxycyclohexyl]oxy-5-methyl-4-(methylamino)oxane-3,5-diol Chemical compound O1C[C@@](O)(C)[C@H](NC)[C@@H](O)[C@H]1O[C@@H]1[C@@H](O)[C@H](O[C@@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H]([C@@H](C)O)O2)N)[C@@H](N)C[C@H]1N BRZYSWJRSDMWLG-DJWUNRQOSA-N 0.000 description 1
- BJFPYGGTDAYECS-UHFFFAOYSA-N (3-chlorophenyl)methanamine Chemical compound NCC1=CC=CC(Cl)=C1 BJFPYGGTDAYECS-UHFFFAOYSA-N 0.000 description 1
- QVSVMNXRLWSNGS-UHFFFAOYSA-N (3-fluorophenyl)methanamine Chemical compound NCC1=CC=CC(F)=C1 QVSVMNXRLWSNGS-UHFFFAOYSA-N 0.000 description 1
- GRRIMVWABNHKBX-UHFFFAOYSA-N (3-methoxyphenyl)methanamine Chemical compound COC1=CC=CC(CN)=C1 GRRIMVWABNHKBX-UHFFFAOYSA-N 0.000 description 1
- YMVFJGSXZNNUDW-UHFFFAOYSA-N (4-chlorophenyl)methanamine Chemical compound NCC1=CC=C(Cl)C=C1 YMVFJGSXZNNUDW-UHFFFAOYSA-N 0.000 description 1
- IIFVWLUQBAIPMJ-UHFFFAOYSA-N (4-fluorophenyl)methanamine Chemical compound NCC1=CC=C(F)C=C1 IIFVWLUQBAIPMJ-UHFFFAOYSA-N 0.000 description 1
- HMTSWYPNXFHGEP-UHFFFAOYSA-N (4-methylphenyl)methanamine Chemical compound CC1=CC=C(CN)C=C1 HMTSWYPNXFHGEP-UHFFFAOYSA-N 0.000 description 1
- LFQSCWFLJHTTHZ-LNLMKGTHSA-N 1,1,2,2-tetradeuterioethanol Chemical compound [2H]C([2H])C([2H])([2H])O LFQSCWFLJHTTHZ-LNLMKGTHSA-N 0.000 description 1
- COVZYZSDYWQREU-UHFFFAOYSA-N 1,4-Butanediol, dimethanesulfonate Chemical compound CS(=O)(=O)OCCCCOS(C)(=O)=O COVZYZSDYWQREU-UHFFFAOYSA-N 0.000 description 1
- MWDBTUUEGXVYOJ-UHFFFAOYSA-N 1-benzyl-2-methyl-5-nitroindole-3-carbaldehyde Chemical compound CC1=C(C=O)C2=CC([N+]([O-])=O)=CC=C2N1CC1=CC=CC=C1 MWDBTUUEGXVYOJ-UHFFFAOYSA-N 0.000 description 1
- LYYSIZACLWYENX-UHFFFAOYSA-N 1-benzyl-5-hydroxy-2-methylindole-3-carboxylic acid Chemical compound CC1=C(C(O)=O)C2=CC(O)=CC=C2N1CC1=CC=CC=C1 LYYSIZACLWYENX-UHFFFAOYSA-N 0.000 description 1
- YZUPZGFPHUVJKC-UHFFFAOYSA-N 1-bromo-2-methoxyethane Chemical compound COCCBr YZUPZGFPHUVJKC-UHFFFAOYSA-N 0.000 description 1
- CSCPPACGZOOCGX-MICDWDOJSA-N 1-deuteriopropan-2-one Chemical compound [2H]CC(C)=O CSCPPACGZOOCGX-MICDWDOJSA-N 0.000 description 1
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 1
- ANOOTOPTCJRUPK-UHFFFAOYSA-N 1-iodohexane Chemical compound CCCCCCI ANOOTOPTCJRUPK-UHFFFAOYSA-N 0.000 description 1
- LKKUYGGQEIJGDR-UHFFFAOYSA-N 1-iodopropane Chemical compound [CH2]CCI LKKUYGGQEIJGDR-UHFFFAOYSA-N 0.000 description 1
- JKTCBAGSMQIFNL-UHFFFAOYSA-N 2,3-Dihydrofuran Chemical compound C1CC=CO1 JKTCBAGSMQIFNL-UHFFFAOYSA-N 0.000 description 1
- QGSDWIHNPWYNIC-UHFFFAOYSA-N 2-(1-benzyl-6-methoxyindol-2-yl)propan-2-ol Chemical compound C12=CC(OC)=CC=C2C=C(C(C)(C)O)N1CC1=CC=CC=C1 QGSDWIHNPWYNIC-UHFFFAOYSA-N 0.000 description 1
- LQLJZSJKRYTKTP-UHFFFAOYSA-N 2-dimethylaminoethyl chloride hydrochloride Chemical compound Cl.CN(C)CCCl LQLJZSJKRYTKTP-UHFFFAOYSA-N 0.000 description 1
- YEDUAINPPJYDJZ-UHFFFAOYSA-N 2-hydroxybenzothiazole Chemical compound C1=CC=C2SC(O)=NC2=C1 YEDUAINPPJYDJZ-UHFFFAOYSA-N 0.000 description 1
- IQRUSQUYPCHEKN-UHFFFAOYSA-N 2-iodobutane Chemical compound CCC(C)I IQRUSQUYPCHEKN-UHFFFAOYSA-N 0.000 description 1
- FMKOJHQHASLBPH-OUBTZVSYSA-N 2-iodopropane Chemical compound CC([13CH3])I FMKOJHQHASLBPH-OUBTZVSYSA-N 0.000 description 1
- DGMOBVGABMBZSB-UHFFFAOYSA-N 2-methylpropanoyl chloride Chemical compound CC(C)C(Cl)=O DGMOBVGABMBZSB-UHFFFAOYSA-N 0.000 description 1
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 1
- XDPCNPCKDGQBAN-UHFFFAOYSA-N 3-Hydroxytetrahydrofuran Chemical compound OC1CCOC1 XDPCNPCKDGQBAN-UHFFFAOYSA-N 0.000 description 1
- USCSRAJGJYMJFZ-UHFFFAOYSA-N 3-methyl-1-butyne Chemical compound CC(C)C#C USCSRAJGJYMJFZ-UHFFFAOYSA-N 0.000 description 1
- CENZODOLKBSOPH-UHFFFAOYSA-N 5-hydroxy-1H-indole-3-carboxamide Chemical compound C1=C(O)C=C2C(C(=O)N)=CNC2=C1 CENZODOLKBSOPH-UHFFFAOYSA-N 0.000 description 1
- RVWZUOPFHTYIEO-UHFFFAOYSA-N 5-hydroxy-1H-indole-3-carboxylic acid Chemical compound C1=C(O)C=C2C(C(=O)O)=CNC2=C1 RVWZUOPFHTYIEO-UHFFFAOYSA-N 0.000 description 1
- 210000002383 AT1 Anatomy 0.000 description 1
- 210000002588 AT2 Anatomy 0.000 description 1
- WETWJCDKMRHUPV-UHFFFAOYSA-N Acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 1
- 229960004373 Acetylcholine Drugs 0.000 description 1
- 206010000891 Acute myocardial infarction Diseases 0.000 description 1
- 206010064930 Age-related macular degeneration Diseases 0.000 description 1
- 206010002329 Aneurysm Diseases 0.000 description 1
- 210000001367 Arteries Anatomy 0.000 description 1
- 206010003816 Autoimmune disease Diseases 0.000 description 1
- 229910015845 BBr3 Inorganic materials 0.000 description 1
- 210000004204 Blood Vessels Anatomy 0.000 description 1
- 229940098773 Bovine Serum Albumin Drugs 0.000 description 1
- 108091003117 Bovine Serum Albumin Proteins 0.000 description 1
- 210000000621 Bronchi Anatomy 0.000 description 1
- KMGBZBJJOKUPIA-UHFFFAOYSA-N Butyl iodide Chemical compound CCCCI KMGBZBJJOKUPIA-UHFFFAOYSA-N 0.000 description 1
- AWFYTMODAXVDKM-UHFFFAOYSA-N C(C)OC=1C=C(C[NH-])C=CC=1 Chemical compound C(C)OC=1C=C(C[NH-])C=CC=1 AWFYTMODAXVDKM-UHFFFAOYSA-N 0.000 description 1
- GUDPJHONHNSJBI-PMMFOGROSA-N C([ClH]([2H])([2H])([2H])([2H])[2H])(Cl)(Cl)[2H] Chemical compound C([ClH]([2H])([2H])([2H])([2H])[2H])(Cl)(Cl)[2H] GUDPJHONHNSJBI-PMMFOGROSA-N 0.000 description 1
- 206010007521 Cardiac arrhythmias Diseases 0.000 description 1
- 206010007541 Cardiac disease Diseases 0.000 description 1
- 102000004201 Ceramidases Human genes 0.000 description 1
- 108090000751 Ceramidases Proteins 0.000 description 1
- 229940107161 Cholesterol Drugs 0.000 description 1
- 208000009863 Chronic Kidney Failure Diseases 0.000 description 1
- LSXDOTMGLUJQCM-UHFFFAOYSA-M Copper(I) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 description 1
- 206010011224 Cough Diseases 0.000 description 1
- 108090000695 Cytokines Proteins 0.000 description 1
- 102000004127 Cytokines Human genes 0.000 description 1
- 210000000172 Cytosol Anatomy 0.000 description 1
- KDXKERNSBIXSRK-RXMQYKEDSA-N D-lysine Chemical compound NCCCC[C@@H](N)C(O)=O KDXKERNSBIXSRK-RXMQYKEDSA-N 0.000 description 1
- 241000252212 Danio rerio Species 0.000 description 1
- YIIMEMSDCNDGTB-UHFFFAOYSA-N Dimethylcarbamoyl chloride Chemical compound CN(C)C(Cl)=O YIIMEMSDCNDGTB-UHFFFAOYSA-N 0.000 description 1
- 206010014561 Emphysema Diseases 0.000 description 1
- 210000002472 Endoplasmic Reticulum Anatomy 0.000 description 1
- 210000000981 Epithelium Anatomy 0.000 description 1
- HVTICUPFWKNHNG-UHFFFAOYSA-N Ethyl iodide Chemical compound CCI HVTICUPFWKNHNG-UHFFFAOYSA-N 0.000 description 1
- SPXZCGSJNVUQCZ-UHFFFAOYSA-N FC1=C(C[NH-])C=CC=C1 Chemical compound FC1=C(C[NH-])C=CC=C1 SPXZCGSJNVUQCZ-UHFFFAOYSA-N 0.000 description 1
- 208000003241 Fat Embolism Diseases 0.000 description 1
- OUVXYXNWSVIOSJ-UHFFFAOYSA-N Fluo-4 Chemical compound CC1=CC=C(N(CC(O)=O)CC(O)=O)C(OCCOC=2C(=CC=C(C=2)C2=C3C=C(F)C(=O)C=C3OC3=CC(O)=C(F)C=C32)N(CC(O)=O)CC(O)=O)=C1 OUVXYXNWSVIOSJ-UHFFFAOYSA-N 0.000 description 1
- 206010017533 Fungal infection Diseases 0.000 description 1
- DDRPCXLAQZKBJP-UHFFFAOYSA-N Furfurylamine Chemical compound NCC1=CC=CO1 DDRPCXLAQZKBJP-UHFFFAOYSA-N 0.000 description 1
- 108091006011 G proteins Proteins 0.000 description 1
- 102100010627 GEMIN7 Human genes 0.000 description 1
- 108060003145 GEMIN7 Proteins 0.000 description 1
- 102000030007 GTP-Binding Proteins Human genes 0.000 description 1
- 108091000058 GTP-Binding Proteins Proteins 0.000 description 1
- 238000003747 Grignard reaction Methods 0.000 description 1
- XKMLYUALXHKNFT-UUOKFMHZSA-N Guanosine-5'-triphosphate Chemical compound C1=2NC(N)=NC(=O)C=2N=CN1[C@@H]1O[C@H](COP(O)(=O)OP(O)(=O)OP(O)(O)=O)[C@@H](O)[C@H]1O XKMLYUALXHKNFT-UUOKFMHZSA-N 0.000 description 1
- 239000007995 HEPES buffer Substances 0.000 description 1
- 101710031679 HEXIM1 Proteins 0.000 description 1
- 241000238631 Hexapoda Species 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 206010027665 Immune disorder Diseases 0.000 description 1
- 206010021425 Immune system disease Diseases 0.000 description 1
- 108010002352 Interleukin-1 Proteins 0.000 description 1
- SNHMUERNLJLMHN-UHFFFAOYSA-N Iodobenzene Chemical compound IC1=CC=CC=C1 SNHMUERNLJLMHN-UHFFFAOYSA-N 0.000 description 1
- 239000007836 KH2PO4 Substances 0.000 description 1
- 210000000265 Leukocytes Anatomy 0.000 description 1
- 206010024585 Lipidosis Diseases 0.000 description 1
- 208000000501 Lipidosis Diseases 0.000 description 1
- 102000004895 Lipoproteins Human genes 0.000 description 1
- 108090001030 Lipoproteins Proteins 0.000 description 1
- 208000004852 Lung Injury Diseases 0.000 description 1
- 206010025327 Lymphopenia Diseases 0.000 description 1
- 208000002780 Macular Degeneration Diseases 0.000 description 1
- 210000000138 Mast Cells Anatomy 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 229940111688 Monobasic potassium phosphate Drugs 0.000 description 1
- 210000002464 Muscle, Smooth, Vascular Anatomy 0.000 description 1
- KVKFRMCSXWQSNT-UHFFFAOYSA-N N,N'-dimethylethane-1,2-diamine Chemical compound CNCCNC KVKFRMCSXWQSNT-UHFFFAOYSA-N 0.000 description 1
- HQABUPZFAYXKJW-UHFFFAOYSA-N N-Butylamine Chemical compound CCCCN HQABUPZFAYXKJW-UHFFFAOYSA-N 0.000 description 1
- IBPMHSYAULYENJ-UHFFFAOYSA-N N-[(3-methoxyphenyl)methyl]-2-methyl-1-(thiophen-2-ylmethyl)indole-3-carboxamide Chemical compound COC1=CC=CC(CNC(=O)C=2C3=CC=CC=C3N(CC=3SC=CC=3)C=2C)=C1 IBPMHSYAULYENJ-UHFFFAOYSA-N 0.000 description 1
- LKQLRGMMMAHREN-YJFXYUILSA-N N-stearoylsphingosine-1-phosphocholine Chemical compound CCCCCCCCCCCCCCCCCC(=O)N[C@@H](COP([O-])(=O)OCC[N+](C)(C)C)[C@H](O)\C=C\CCCCCCCCCCCCC LKQLRGMMMAHREN-YJFXYUILSA-N 0.000 description 1
- 210000000440 Neutrophils Anatomy 0.000 description 1
- 235000019502 Orange oil Nutrition 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N P-Toluenesulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 102000004160 Phosphoric Monoester Hydrolases Human genes 0.000 description 1
- 108090000608 Phosphoric Monoester Hydrolases Proteins 0.000 description 1
- 229950010765 Pivalate Drugs 0.000 description 1
- 210000002381 Plasma Anatomy 0.000 description 1
- 206010065918 Prehypertension Diseases 0.000 description 1
- DBABZHXKTCFAPX-UHFFFAOYSA-N Probenecid Chemical compound CCCN(CCC)S(=O)(=O)C1=CC=C(C(O)=O)C=C1 DBABZHXKTCFAPX-UHFFFAOYSA-N 0.000 description 1
- 102000014961 Protein Precursors Human genes 0.000 description 1
- 108010078762 Protein Precursors Proteins 0.000 description 1
- 208000002815 Pulmonary Hypertension Diseases 0.000 description 1
- 206010037370 Pulmonary contusion Diseases 0.000 description 1
- 206010038444 Renal failure chronic Diseases 0.000 description 1
- 206010061485 Respiratory fume inhalation disease Diseases 0.000 description 1
- 241000283984 Rodentia Species 0.000 description 1
- 102100014085 S1PR1 Human genes 0.000 description 1
- 101700071062 S1PR2 Proteins 0.000 description 1
- 102100014087 S1PR2 Human genes 0.000 description 1
- 240000004808 Saccharomyces cerevisiae Species 0.000 description 1
- 210000001013 Sinoatrial Node Anatomy 0.000 description 1
- 108020004459 Small Interfering RNA Proteins 0.000 description 1
- 229910002850 SnCl2 Inorganic materials 0.000 description 1
- 208000005392 Spasm Diseases 0.000 description 1
- 208000010110 Spontaneous Platelet Aggregation Diseases 0.000 description 1
- FDDDEECHVMSUSB-UHFFFAOYSA-N Sulfanilamide Chemical compound NC1=CC=C(S(N)(=O)=O)C=C1 FDDDEECHVMSUSB-UHFFFAOYSA-N 0.000 description 1
- FIAFUQMPZJWCLV-UHFFFAOYSA-N Suramin Chemical compound OS(=O)(=O)C1=CC(S(O)(=O)=O)=C2C(NC(=O)C3=CC=C(C(=C3)NC(=O)C=3C=C(NC(=O)NC=4C=C(C=CC=4)C(=O)NC=4C(=CC=C(C=4)C(=O)NC=4C5=C(C=C(C=C5C(=CC=4)S(O)(=O)=O)S(O)(=O)=O)S(O)(=O)=O)C)C=CC=3)C)=CC=C(S(O)(=O)=O)C2=C1 FIAFUQMPZJWCLV-UHFFFAOYSA-N 0.000 description 1
- 229960005314 Suramin Drugs 0.000 description 1
- 208000007536 Thrombosis Diseases 0.000 description 1
- 210000001578 Tight Junctions Anatomy 0.000 description 1
- AXZWODMDQAVCJE-UHFFFAOYSA-L Tin(II) chloride Chemical compound [Cl-].[Cl-].[Sn+2] AXZWODMDQAVCJE-UHFFFAOYSA-L 0.000 description 1
- 206010069363 Traumatic lung injury Diseases 0.000 description 1
- 208000010019 Vascular System Injury Diseases 0.000 description 1
- 206010027701 Vascular injury Diseases 0.000 description 1
- YKNZTUQUXUXTLE-UHFFFAOYSA-N [3-(trifluoromethyl)phenyl]methanamine Chemical compound NCC1=CC=CC(C(F)(F)F)=C1 YKNZTUQUXUXTLE-UHFFFAOYSA-N 0.000 description 1
- NNSWCNSHUAZHEL-UHFFFAOYSA-N [NH-]CC1=CC=CC(C(F)(F)F)=C1 Chemical compound [NH-]CC1=CC=CC(C(F)(F)F)=C1 NNSWCNSHUAZHEL-UHFFFAOYSA-N 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K [O-]P([O-])([O-])=O Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 239000012346 acetyl chloride Substances 0.000 description 1
- OIPILFWXSMYKGL-UHFFFAOYSA-N acetylcholine Chemical compound CC(=O)OCC[N+](C)(C)C OIPILFWXSMYKGL-UHFFFAOYSA-N 0.000 description 1
- 231100000403 acute toxicity Toxicity 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 150000001338 aliphatic hydrocarbons Chemical class 0.000 description 1
- 150000001345 alkine derivatives Chemical group 0.000 description 1
- 125000003282 alkyl amino group Chemical group 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- 230000002009 allergen Effects 0.000 description 1
- 201000005794 allergic hypersensitivity disease Diseases 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 230000002491 angiogenic Effects 0.000 description 1
- 210000004102 animal cell Anatomy 0.000 description 1
- 230000000489 anti-atherogenic Effects 0.000 description 1
- 230000003276 anti-hypertensive Effects 0.000 description 1
- 239000000427 antigen Substances 0.000 description 1
- 102000038129 antigens Human genes 0.000 description 1
- 108091007172 antigens Proteins 0.000 description 1
- 238000009246 art therapy Methods 0.000 description 1
- 125000004104 aryloxy group Chemical group 0.000 description 1
- 230000036523 atherogenesis Effects 0.000 description 1
- 210000002072 atrial myocyte Anatomy 0.000 description 1
- 230000002238 attenuated Effects 0.000 description 1
- 201000009596 autoimmune hypersensitivity disease Diseases 0.000 description 1
- 230000004888 barrier function Effects 0.000 description 1
- 125000000440 benzylamino group Chemical group [H]N(*)C([H])([H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 150000005347 biaryls Chemical group 0.000 description 1
- 238000004166 bioassay Methods 0.000 description 1
- 230000000903 blocking Effects 0.000 description 1
- 230000017531 blood circulation Effects 0.000 description 1
- 230000036770 blood supply Effects 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- CURLTUGMZLYLDI-UHFFFAOYSA-N carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 1
- 235000011089 carbon dioxide Nutrition 0.000 description 1
- 230000003293 cardioprotective Effects 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 230000022131 cell cycle Effects 0.000 description 1
- 230000030833 cell death Effects 0.000 description 1
- 230000032823 cell division Effects 0.000 description 1
- 230000009087 cell motility Effects 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 239000003610 charcoal Substances 0.000 description 1
- 230000001713 cholinergic Effects 0.000 description 1
- 230000001684 chronic Effects 0.000 description 1
- 230000001010 compromised Effects 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 201000008739 coronary artery disease Diseases 0.000 description 1
- 230000002596 correlated Effects 0.000 description 1
- 230000000875 corresponding Effects 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000005712 crystallization Effects 0.000 description 1
- OKKJLVBELUTLKV-VMNATFBRSA-N deuteriooxymethane Chemical compound [2H]OC OKKJLVBELUTLKV-VMNATFBRSA-N 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 230000004069 differentiation Effects 0.000 description 1
- 201000009910 diseases by infectious agent Diseases 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 230000000547 effect on apoptosis Effects 0.000 description 1
- 238000001493 electron microscopy Methods 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 210000002253 embryonic cardiomyocyte Anatomy 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-N ethanesulfonic acid Chemical compound CCS(O)(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-N 0.000 description 1
- KLKFAASOGCDTDT-UHFFFAOYSA-N ethoxymethoxyethane Chemical compound CCOCOCC KLKFAASOGCDTDT-UHFFFAOYSA-N 0.000 description 1
- QBJZQAQWVLGNJY-UHFFFAOYSA-N ethyl 3-amino-4-iodobenzoate Chemical compound CCOC(=O)C1=CC=C(I)C(N)=C1 QBJZQAQWVLGNJY-UHFFFAOYSA-N 0.000 description 1
- GKKZMYDNDDMXSE-UHFFFAOYSA-N ethyl 3-oxo-3-phenylpropanoate Chemical compound CCOC(=O)CC(=O)C1=CC=CC=C1 GKKZMYDNDDMXSE-UHFFFAOYSA-N 0.000 description 1
- YCBJOQUNPLTBGG-UHFFFAOYSA-N ethyl 4-iodobenzoate Chemical compound CCOC(=O)C1=CC=C(I)C=C1 YCBJOQUNPLTBGG-UHFFFAOYSA-N 0.000 description 1
- XCLDSQRVMMXWMS-UHFFFAOYSA-N ethyl 4-methyl-3-oxopentanoate Chemical compound CCOC(=O)CC(=O)C(C)C XCLDSQRVMMXWMS-UHFFFAOYSA-N 0.000 description 1
- MVEAAGBEUOMFRX-UHFFFAOYSA-N ethyl acetate;hydrochloride Chemical compound Cl.CCOC(C)=O MVEAAGBEUOMFRX-UHFFFAOYSA-N 0.000 description 1
- UREBWPXBXRYXRJ-UHFFFAOYSA-N ethyl acetate;methanol Chemical compound OC.CCOC(C)=O UREBWPXBXRYXRJ-UHFFFAOYSA-N 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N furane Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 238000005227 gel permeation chromatography Methods 0.000 description 1
- 230000005182 global health Effects 0.000 description 1
- 230000012010 growth Effects 0.000 description 1
- 239000003102 growth factor Substances 0.000 description 1
- 239000001963 growth media Substances 0.000 description 1
- 230000009067 heart development Effects 0.000 description 1
- 230000004217 heart function Effects 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- VLKZOEOYAKHREP-UHFFFAOYSA-N hexane Substances CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 150000002429 hydrazines Chemical class 0.000 description 1
- 150000007857 hydrazones Chemical class 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 238000003384 imaging method Methods 0.000 description 1
- 239000000411 inducer Substances 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 230000003834 intracellular Effects 0.000 description 1
- 238000009114 investigational therapy Methods 0.000 description 1
- VQTUBCCKSQIDNK-UHFFFAOYSA-N isobutene Chemical compound CC(C)=C VQTUBCCKSQIDNK-UHFFFAOYSA-N 0.000 description 1
- 231100000515 lung injury Toxicity 0.000 description 1
- 231100001023 lymphopenia Toxicity 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- CSNNHWWHGAXBCP-UHFFFAOYSA-L magnesium sulphate Substances [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- 230000036210 malignancy Effects 0.000 description 1
- 239000003550 marker Substances 0.000 description 1
- 230000035800 maturation Effects 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 238000005399 mechanical ventilation Methods 0.000 description 1
- 239000002609 media Substances 0.000 description 1
- 230000001404 mediated Effects 0.000 description 1
- 230000037353 metabolic pathway Effects 0.000 description 1
- JUVSRACZYLMJQD-UHFFFAOYSA-N methyl 1-(2,3-dihydroxypropyl)-4-oxo-3-phenylmethoxypyridine-2-carboxylate Chemical group O=C1C=CN(CC(O)CO)C(C(=O)OC)=C1OCC1=CC=CC=C1 JUVSRACZYLMJQD-UHFFFAOYSA-N 0.000 description 1
- 239000002480 mineral oil Substances 0.000 description 1
- 235000010446 mineral oil Nutrition 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 230000011278 mitosis Effects 0.000 description 1
- 230000035772 mutation Effects 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L na2so4 Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 210000000653 nervous system Anatomy 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 150000002828 nitro derivatives Chemical class 0.000 description 1
- GQPLMRYTRLFLPF-UHFFFAOYSA-N nitrous oxide Inorganic materials [O-][N+]#N GQPLMRYTRLFLPF-UHFFFAOYSA-N 0.000 description 1
- 235000015097 nutrients Nutrition 0.000 description 1
- 230000000414 obstructive Effects 0.000 description 1
- 239000010502 orange oil Substances 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 210000000056 organs Anatomy 0.000 description 1
- WWCNXHYRAKUQDB-UHFFFAOYSA-N oxolan-3-yl 4-methylbenzenesulfonate Chemical compound C1=CC(C)=CC=C1S(=O)(=O)OC1COCC1 WWCNXHYRAKUQDB-UHFFFAOYSA-N 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 230000002085 persistent Effects 0.000 description 1
- 150000003904 phospholipids Chemical class 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- 125000004437 phosphorous atoms Chemical group 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 102000004257 potassium channel family Human genes 0.000 description 1
- 108020001213 potassium channel family Proteins 0.000 description 1
- 229910000160 potassium phosphate Inorganic materials 0.000 description 1
- 229940093916 potassium phosphate Drugs 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 229960003081 probenecid Drugs 0.000 description 1
- 230000000750 progressive Effects 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- RZWZRACFZGVKFM-UHFFFAOYSA-N propanoyl chloride Chemical compound CCC(Cl)=O RZWZRACFZGVKFM-UHFFFAOYSA-N 0.000 description 1
- 239000003881 protein kinase c inhibitor Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000000611 regression analysis Methods 0.000 description 1
- 238000007634 remodeling Methods 0.000 description 1
- 230000004202 respiratory function Effects 0.000 description 1
- 230000029058 respiratory gaseous exchange Effects 0.000 description 1
- 230000003938 response to stress Effects 0.000 description 1
- 230000000250 revascularization Effects 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 230000035939 shock Effects 0.000 description 1
- 102000035261 signaling receptors Human genes 0.000 description 1
- 108091005516 signaling receptors Proteins 0.000 description 1
- 239000002924 silencing RNA Substances 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 108010035597 sphingosine kinase Proteins 0.000 description 1
- JLVSPVFPBBFMBE-HXSWCURESA-O sphingosylphosphocholine acid Chemical compound CCCCCCCCCCCCC\C=C\[C@@H](O)[C@@H]([NH3+])COP([O-])(=O)OCC[N+](C)(C)C JLVSPVFPBBFMBE-HXSWCURESA-O 0.000 description 1
- 235000011150 stannous chloride Nutrition 0.000 description 1
- 230000004936 stimulating Effects 0.000 description 1
- 229960001663 sulfanilamide Drugs 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 230000004083 survival Effects 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 230000002195 synergetic Effects 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 125000004953 trihalomethyl group Chemical group 0.000 description 1
- 235000019798 tripotassium phosphate Nutrition 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 238000009423 ventilation Methods 0.000 description 1
- 230000035899 viability Effects 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Abstract
The invention provides compounds represented by the formula I, each of which compounds may have sphingosine-1 -phosphate receptor agonist and or antagonist biological activity:and wherein the variables Y, R4, n, A, X, Z, R1, o, R3, R2and p are as defined in the specification. These compounds are useful for treating a disease or condition selected from the group consisting of glaucoma, dry eye, angiogenesis, cardiovascular conditions and diseases, and wound healing.
Description
COMPOUNDS OF AMID, ESTER, TIOAMIDE AND TIOL-ESTER OF INDOL-3-CARBOXILIC ACID THAT HAVE ARILO OR HETEROARILO GROUPS THAT HAVE BIOLOGICAL ACTIVITY ANTAGONIST OF RECEPTOR OF SPHYNGOSINE-1-PHOSPHATE (S1P)
Field of the Invention The present invention relates to sphingosine derivatives and / or analogs and pharmaceutical compositions, including these derivatives and / or analogs, which are useful as drugs for the treatment of fungal infections, allergic diseases, immune disorders, etc.
BACKGROUND OF THE INVENTION Sphingosine is a compound having the chemical structure shown in the general formula described below, in which Y1 is hydrogen. It is known that several sphingolipids, which have sphingosine as a constituent, are widely distributed in the body. living including on the surface of cell membranes of cells in the nervous system. H OH NH2
H3C - (CH2) 12- C = CH - CH - CH - CH20 - Y '
H
Ref. : 195691
A sphingolipid is one of the lipids that have important roles in the living body. A disease called lipidosis is caused by the accumulation of a specified sphingolipid in the body. Sphingolipids present in cell membranes function to regulate cell growth; they participate in the development and differentiation of cells; they work on nerves; they are included in the infection and malignancy of cells; etc. Many of the physiological roles of sphingolipids remain to be solved. Recently, it has been indicated that the possibility that ceramide, a derivative of sphingosine, has an important role in the mechanism of cell signal transduction, and studies have been reported about its effect on apoptosis and cell cycle. Sphingosine-1-phosphate is an important cellular metabolite, derived from ceramide that is synthesized de novo or as part of the sphingomyelin cycle (in animal cells). It has also been found in insects, yeasts and plants. The enzyme, ceramidase, acts on ceramides to release sphingosine, which is phosphorylated by sphingosine kinase, a ubiquitous enzyme in the cytosol and endoplasmic reticulum, to form sphingosine-1-phosphate. The reverse reaction can also occur by the action of sphingosine phosphatases, and the enzymes act in conjunction to control the cellular concentrations of the metabolite, concentrations that are always
low. In plasma, this concentration can reach 0.2 to 0.9 μ ?, and the metabolite is found in association with lipoproteins, especially HDL. It should also be noted that the formation of sphingosine-1-phosphate is an essential step in the catabolism of the sphingoid bases. Similar to precursors, sphingosine-1-phosphate is a potent messenger molecule that perhaps operates uniquely both intra- and inter-cellular, but with functions very different from those with ceramides and sphingosine. The balance between these various sphingolipid metabolites can be important for health. For example, within the cell, sphingosine-1-phosphate promotes cell division (mitosis) as the opposite of cell death (apoptosis), which inhibits. Intracellular, it also functions to regulate calcium metabolism and cell growth in response to a variety of extracellular stimuli. Current opinion seems to suggest that the balance between sphingosine-1-phosphate and ceramide and / or sphingosine levels in cells is critical for its viability. In common with lysophospholipids, especially lysophosphatidic acid, with which they have some structural similarities, sphingosine-1-phosphate exerts many of its extracellular effects through interaction with five specific receptors coupled to G protein on cell surfaces. These are important for the
growth of new blood vessels, vascular maturation, cardiac development and immunity, and for directed cell movement. In this way, sphingosine ligands would be useful in the treatment of angiogenic disorders such as age-related macular degeneration (AR D) and various cancers, etc. Sphingosine-1-phosphate is stored in relatively high concentrations in human platelets, which lack the enzymes responsible for their catabolism, and is released into the bloodstream in the activation of physiological stimuli, such as growth factors, cytokines, and agonists of receptors and antigens. It can also have a critical role in platelet aggregation and thrombosis and may aggravate cardiovascular disease. On the other hand, the relatively high concentration of the metabolite in high density lipoproteins (HDL) may have beneficial implications for atherogenesis. For example, there are recent suggestions that sphingosine-1-phosphate, together with other lysolipids such as sphingosylphosphorylcholine and lysulfuride, are responsible for the beneficial clinical effects of HDL by stimulating the production of the potent anti-atherogenic signaling molecule, nitric oxide, by the vascular endothelium. In addition, like lysophosphatidic acid, it is a marker of certain types of cancer, and there is evidence that its role in division or proliferation
cellular can have an influence on the development of cancers. These are the current topics that are attracting great interest among medical researchers, and the potential for therapeutic intervention in the metabolism of sphingosine-1-phosphate is under active investigation. Fungi and plants have sphingolipids and the main sphingosine contained in these organisms has the formula described below. It is known that these lipids have important roles in the cell growth of fungi and plants, but they remain to resolve the details of the papers
OH OH NH2
H3C - (CH2) i2 - CH2 - CH - CH - CH - CH2OH
Recently, it has been known that derivatives of sphingolipids and their related compounds exhibit a variety of biological activities through the inhibition or stimulation of metabolic pathways. These compounds include protein kinase C inhibitors, inducers of apoptosis, immunosuppressant compounds, antimycototic compounds, and the like. It is expected that substances that have these biological activities are useful compounds for various diseases. Sphingosine derivatives have been prepared in several
patents See, for example, United States Patents 4,952,683; 5,110,987; 6,235,912 Bl and 6,239,297 Bl. Also, compounds that are similar to certain sphingosine derivatives, but are not reported as being ligands for sphingosine receptors are reported in several patents and published patent applications. See, for example, United States Patents Nos. 5,294,722; 5,102,901; 5,403,851 and 5,580,878. U.S. Patent Application Publication No. US 2003/0125371 A2. While certain compounds reported in the above patents are indoles, it does not appear that indole compounds have been reported as being ligands for the sphingosine receptor or having activity as sphingosine agonists or antagonists.
Brief Description of the Invention The present invention provides a sphingosine derivative or analog that is capable of regulating sphingolipid functions, and pharmaceutical compositions comprising the derivative or analog. These compounds are represented by formula I, each of these compounds can have biological agonist activity and / or sphingosine-1-phosphate receptor antagonists.
where X is NR5, 0, S; Z is 0 or S; n is 0 or an integer from 1 to 5, for example from 1 to 4, or is 0 or an integer from 1 to 3; p is 0 or an integer of 1 a, e.g. 1 to 3; (C (R5) 2) m, where m is 0 or an integer from 1 to 6; R5 is selected from the group consisting of hydrogen, straight or branched chain alkyl having 1 to 12 carbon atoms, cycloalkyl having 3 to 6 carbons, alkenyl having 2 to 6 carbons and 1 or 2 double bonds, alkenyl having from 2 to 6 carbons and 1 or 2 triple bonds, aryl (as defined below), halo, Ci to Ci2 haloalkyl, hydroxyl, Ci to Ci2 alkoxy, Ci to Ci2 alkylcarbonyl, formyl, oxycarbonyl, carboxy, Ci to Ci2 alkyl carboxylate, Ci to Ci2 alkyl amide, aminocarbonyl, amino, cyano, diazo, nitro, thio, sulfoxyl or sulfonyl.
Y is a carbocyclic aryl or heterocyclic aryl group wherein the carbocyclic aryl comprises from 6 to 20 atoms and the heterocyclic aryl comprises from 2 to 20 carbon atoms and from 1 to 5 heteroatoms selected from the group consisting of nitrogen, sulfur and oxygen, and wherein the aryl can be attached to A in any position; R1, R2, R3, R4 are selected from the group consisting of hydrogen, straight or branched chain alkyl having 1 to 12 carbons, cycloalkyl having 3 to 6 carbons, alkenyl having 2 to 6 carbons and 1 or 2 double bonds, alkenyl having from 2 to 6 carbons and 1 or 2 triple bonds, aryl (as defined below), halo, Ci to C12 haloalkyl, hydroxyl, Ci to C12 alkoxy, C3 to C22 arylalkyloxy, Ci to C12 alkylcarbonyl, formyl, oxycarbonyl, carboxy, Cx to C12 alkyl carboxylate, Ci to Ci2 alkyl amide, aminocarbonyl, amino, cyano, diazo, nitro, thio, sulfoxyl or sulfonyl groups, or a group selected from the group consisting of:
wherein R is C02H or P03H2, p is an integer of 1 or 2 and q is 0 or an integer from 1 to 5. The aryl group is a carbocyclic aryl or heterocyclic aryl group wherein the carbocyclic aryl comprises
from 6 to 20 atoms and the heterocyclic aryl comprises from 2 to 20 carbon atoms and from 1 to 5 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, and preferably the aryl group is selected from the group consisting of benzene, pyridine, pyrazine, pyridazine, pyrimidine, triazine, thiophene, furan, thiazole, thiazole, isothiazole, oxazole, oxadiazole, isooxazole, naphthalene, quinoline, tetralin, chroman, thiochroman, tetrahydroquinoline, dihydronaphthalene, tetrahydronaphthalene, chromene, thiochromen, dihydroquinoline, Indan, dihydrobenzofuran, dihydrobenzothiophene, indene, benzofuran, benzothiophene, coumarin and coumarinone. These aryl groups can be attached to the foregoing portion at any position. This aryl group can be substituted by itself with any common organic functional group including but not limited to Ci groups to Ci2 alkyl, C2 to C6 alkenyl, Ci to C6 alkynyl, halo, Ci to Ci2 haloalkyl, hydroxyl, Ci to Ci2 alkoxy, Ci to Ci2 alkylcarbonyl, formyl, oxycarbonyl, carboxyl, Ci to Ci2 alkyl carboxylate, Ci to Ci2 alkyl amide, aminocarbonyl, amino, cyano, diazo, nitro, thio, sulfoxyl or sulfonyl. Preferably, Z is O. Preferably, the carbocyclic aryl group will comprise from 6 to 14 carbon atoms, for example from 6 to 10 carbon atoms. Preferably, the aryl or heterocyclic group will comprise from 2 to 14 carbon atoms and one or
more, for example, from 1 to 3 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur. In a preferred embodiment of the invention, one or
more, for example, an R is replaced by
wherein A1 and A2 are independently selected from the group consisting of (CH2) V wherein v is 0 or an integer from 1 to 12, branched chain alkyl having from 3 to 12 carbons, cycloalkyl having from 3 to 12 carbons, alkenyl having 2 to 10 carbons and 1-3 double bonds and alkenyl having 2 to 10 carbons and 1 to 3 triple bonds; B is selected from the group consisting of hydrogen, OR6, COOR7, NR8R9, CONR8R9, COR10, CH = N0Rn, CH = NNR12R13 wherein R6, R7, R10 and R11 are independently selected from the group consisting of hydrogen, straight-chain alkyl or branched having 1 to 12 carbons, alkenyl having 2 to 6 carbons and 1 or 2 double bonds, alkynyl having 2 to 6 carbons and 1 or 2 triple bonds, a carbocyclic hydrocarbon group having 3 to 20 carbon atoms, a heterocyclic group having up to 20 carbon atoms and at least one of oxygen, nitrogen and / or sulfur in the ring. R8, R9, R12 and R13 are independently selected from the group consisting of hydrogen, straight or branched chain alkyl having from 1 to 12 carbons, alkenyl having
of 2 to 6 carbons and 1 or 2 double bonds, alkynyl having from 2 to 6 carbons and 1 or 2 triple bonds, a carbocyclic hydrocarbon group having from 3 to 20 carbon atoms, a heterocyclic group having up to 20 atoms carbon and at least one of oxygen, nitrogen and / or sulfur in the ring, or R8 and R9 and / or R12 and R13, with which they can form a divalent carbon radical of 2 to 5 carbons to form a heterocyclic ring with nitrogen , wherein any of R6, R7, R8, R9, R10, Ru, R12 or R13 may be substituted with one or more halogen, hydroxy, alkyloxy, cyano, nitro, mercapto or thiol radicals; with the condition, however, that when v is 0, and r is 0, B is not hydrogen; or B is a carbocyclic hydrocarbon group having from 3 to 20 carbon atoms, or a heterocyclic group having up to 20 carbon atoms and at least one oxygen, nitrogen and / or sulfur in the ring, and wherein when B is a carbocyclic or heterocyclic group, B may be attached to A2 in any position, or a pharmaceutically acceptable salt of this compound. In the preferred embodiment of the present invention: Preferably, A is CH2. Preferably, X is NH. Preferably, N is 0 or an integer of 1 or 2 and R 4 is fluoro. Preferably, R1 is i-propyl. Preferably, R3 is selected from the group that
it consists of phenyl, which may be substituted with one or two fluoro groups, and pyridyl. Preferably, p is 0. Preferably, A1 and A2 are absent. Preferably, B is OR6 or COOR7. Preferably, X is O, r is 1, A1 is absent, A2 is (CH2) V, where v is 1 or 2, B is OR6 or NR8R9, and R6, R8 and R9 are methyl. Preferably, B is CR10 = NOR R10 wherein R10 is H and R11 is methyl or i-butyl or B is CONR8R9 wherein R8 and R9 are selected from the group consisting of H, methyl, ethyl and propyl, or R8 and R9, together with N, form a 5-membered ring. Preferably, A1 is absent, R1 is 0, A2 is CH2 and B is OR6, wherein R6 is H, or X is O, r is 1 and B is COR10, wherein R10 is methyl. Specific examples of the compounds of the formula I include
These compounds can be synthesized as illustrated by the reaction scheme below:
Reaction Scheme 1
In general, a beta-ketoester (e.g., ethyl acetoacetate) is treated with an amine (e.g., 2-thiophenemethylamine) in the presence of an organic acid (e.g., para-toluenesulfonic acid), and 1, 4 - benzoquinone to produce a 5-hydroxyindole-3-carboxylic acid (e.g., 5-hydroxy-2-methyl-1- (2-thiophenemethyl) indole-3-carboxylic acid) after hydrolysis of the ester with a strong base such as hydroxide of sodium in a suitable solvent such as ethanol. The carboxylic acid is further reacted with an amine in the presence of N- (3-dimethylaminopropyl) -N'-ethylcarbodiimide (EDC) to produce 5-hydroxyindole-3-carboxamide (e.g., 3,4-difluorophenylmethyl-5-) hydroxy-2-methyl-1- (2-thiophenemethyl) indole-3-carboxamide). The carboxylic acid can also be treated with an alcohol or thiol in the presence of EDC to produce ester and thiol ester derivatives, respectively. The specific examples of
compounds of one of the preferred embodiments include
Some compounds within the scope of the invention can be prepared as depicted in Reaction Scheme 1. In this manner, methyl 6-methoxyindole-2-carboxylate is treated with an electrophilic compound (e.g., benzyl bromide) in the presence of a weak base (e.g., potassium carbonate) to produce indole N-alkylane (e.g., methyl l-benzyl-6-methoxyindole-2-carboxylate). The 2-carboxylate group is converted to an alkyl group by a three-step process: Grignard reaction, elimination and hydrogenation. The resulting 2-alkyl-indole is carboxylated in the 3-position by treatment with dimethylformamide and phosphorus oxychloride followed by oxidation with sodium hypochlorite of the resulting aldehyde. The carboxylic acid can be further functionalized by
treatment with an amine in the presence of N- (3-dimethylaminopropyl) -N'-ethylcarbodiimide (EDC) to produce a 6-methoxyindole-3-carboxamide derivative (for example 3,4-difluorophenylmethyl-6-methoxy-2-) isopropyl-1-benzylindol-3-carboxamide). The carboxylic acid can also be treated with an alcohol or thiol in the presence of EDC to produce an ester derivative and thiol ester, respectively. The 6-methoxy group can then be deprotected using boron tribromide and the resulting hydroxide is subjected to alkylation reagents (eg, cyclopentyl iodide / potassium carbonate) or acylation (eg, pivaloyl chloride / pyridine) to produce a wide variety of 6-substituted indole homologs and derivatives within the scope of the invention.
Reaction Scheme 2
Many other compounds within the scope of the invention can be prepared as depicted in Reaction Scheme 2. In this manner, the ethyl 4-iodobenzoate can be nitrated in the 3-position with nitrous fumed acid and the resultant reduced nitro compound moderate conditions (for example SnCl2 ~ H20) to produce ethyl 3-amino-4-iodobenzoate. This compound can be converted to indole by treatment with a terminal alkyne (for example, 3-methylbutyne) in the presence of a palladium and copper iodide catalyst followed by heating of the aryl-alkyne in the presence of copper iodide. The resulting 2-alkyl-indole can then be carbonylated in the 3-position by treatment with dimethylformamide and phosphorus oxychloride and N-alkylated as described above (benzyl bromide, potassium carbonate), followed by oxidation with sodium hypochlorite to produce an N-alkylindol-3-carboxylic acid. The carboxylic acid can be further functionalized by treatment with an amine in the presence of EDC to produce a 6-methoxyindole-3-carboxamide derivative (e.g., 3-pyridylmethyl-1-benzyl-6-carboethoxy-2-isopropylindole-3). -carboxamide).
Reaction Scheme 3
The carboxylic acid can also be treated with an alcohol or thiol in the presence of EDC to produce an ester derivative and thiol ester, respectively. The 6-carboethoxy group can be further functionalized to produce a wide variety of 6-substituted indole homologs and derivatives within the scope of the invention. For example, the 6-carboethoxy group is
hydrolyzes with strong base and the resulting carboxylic acid is converted to the carboxylic acid chloride, which can be reacted with various alcohols or amines in the presence of base to produce ester or amide derivatives, respectively, such as 3-pyridylmethyl-1 benzyl-2-isopropyl-6- (1-pyrrolidinyl-carbamoyl) indole-3-carboxamide. Alternatively, the 6-carboethoxy group can be reduced to an alcohol and re-oxidized to an intermediate aldehyde compound, which can then be treated with an amine under reducing conditions to give amine derivatives such as 3-pyridylmethyl-1- benzyl-2-isopropyl-6- (1-pyrrolidinylmethyl) indole-3-carboxamide. The aldehyde can also be treated with oxime or hydrazine compounds to produce oxime and hydrazone derivatives, respectively. In this manner, many compounds within the scope of the invention can be produced by the general route depicted in Reaction Scheme 3. The corresponding benzyl-amino compounds can be prepared according to Reaction Scheme 4, below.
Reaction Scheme 4
Detailed Description of the Invention Unless otherwise indicated, the following terms as used throughout this specification have the following meanings: "Me" refers to methyl. "Et" refers to ethyl. "tBu" refers to t-butyl. "iPr" refers to i-propyl. "Ph" refers to phenyl. "Pharmaceutically acceptable salt" refers to those salts which retain the biological effectiveness and properties of the free bases and which can be obtained by reaction with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, acid methanesulfonic, ethanesulfonic acid, acid
p-toluenesulfonic, salicylic acid and the like. "Alkyl" refers to a straight chain branched or cyclic saturated aliphatic hydrocarbon. Preferably, the alkyl group has from 1 to 12 carbons. More preferably, it is a lower alkyl of 1 to 7 carbons, more preferably 1 to 4 carbons. Typical alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, hexyl, and the like. The alkyl group may be optionally substituted with one or more substituents selected from the group consisting of hydroxyl, cyano, alkoxy, = 0, = S, N02, halogen, dimethylamino and SH. "Alkenyl" refers to a straight chain, branched or cyclic unsaturated hydrocarbon group containing at least one carbon-carbon double bond. Preferably, the alkenyl group has from 2 to 12 carbons. More preferably, it is a lower alkyl of 2 to 7 carbons, more preferably 2 to 4 carbons. The alkenyl group may be optionally substituted with one or more substituents selected from the group consisting of hydroxyl; cyano, alkoxy, 0, S, N02, halogen, dimethylamino and SH. "Alkynyl" refers to a straight chain, branched or cyclic unsaturated hydrocarbon containing at least one carbon-carbon triple bond. Preferably, the group
Alkynyl has 2 to 12 carbons. More preferably, it is a lower alkenyl of 2 to 7 carbons, more preferably 2 to 4 carbons. The alkynyl group may be optionally substituted with one or more substituents selected from the group consisting of hydroxyl, cyano, alkoxy, 0, S, N02, halogen, dimethylamino and SH. "Alkoxy" refers to a "0-alkyl" group. "Aryl" refers to an aromatic group having at least one ring that has a conjugated pi electron system and includes aryl carboxyl groups, heterocyclic aryl and biaryl. The aryl group may be optionally substituted with one or more substituents selected from the group consisting of halogen, trihalomethyl, hydroxyl, SH, OH, N02, amine, thioether, cyano, alkoxy, alkylamino and amino. "Alkaryl" refers to an alkyl that is covalently linked to an aryl group. Preferably, the alkyl is a lower alkyl. "Aryloxy" refers to a "0-aryl" group. "Arylalkyloxy" refers to a "0-alkaryl" group. "Carbocyclic aryl" refers to an aryl group in which the ring atoms are carbon. "Heterocyclic aryl" refers to an aryl group having 1 to 3 heteroatoms as ring atoms, the remainder of the ring atoms being carbons. The
heteroatoms include oxygen, sulfur and nitrogen. "Hydrocarbyl" refers to a hydrocarbon radical having only carbon and hydrogen atoms. Preferably, the hydrocarbyl radical has from 1 to 20 carbon atoms, more preferably from 1 to 12 carbon atoms and more preferably from 1 to 7 carbon atoms. "Substituted hydrocarbyl" refers to a hydrocarbyl radical wherein one or more, but not all, hydrogen and / or carbon atoms are replaced by a halogen, nitrogen, oxygen, sulfur or phosphorus atom or a radical that includes a halogen, nitrogen atom, oxygen, sulfur or phosphorus, for example, fluoro, chloro, cyano, nitro, hydroxyl, phosphate, thiol, etc. "Amide" refers to -C (0) -NH-R 'wherein R' is alkyl, aryl, alkylaryl or hydrogen. "Ester" refers to -C (0) -0-R ', wherein R' is alkyl, aryl or alkylaryl. "Thioamide" refers to -C (S) NH-R ', wherein R' is alkyl, aryl, alkylaryl or hydrogen. "Thio-ester" refers to -C (0) -S-R ', wherein R' is alkyl, aryl, alkylaryl or hydrogen. "Amina" refers to a group -N (R ") R '' '/ wherein R" and R "" are independently selected from the group consisting of alkyl, aryl, and alkylaryl.
"Thioether" refers to -S-R ", wherein R" is alkyl, aryl or alkylaryl. "Sulfonyl" refers to -S-R "", wherein R "'" is aryl, C (CN) = C-aryl, CH2CN, alkylaryl, sulfonamide, NH-alkyl, NH-alkylaryl, NH-aryl. Also, alternatively, the substituent on the phenyl portion, as shown below, is referred to as a substituent o, m or p or substituent 2, 3 or 4, respectively. (Obviously, substituent 5 is also a substituent m and substituent 6 is a substituent o). The specific compounds of the invention are reported in Table 1 below. The compounds can be titrated for their ability to activate or block the activation of human S1P3 receptor on T24 cells stably expressing the human S1P3 receptor. In this assay, ten thousand cells / concavity are plated on plates coated with poly-D-lysine from 384 concavities one day before use, the growth medium for the line of cells expressing the S1P3 receptor is the McCoy medium 5A supplemented with 10% charcoal-treated fetal bovine serum (FBS), 1% antibiotic-antifungal and 400 μ? /? of geneticin. On the day of the experiment, the cells are washed twice with Hank's Balanced Saline Solution supplemented with 20 m HEPES (HBSS / Hepes buffer). The cells are then loaded with dye with Fluo-4 2 u
diluted in the HBSS / Hepes buffer with Probenecid 1.25 mM and incubated at 37 ° C for 40 minutes. The extracellular dye is removed by washing the cell plates four times before placing the plates in the FLIPR (Fluorometric Imaging Plate Reader, Molecular Devices). The ligands are diluted in HBSS / Hepes buffer and prepared in microplates of 384 concavities. The positive control, Esf ingosine-1-Fosf ato (SIP), is diluted in HBSS / Hepes buffer with 4 mg / ml of bovine serum albumin free of fatty acid. The FLIPR transfers 12.5 μ? of the microplate bound to the cell plate and takes fluorescent measurements for 75 seconds, taking readings every second, and then for 2.5 minutes, taking readings every 10 seconds. The drugs are tested over the concentration range of 0.61 nM to 10,000 nM. Data are obtained for Ca + 2 responses in arbitrary fluorescence units and are not translated at Ca + 2 concentration. The IC50 values are determined through a linear regression analysis using the Levenburg Marquardt algorithm.
Table 1. Activity of SIP Receptor Antagonist
??
??
??
??
The preferred compounds of the invention are described in Table 2 below: Table 2 No of compound Structure
??
The compounds of Table 3 are prepared according to procedures analogous to the procedures of Reaction Schemes 1 through 4 and / or the subsequent Examples.
??
??
??
??
??
??
As a result of the activity of the compounds, that is, as sphingosine ligands, the above compounds can be used in the treatment of the following diseases and conditions for the following reasons.
Glaucoma Subtypes of S1P3 are expressed in cells in the form of
trabecular mesh, human, primary and SIP decreases the ease of spill > 30% in porcine impregnated eyes (see IOVS 45, 2263, 2004) when altering paracellular permeability.
Dry Eye / Immunity Induces lymphocyte sequestration without affecting T cell proliferation
Angiogenesis Disorders The S1P3 receptor subtype is expressed in vascular endothelial cells and exhaustion of siRNA from S1P1 and S1P3 inhibits angiogenesis. SIP also promotes the migration of vascular endothelial cells and promotes assembly and barrier integrity.
Cardiovascular (S1P3) Mice "with inactivated genes" of S1P3 lack pulmonary edema induced by SIP.
Additional Clinical Potential of SIP Receptors Ligands, Agonists and Selective Antagonists of the Invention Blockade of S1P3 to Protect Epithelial Integrity in Lung Disease Type Acute Respiratory Effort Syndrome Acute Respiratory Distress Syndrome (ARDS,
for its acronym in English) is a serious reaction to various forms of lung injury. This is the most important disorder that results in increased pulmonary edema of permeability. The annual incidence of ARDS is between 1.5 to 13.5 people per 100,000 in the general population. Mechanical ventilation, sepsis, pneumonia, shock, aspiration, trauma (especially pulmonary contusion), major surgery, massive transfusions, smoke inhalation, drug reaction or overdose, fat embolism and pulmonary edema after lung transplantation or pulmonary embolectomy can activate all ARDS. Pneumonia and sepsis are the most common activations, and pneumonia is present in up to 60% of patients. Pneumonia and sepsis can be either causes or complications of ARDS. It is difficult to find a good method to treat ARDS in the clinic. The most reliable treatment is positive end-expiratory pressure ventilation (PEEP). Pulmonary diseases that include respiratory effort syndrome in adults are characterized by rupture of pulmonary integrity and edema that compromises respiratory function. Sphingosine-1-phosphate (S1P) is a lipid mediator synthesized and / or stored in mast cells, platelets, and epithelial cells, with production favored by the proinflammatory cytokines IL-1 and TNF. The
administration of SIP through the airways but not through the vasculature induces pulmonary leak. Using null mice in recipients, the results show that SIP, which acts on the S1P3 receptor expressed in both type I and type II alveolar epithelial cells but not vascular endothelium, induces pulmonary edema by acute narrow junction. WT mice but not nulls of S1P3 showed rupture of narrow pulmonary epithelial junctions and the appearance of paracellular separations between epithelial cells by electron microscopy in the space of 1 hour of exposure of the airways to SIP. SIP shows synergistic activity with the proinflammatory cytokine TNF, showing both pulmonary edema and mortality at sub-threshold doses of SIP. Specifically, pre-exposure of mice at sub-threshold doses of TNF, which did not induce pulmonary edema alone, exacerbated SIP-induced edema and impaired survival. SIP, which acts through S1P3 regulates epithelial integrity and acts additively with TNF by compromising the respiratory barrier function. Because null SIP3 mice are resistant to SIP-induced pulmonary leak, either alone or in the presence of TNF, the S1P3 antagonist may be useful in protecting epithelial integrity in lung disease. Based on the data showing that SIP, which acts through the S1P3 receptor expressed in epithelium
pulmonary, is an acute regulator of epithelial integrity when breaking tight junctions. It is believed that S1P3 blockers are useful for treating ARDS.
S1P Signaling EDG Receptor Route Regulation to Improve the Condition of Congestive Heart Failure Congestive Heart Failure (CHF), also called Congestive Heart Failure (CCF) or just Heart failure is a condition that results from any structural or functional heart disorder that impairs the heart's ability to fill or pump a sufficient amount of blood throughout the body. The most common cause of heart failure is ischemic heart disease (myocardial infarction of coronary artery disease). Left ventricular failure will increase hypertension in the pulmonary system, and fail to remove fluid in the pulmonary circulation to lead to pulmonary edema. There is a vicious circle in left ventricular failure and pulmonary edema. Cardiac ischemia and infarction reduce myocardial contraction to induce heart failure, pulmonary hypertension, and pulmonary edema. Pulmonary edema increases the oxygen barrier of the lung to
blood from the pulmonary circulation, then Po2 in the artery will decrease sharply. The supply of oxygen to the heart will shorten the requirement to maintain the causes of contraction, then force heart failure. The most common cause of CHF in the United States is ischemic heart disease. The treatment of CHF in clinical studies includes improving cardiac function, reducing pre-loading of the heart and post-loading. Research has shown that the route of the Edg S1P signaling receptor may be included in the regulation of cardiovascular systems and pulmonary leakage. S1P sharply protects the heart against ischemia / reperfusion injury, decreases the myocardial ischemia infarction region, and keeps the coronary artery in dilatation. S1P can also improve the pulmonary endothelial cell barrier to reduce pulmonary edema that was induced by left ventricular failure. The S1P3 receptor antagonist can block the contraction of vascular smooth muscle, and decrease cardiac afterload. Blocking the S1P3 receptor can also prevent one of S1P toxicity, bradycardia.
Treatment of Asthma and Chronic Obstructive Pulmonary Disease Asthma is a chronic disease of the respiratory system in which the airways occasionally contract, becoming inflamed, and covered with amounts
excessive mucus, often in response to one or more activators. In response to exposure to these activators, the bronchial tubes contract in spasm (an "asthma attack"). Inflammation follows promptly, leading to further narrowing of the airways and excessive production of mucus, which leads to coughing and other breathing difficulties. Chronic obstructive pulmonary disease (COPD) almost corresponds to bronchial asthma to the most important diseases of the respiratory tract. COPD is a major global health problem, and it is predicted to become the third most common cause of death by 2020. COPD is a disease characterized by progressive obstruction of airflow in the peripheral airways, associated with inflammation. pulmonary, emphysema and hypersecretion of mucus. The main problem in asthma and COPD is contraction and inflammation of the bronchi. Recently, many scientific papers reported that S1P is involved in the construction of smooth muscle cells of human airways. S1P stimulates the constriction of smooth muscle cells of human airways by S1P3 receptors. Recent work has revealed that S1P levels are elevated in the airways of asthmatics and not in healthy individuals after stimulation with segmental allergen. Research has shown that the
S1P signaling path contributes to cholinergic constriction of murine peripheral airways. In this way, the S1P3 receptor is a potential new therapeutic target for asthma and COPD. The S1P3 antagonist will block the stimulation of S1P to the S1P3 receptor of the smooth muscle cells of the human airways preventing the bronchial contraction.
Use of Selective S1P3 Receptor Antagonist in the Control of Human Hypertension Hypertension, commonly referred to as "high blood pressure," is a medical condition where blood pressure rises chronically. Persistent hypertension is one of the risk factors for attacks, heart attacks, heart failure and arterial aneurysm, and is a leading cause of chronic renal failure. Currently, it is estimated that 58 million adults in the United States have hypertension or are taking anti-hypertensive medications. In addition to definitive hypertension, an additional 45 million adults in the United States have pre-hypertension. Recently, it has been found that S1P, a bioactive lipid mediator, comprised in the cardiovascular system, and cholesterol metabolism. The evidence links the activity of the S1P3 receptor with acute toxicity and
cardiovascular regulation; power of the compound in S1P3 correlated with toxicity and bradycardia; the change in the potency of phosphorylated FTY720 to induce lymphopenia versus bradycardia and hypertension was consistent with affinity for SIPi in relation to S1P3; and toxicity, bradycardia, and hypertension were absent in SlP3 mice. "_ The effects on blood pressure of agonists in anesthetized rats were complex, while hypertension was the most prevalent effect in conscious rats and mice.The immunolocalization of S1P3 in the heart of the rodents revealed abundant expression in myocytes and perivascular smooth muscle cells consistent with regulation of bradycardia and hypertension, while the expression of SIPi was restricted to the vascular endothelium In conclusion, hypertension is clearly associated with the activation of S1P3 and its expression patterns in cardiovascular tissue S1P and the S1P3 receptor are thought to play an important role in regulating blood pressure.
The S1P3 signaling pathway heart rate regulation can be used to control tachycardia, one of the most common cardiac arrhythmias. Tachycardia refers to a rapid heartbeat. By convention, the term refers to heart rates greater than 100 beats per minute in the patient
adult. Tachycardia can be a perfectly normal physiological response to stress. However, depending on the mechanism of the tachycardia and the state of health of the patient, the tachycardia can be dangerous, and requires medical treatment. In extreme cases, tachycardia can be life-threatening. Tachycardia can be harmful in two ways. First, when the heart beats too quickly, it can perform inefficiently. Second, the faster the heart beats, the more oxygen and nutrients the heart requires. This can be especially problematic for patients suffering from ischemic heart disease. Sphingosine-l-phosphate (SIP) influences heart rate, coronary artery caliber, endothelial integrity and lymphocyte recirculation through five related high affinity protein G-coupled receptors. Largely circumstantial evidence of cultured atrial myocytes and using inhibition with suramin as a measure of S1P3 function has postulated a role for S1P3 in the activation of an IKAch-inducing bradycardia. The in vivo demonstration that a non-selective receptor agonist SIP active to S1P3 induces bradycardia in wild type mice that are nullified in S1P3 - / - mice provides additional support for the role of S1P3 in the heart. Also SIPi as S1P3 will
expressed in cardiac endothelium and perhaps in the myocardium, even suppression of S1P3 abolishes only the bradycardia induced by non-selective agonists of the S1P receptor, and a selective SIPi agonist does not induce bradycardia. The sphingolipid drug FTY720 shows structural similarity to S1P and efficiency as an immunosuppressant in models of autoimmune disease and in solid organ transplantation. While the FTY720 is well tolerated in humans, it produces a momentary reduction in heart rate (HR). Since S1P activates the cardiac potassium channel activated by protein G, IKACh, the reduction in HR induced by FTY720 reflects the activation of IKACh. In wild type myocytes, the active phosphate metabolite of FTY720 (FTY720-P) induced individual channel activity with conductance, open time, GTP sensitivity and rectification identical to that of IKACh. In whole-cell readings, FTY720-P caused an inward rectifying potassium current in approximately 90% of the myocytes that respond to acetylcholine. Comparable channel activity was never observed in myocytes from mice deficient in IKACh. In wild-type mice, administration of acute FTY720 produced a strong, dose-dependent reduction in HR. In contrast, the reduction of HR induced by FTY720 in mice deficient in IKACh was impaired. The research concludes that the effect of acute administration of FTY720 in
HR is mainly mediated by the activation of IKACh.
Clinical Pathway Potential of S1P Signaling EDG Receptors in the Protection of Myocardial Ischemia and Repercussion Injury Myocardial infarction, commonly known as heart attack, is a disease state that occurs when the blood supply to the heart is interrupted. a part of the heart. The resulting deficit of oxygen causes damage and potential death of cardiac tissue. It is a medical emergency, and the leading cause of death for both men and women around the world. The main therapeutic objectives in patients with acute myocardial infarction are to minimize myocardial damage, improve cardiac separation, and reduce myocardial remodeling. Prior art therapy is rapid reperfusion of the infarcted myocardium through revascularization of the occluded vessel. However, the benefit of the repercussion is compromised by the endothelial injury and inflammation that follows the reinstitution of blood flow, leading to additional myocardial damage, a process called "ischaemia / reperfusion injury". Despite all efforts to prevent the sequelae of the impact injury in patients, currently there are no clinical strategies available to effectively protect the heart tissue of the patient.
repercussion inherent to inflammatory damage. SIP is a bioactive phospholipid that is stored mainly in platelets. Platelets play a major role in the response to acute vascular injury. SIP potentially affects the development and function of the heart. The mutation in a SIP receptor in the zebrafish called Miles Apart (which is very similar to the mammalian S1P2 receptor) results in a defect in the migration of myocardial precursor cells and the formation of the bifid cardiac condition, where two structures of the primitive cardiac tube fail to coalesce and form an individual mature cardiac structure. Studies in adult cardiac cells showed that SIP regulates calcium metabolism and ionic currents in cells of the sinoatrial node, which controls the cardiac sequence. In addition, it was shown that SIP prevents death of cardiac myocytes in ischemia / reperfusion injury. Cardiomyocytes express SIP1-3 receptors, suggesting that the signaling pathways stimulated by these receptors may contribute to myocardial intrinsic function. In a model of injury caused by ischemia / repercussion of the heart in animals, SIP was found to be cardioprotective. In a myocardial ischemia / reperfusion model in mice, SIP dramatically attenuated infarct size by approximately 20% and 40%, respectively. The underlying mechanism was an inhibition of recruitment
of inflammatory neutrophils and apoptosis of cardiomyocytes in the infarcted area. S1P potentially suppressed the adhesion of leukocytes to activated endothelium under flow and protected neonatal cardiomyocytes from rat against apoptosis. The invention is further illustrated by the following examples which are illustrative of a specific mode for practicing the invention and are not proposed as limiting the scope of the claims. Unless otherwise indicated, the following chemical abbreviations are used in the examples: NaOH: Sodium hydroxide EtOH: Ethanol HC1: Hydrogen chloride EtOAc: Ethyl acetate Na2S04: Sodium sulfate MeOH: Methanol Pd-C: Palladium in activated carbon Et20: Diethyl ether EDC: N- (3-dimethylaminopropyl) -N'-ethylcarbodiimide hydrochloride
HOBt: 1-hydroxybenzotriazole CH2C12: Methylene chloride D F: N, N-dimethylformamide DCC: N, N'-dicyclohexylcarbodiimide DMSO: dimethylsulfoxide
They were purchased from Aldrich Chemical Company, benzylamine, benzyl bromide, n-butylamine, 3-chlorobenzylamine, 4-chlorobenzylamine, furfuryl-amine, 2,5-difluorobenzylamine, 3,4-difluorobenzylamine, 3,5-difluorobenzylamine, iodobenzene, 2 -yodopyridine, 2-iodothiophene, ethyl acetoacetate, ethyl benzoylacetate, ethyl 5-hydroxy-2-methylindol-3-carboxylate, ethyl isobutyrylacetate, ethyl 3-oxovelarate, 2-fluorobenzylamine, 3-fluorobenzylamine, 4-fluorobenzylamine , 2-methoxybenzylamine, 3-methoxybenzylamine, 4-methylbenzylamine, 2-thiophenemethylamine and 3- (trifluoromethyl) benzylamine. 5-Benzyloxyindole-3-carboxaldehyde was purchased from Sigma Chemical Company. 2-Methyl-5-nitro-lH-indole-3-carboxaldehyde was purchased from Fisher Scientific Company.
Example 1 Ethyl l-Benzyl-5-hydroxy-2-methyl-lH-indole-3-carboxylate (Compound 1). General Procedure 1. To a solution of ethyl acetoacetate (1.3 ml, 10 mmol) and benzylamine (1.2 ml, 10.5 mmol) in toluene (10 ml) was added p-toluenesulfonic acid monohydrate (95 mg, 0.5 mmol). The mixture was heated at 140 ° C under reflux for 4 hours, cooled to 0 ° C and filtered. The filtrate was concentrated under reduced pressure to give a
yellow oil (2.6 g). To a solution of 1,4-benzoquinone (1.49 g, 13.8 mmol) in nitromethane (5 mL) was added a solution of the above yellow oil in nitromethane (3.5 mL) slowly. The resulting mixture was stirred at room temperature for 18 hours and then cooled to 0 ° C and filtered. The solid was washed with cold nitromethane to produce ethyl 1-benzyl-5-hydroxy-2-methyl-1H-indole-3-carboxylate (Compound 1) as a beige solid. RMNXH (Chloroform-d) d 1.45 (t, J = 7.0 Hz, 3H), 2.70 (s, 3H), 4.40 (q, J = 7.2 Hz, 2H), 5.09 (s, 1H), 5.31 (s, 2H) ), 6.75 (dd, J = 8.6, 2.5Hz, 1H), 6.92-7.01 (m, 2H), 7.08 (d, J = 8.8 Hz, 1H), 7.23-7.32 (m, 3H), 7.65 (d, J = 2.6 Hz, 1H).
Example 2 L-Benzyl-5-hydroxy-2-methyl-lH-indole-3-carboxylic acid (Compound 2). General Procedure 2. A solution of ethyl 1-benzyl-5-hydroxy-2-methyl-1H-indole-3-carboxylate (Compound 1, 873 mg, 2.83 mmol) and NaOH (2.2 g, 56 mmol) in EtOH ( 10 mL) and H20 (10 mL) was heated at 90 ° C for 16 hours. The reaction was quenched with 6M HC1 (10 mL), extracted with EtOAc, washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (30% EtOAc-hexanes a
% MeOH -EtOAc) to produce l-benzyl-5-hydroxy-2-methyl-lH-indole-3-carboxylic acid (Compound 2) as a red brown solid. NMR1H (Methanol-d4) d 2.67 (s, 3H), 5.41 (s, 2H), 6.68 (dd, J = 8.8, 2.3 Hz, 1H), 6.96-7.03 (m, 2H), 7.15 (d, J = 8.8 Hz, 1H), 7.20-7.32 (m, 3H), 7.55 (d, J = 2.1 Hz, 1H).
Example 3 3, 5-Difluorobenzylamide of l-benzyl-5-hydroxy-2-methyl-lH-indole-3-carboxylic acid (Compound 3). General Procedure 3. To a solution of 1-benzyl-5-hydroxy-2-methyl-1H-indole-3-carboxylic acid (Compound 2, 205 mg, 0.73 mmol) in CH2C12 (5 mL) and DF (3 mL) EDC was added (211 mg, 1.1 mmol), HOBT (149 mg, 1.1 mmol) and 3,5-difluorobenzylamine (260 μ ?, 2.2 mmol). The mixture was stirred at room temperature for 16 hours, diluted with EtOAc, and washed with 1M HC1, and brine, and dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (30% to 50% EtOAc-hexanes) to give 3,5-difluorobenzylamide of l-benzyl-5-hydroxy-2-methyl-1H-indol-3 acid. -carboxylic
(Compound 3) as a beige solid. NMR1H (Methanol-d4) d 2.57 (s, 3H), 4.61 (s, 2H), 5.40 (s, 2H), 6.70 (dd, J = 8.8, 2.3 Hz, 1H), 6.77-6.88 (m, 1H) ,
6. 97-7.07 (m, 4H), 7.14-7.19 (m, 1H), 7.20-7.32 (m, 4H). The following compounds were prepared using General Procedures 1, 2 and 3 and the appropriate amines and beta-ketoester start materials, which are available from Aldrich Chemical Company or are prepared as described below:
Example 4 3. 5-Hydroxy-2-methyl-1-thiophen-2-ylmethyl-1H-indole-3-carboxylic acid difluorobenzylamide (Compound 4). RMN1! -! (Acetone-d6) d 2.73 (s, 3 H), 4.64 (d, J = 6.1 Hz, 2 H), 5.59 (s, 2 H), 6.77 (dd, J = 8.5, 2.0 Hz, 1 H), 6.93-7.01 (m, 2 H), 7.25-7.40 (m, 6 H), 7.88 (br s, 1 H).
Example 5 2.5-Difluorobenzylamide of 5-hydroxy-2-methyl-1-thiophen-2-ylmethyl-1H-indole-3-carboxylic acid 1H NMR (Acetone-e ^) d 2.74 (s, 3 H), 4.68 (d, J = 5.9 Hz, 2 H), 5.59 (s, 2 H), 6.77 (dd, J = 8.8, 2.4 Hz, 1 H), 6.93-7.33 (m, 6 H), 7.38 (d, J = 15.6 Hz , 2 H), 7.9 (br s, 1 H).
Example 6 3, 5-Difluorobenzylamide of l-butyl-5-hydroxy-2-methyl-
1H-indole-3-carboxylic acid (Compound 6). 1H-NMR (Chloroform-d) d 0.95 (t, J = 7.5 Hz, 3 H), 1.38 (m, 2 H), 1.70 (m, 2 H), 2.69 (s, 3 H), 4.03 (t, J = 7.5 Hz, 2 H), 4.59 (d, J = 6.1 Hz, 2 H), 5.81 (s, 1 H), 6.23 (br t, 1 H), 6.66 (m, 1 H), 6.80 (dd, J = 2.2, 8.8 Hz, 1 H), 6.86 (br d, 2 H), 7.15 (br d, 2 H).
Example 7 3, 4-Difluorobenzylamide of 1-butyl-5-hydroxy-2-methyl-1H-indole-3-carboxylic acid (Compound 7). NMR ^ H (Chloroform-d) d 0.95 (t, J = 7.5 Hz, 3 H), 1.36 (m, 2 H), 1.70 (m, 2 H), 2.69 (s, 3 H), 4.03 (t, J = 7.5 Hz, 2 H), 4.58 (d, J = 6.1 Hz, 2 H), 5.75 (s, 1 H), 6.20 (br, t, 1 H), 6.76 (dd, J = 2.6, 8.8 Hz , 1 H), 7.05-7.16 (m, 5 H). Example 8 L-benzyl-5-hydroxy-2-methyl-lH-indole-3-carboxylic acid 3-methoxybenzylamide (Compound 8). NMR1H (Chloroform-d) d 2.67 (s, 3?), 3.81 (s, 3?), 4.67 (d, J = 5.6 Hz, 2?), 5.30 (s, 2?), 6.17 (t, J = 5.6 Hz, 1?), 6.73 (dd, J = 8.8, 2.3 Hz, 1 H), 6.83 (dd, J = 7.8, 2.2 Hz, 1 H), 6.94-7.02 (m, 4 H), 7.09 (d , J = 9.1 Hz, 1 H), 7.22 (d, J = 2.3 Hz, 1 H), 7.23-7.33 (m, 4 H).
Example 9 3, 4-Difluorobenzylamide of 1-furan-2-ylmethyl-5-hydroxy-2-methyl-1H-indole-3-carboxylic acid (Compound 9). R 1H (Acetone-dg) d 2.78 (s, 3 H), 4.64 (d, J = 6. Hz, 2H), 5.38 (s, 2 H), 6.34-6.37 (m, 2 H), 6.74 (dd) , J = 8.8 2.3 Hz, 1 H), 7.23-7.45 (m, 6 H), 7.81 (s, 1 H).
Example 10 2-Difluorobenzylamide of 1-furan-2-ylmethyl-5-hydroxy-2-methyl-1H-indole-3-carboxylic acid (Compound 10). NMR ^ H (Acetone-d &) d 2.77 (s, 3 H), 4.68 (d, J = 6.1 Hz, 2 H), 5.38 (s, 2 H), 6.34-6.39 (m, 2 H), 6.77 (dd, J = 8.8, 2.3 Hz, 1 H), 7.04-7.33 (m, 3 H), 7.39 (d, J = .16.1 Hz, 2 H), 7.45 (d, J = 2.6 Hz, 1 H) , 7.88 (bs, 1 H).
Example 11 3,5-Difluorobenzylamide of 5-hydroxy-2-methyl-1-thiophen-2-ylmethyl-1H-indole-3-carboxylic acid (Compound 11). RM 1H (Acetone-d6) d 2.78 (s, 3 H), 4.66 (d, J = 6.2
Hz, 2 H), 5.59 (s, 2 H), 6.74 (dd, J = 8.8, 2.4 Hz, 1 H), 6.80-7.02 (m, 3 H), 7.08 (d, J = 8.8 Hz, 1 H ), 7.28 (d, J = 2.4 Hz, 1 H), 7.32 (d, J = 5.0 Hz, 1 H), 7.38 (d, J = 16 Hz, 2 H), 7.42 (bs, 1 H).
Example 12 3, 5-Diflurobenzylamide of 1-furan-2-ylmethyl-5-hydroxy-2-methyl-lH-indole-3-carboxylic acid (Compound 12). NMR1H (Acetone-d6) d 2.78 (s, 3 H), 4.66 (d, J = 6.2 Hz, 2 H), 5.38 (s, 2 H), 6.34-6.39 (m, 2 H), 6.74 (dd, J = 8.8, 2.4 Hz, 1 H), 6.80-6.90 (m, 1 H), 7.08 (dd, J = 8.8, 2.4 Hz, 1 H), 7.23-7.32 (m, 3 H), 7.27 (d, J = 2.4 Hz, 1 H), 7.42 (d, J = 15.9 Hz, 2 H), 7.45 (d, J = 2.1 Hz, 1 H), 7.84 (s, 1 H).
EXAMPLE 13 L-Benzyl-5-hydroxy-2-methyl-lH-indole-3-carboxylic acid 3-difluorobenzylamide (Compound 13). RM 1 H (Methanol-d 4) d 2.55 (s, 3 H), 4.57 (s, 2 H), 5.38 (s, 2 H), 6.69 (dd, J = 2.2, 8.8 Hz, 1 H), 6.99 (2 H), br d,
2 H), 7.16 (d, J = 8.8 Hz, 1 H), 7.17-7.30 (m, 7 H).
Example 14 3-Fluorobenzylamide of 5-hydroxy-2-methyl-1-thiophen-2-ylmethyl-1H-indole-3-carboxylic acid (Compound 14). NMR1H (Methanol-d4) d 2.65 (s, 3 H), 4.60 (s, 2 H), 5.52 (s, 2 H), 6.73 (dd, J = 2.2, 8.8 Hz, 1 H), 6.90-7.00 (s) m,
3 H), 7.10-7.39 (m, 6 H).
Example 15 5-Hydroxy-2-methyl-1-thiophen-2-ylmethyl-1H-indole-3-carboxylic acid benzylamide (Compound 15). NMR1H (Methanol-cL,) d 2.64 (s, 3 H), 4.60 (s, 2 H), 5.52 (s, 2 H), 6.72 (dd, J = 2.2, 8.8 Hz, 1 H), 6.91 (2 br d, 2 H), 7.16 (d, J = 2.2 Hz, 1 H), 7.24-7.27 (m, 2 H), 7.31 (d, J = 4.0 Hz, 1 H), 7.35 (d, J = 7.0 Hz, 2 H), 7.42 (d, J = 7.5 Hz, 2 H).
Example 16 2-Fluorobenzylamide of 5-hydroxy-2-methyl-1-thiophen-2-ylmethyl-1H-indole-3-carboxylic acid (Compound 16). NMR1H (Methanol-cL,) d 2.67 (s, 3 H), 4.69 (s, 2 H), 5.55 (s, 2 H), 6.72 (dd, J = 2.6, 8.8 Hz, 1 H), 6.94 (m , 2 H), 7.40 (m, 1 H), 7.20 (m, 2 H), 7.28 (m, 1 H), 7.32 (overlap m,
1 H), 7.32 (d, J = 8.8 Hz, 1 H), 7.50 (t, J = 7.5 Hz, 1 H).
Example 17 5-Hydroxy-2-methyl-1-thiophen-2-ylmethyl-1H-indole-3-carboxylic acid 3-methoxy-benzylamide (Compound 17). NMR1H (Methanol-d4) d 2.68 (s, 3 H), 3.81 (s, 3 H), 4.61 (s, 2 H), 5.55 (s, 2 H), 6.75 (dd, J = 2.6, 8.8 Hz, 1 H), 6.85 (dd, J = 2.5, 8.4 Hz, 1 H), 6.94 (m, 2 H), 7.02 (2 br d,
2 H), 7.19 (d, J = 2.5 Hz, 1 H), 7.28 (m, 2 H), 7.32 (d, J =
8. 7 Hz, 1 H).
Example 18 3-Methoxy-benzylamide of 1-butyl-5-hydroxy-2-methyl-1H-indole-3-carboxylic acid (Compound 18). NMR1H (Methanol-d4) d 0.95 (t, J = 7.5 Hz, 3 H), 1.39 (m, 2 H), 1.71 (m, 2 H), 2.60 (s, 3 H), 3.78 (s, 3 H) ), 4.11 (t, J = 7.5 Hz, 2 H), 4.58 (s, 2 H), 6.72 (dd, J = 2.2, 8.8 Hz, 1 H), 7.03 (dd, J = 2.2, 8.4 Hz, 1 H), 6.90 (2 br, d, 2 H), 7.15 (d, J = 2.2 Hz, 1 H), 7.21 (d, J = 8.8 Hz, 1 H), 7.26 (d, J = 8.4 Hz, 1 H).
Example 19 4-Fluorobenzylamide of 5-hydroxy-2-methyl-1-thiophen-2-ylmethyl-1H-indole-3-carboxylic acid (Compound 19). NMR1H (Methanol-d4) d 2.63 (s, 3 H), 4.58 (s, 2 H), 5.53 (s, 2 H), 6.72 (dd, J = 2.6, 8.8 Hz, 1 H), 6.91 (2 br) d, 2 H), 7.06 (t, J = 8.8 Hz, 2 H), 7.15 (d, J = 2.2 Hz, 1 H), 7.25 (dd, J = 4.0, 6.6 Hz, 1 H), 7.29 (d , J = 8.8 Hz, 1 H), 7.35 (dd, J = 13.6, 8.4 Hz, 2 H).
Example 20 4- 5-Hydroxy-2-methyl-1-thiophen-2-ylmethyl-1H-indole-3-carboxylic acid ethylbenzylamide (Compound 20).
RM 1 H (Methanol-d 4) d 2.32 (s, 3 H), 2.64 (s, 3 H), 4.55 (s, 2 H), 5.52 (s, 2 H), 6.73 (dd, J = 2.6, 8.8 Hz , 1 H), 6.91 (m, 2 H), 7.14 (d, J = 2.2 Hz, 1 H), 7.15 (d, J = 9 Hz, 2 H), 7.24 - 7.30 (m, 4 H).
Example 21 3-Chlorobenzylamide of 5-hydroxy-2-methyl-1-thiophen-2-ylmethyl-1H-indole-3-carboxylic acid (Compound 21). NMRH (Methanol-d4) d 2.65 (s, 3 H), 4.58 (s, 2 H), 5.53 (s, 2 H), 6.72 (dd, J = 2.6, 8.8 Hz, 1 H), 6.91 (2 br) d, 2 H), 7.16 (d, J = 2.2 Hz, 1 H), 7.24-7.34 (m, 5 H), 7.42 (s,
1 HOUR) .
Example 22 4-Chlorobenzylamide of 5-hydroxy-2-methyl-1-thiophen-2-ylmethyl-1H-indole-3-carboxylic acid (Compound 22). NMR1H (Methanol-d4) d 2.64 (s, 3 H), 4.57 (s, 2 H), 5.52 (s, 2 H), 6.72 (dd, J = 2.6, 8.8 Hz, 1 H), 6.91 (2 br) dd,
2 H), 7.15 (d, J = 2.2 Hz, 1 H), 7.25 (dd, J = 2.2, 4.0 Hz, 1 H), 7.29 (d, J = 9 Hz, 1 H), 7.35 (d, J) = 8.4 Hz, 2 H), 7.40 (d, J = 8.4 Hz, 2 H).
EXAMPLE 23 5-Hydroxy-2-methyl-1-thiophene-2-methoxybenzylamide
ILYMETHYL-1H-Indole-3-carboxylic acid (Compound 23). RM ^ (Methanol-d4) d 2.64 (s, 3 H), 3.91 (s, 3 H), 4.60 (s, 2 H), 5.52 (s, 2 H), 6.72 (dd, J = 2.6, 8.8 Hz , 1 H), 6.88-6.95 (m, 3 H), 7.00 (d, J = 8.0 Hz, 1 H), 7.14 (d, J = 2.2 Hz, 1 H), 7.24-7.35 (m, 4 H) .
Example 24 3-Trifluoromethylbenzylamide of 5-hydroxy-2-methyl-1-thiophen-2-ylmethyl-1H-indole-3-carboxylic acid (Compound 24). NMR1H (Methanol-d4) d 2.64 (s, 3 H), 4.67 (s, 2 H),
. 53 (s, 2 H), 6.73 (dd, J = 2.6, 8.8 Hz, 1 H), 6.91 (m, 2 H), 7.17 (d, J = 2.2 Hz, 1 H), 7.25 (dd, J = 2.2, 4.0 Hz, 1 H), 7.30 (d, J = 9.0 Hz, 1 H), 7.53 (m, 2 H), 7.70 (m, 2 H).
Example 25 3,4-Difluorobenzylamide of l-benzyl-2-ethyl-5-hydroxy-lH-indole-3-carboxylic acid (Compound 25). NMR1H (Methanol-d4) d 1.13 (t, J = 7.5 Hz, 3 H), 3.04 (q, J = 7.5 Hz, 2 H), 4.58 (s, 2 H), 5.41 (s, 2 H), 6.64 (dd,
J = 2.6, 8.8 Hz, 1 H), 6.98 (2, br d, 2 H), 7.10 (d, J = 8.8 Hz, 1 H), 7.17 (d, J = 2.2 Hz, 1 H), 7.20- 7.35 (m, 6 H).
Example 26 3- Ethoxy-benzylamide of l-benzyl-2-ethyl-5-hydroxy-lH-
Indole-3-carboxylic acid (Compound 26). NMR1H (Methanol-d4) d 1.13 (t, J = 7.5 Hz, 3 H), 3.04 (q, J = 7.5 Hz, 2 H), 3.78 (s, 3 H), 4.60 (d, J = 6.2 Hz, 2 H), 5.39 (s, 2 H), 6.64 (dd, J = 2.6, 8.8 Hz, 1 H), 6.80 (br d, 1 H), 6.98 (2br d, 4 H), 7.08 (d, 8.8 Hz, 1 H), 7.17 (d, J = 2.2 Hz, 1 H), 7.22-7.25 (m, 4 H).
Example 28 3.4-Difluorobenzamide of l-benzyl-5-hydroxy-2-isopropyl-lH-indole-3-carboxylic acid (Compound 28). RMNXH (Chloroform-d) d 1.34 (d, J = 7.0 Hz, 6 H), 3.57-3.74 (m, 1 H), 4.51 (d, J = 5.9 Hz, 2 H), 5.36 (s, 2 H) , 6.38 (t, J = 6.0 Hz, 1 H), 6.68 (dd, J = 8.8, 2.3 Hz, 1 H), 6.87-6.95 (m, 3 H), 6.97-7.05 (m, 2 H), 7.05 -7.16 (m, 2 H), 7.17-7.28 (m, 3 H).
Example 32 3.5-Difluorobenzylamide of l-benzyl-2-ethyl-5-hydroxy-lH-indole-3-carboxylic acid (Compound 32). RM 1 H (methanol-d 4) d 1.13 (t, J = 7.5 Hz, 3 H), 3.05 (q, J = 7.5 Hz, 2 H), 4.61 (s, 2 H), 5.41 (s, 2 H), 6.68 (dd, J = 2.2, 8.8 Hz, 1 H), 6.82 (m, 1 H), 7.00 (m, 4 H), 7.11 (d, J = 8.8 Hz, 1 H), 7.18-7.30 (m, "4 H).
Example 33 3, 5-Difluorobenzylamide of l-benzyl-5-hydroxy-2-isopropyl-1H-indole-3-carboxylic acid (Compound 33). RMI ^ H (Chloroform-d) d 1.39 (d, J = 7.3 Hz, 6 H), 3.65-3.79 (m, 1H), 4.68 (d, J = 6.2 Hz, 2 H), 5.42 (s, 2 H) ), 6.32 (t, J = 6.0 Hz, 6.66-6.77 (m, 2 H), 6.89-6.98 (m, 4 H), 7.01 (d, J = 8.8 Hz, 1 H), 7.13 (d, J = 2.1 Hz), 7.21-7.34 (m, 3 H).
EXAMPLE 34 L-Benzyl-5-hydroxy-2-isopropyl-1H-indole-3-carboxylic acid 3-methoxy-benzylamide (Compound 34). 1H-NMR (Cloroform-d) d 1.38 (d, J = 7.0 Hz, 6 H), 3.80 (s, 3 H), 4.67 (d, J = 5.9 Hz, 2 H), 5.39 (s, 2 H), 6.22 (t, J = 5.6 Hz, 1 H), 6.67 (dd, J = 8.6, 2.5 Hz, 1 H), 6.79-6.85 (m, 1 H), 6.89-7.02 (m, 5 H), 7.11 (d , J = 2.3 Hz, 1 H), 7.20-7.32 (m, 4 H).
Example 48 3,5-Difluorobenzylamide of l-benzyl-5-hydroxy-2-phenyl-1H-indole-3-carboxylic acid (Compound 48) RM 1H (methanol-d) d 4.39 (s, 2 H), 5.23 ( s, 2 H), 6.67 (2d, J = 8.4 Hz, 2 H), 6.79 (m, 2 H), 6.90 (2 d, 8.4 Hz, 2 H), 7.17 (d, J = 8.4 Hz, 1 H ), 7.22 (m, 3 H), 7.39-7.47 (m,
6 H). The following compounds were prepared, by the General Procedures illustrated in Reaction Schemes 2 and 3, below, from ethyl l-benzyl-2-methyl-lH-indol-3-carboxylate (Compound 57), which was synthesized as described in General Procedure 11:
Example 36 3, 5-Diflurobenzylamide of l-benzyl-2-methyl-lH-indole-3-carboxylic acid (Compound 36) R N1H (Chloroform-d) d 2.72 (s, 3 H), 4.71 (d, J = 3.9 Hz, 2 H), 5.37 (s, 2 H), 6.72 (dt, J = 2.6, 8.8 Hz, 1 H), 6.97 (br dd, 3 H), 7.19-7.30 (m, 6 H), 7.72 (d, J = 7.0 Hz, 1 H).
Example 37 3-l-Benzyl-2-methyl-lH-indole-3-carboxylic acid difluorobenzylamide (Compound 37). NMR1H (Chloroform-d6) d 2.72 (s, 3 H), 4.68 (d, J = 6.1 Hz, 2 H), 5.37 (s, 2 H), 6.33 (br s, 1 H), 6.99 (br, d 2 H), 7.14-7.30 (m, 9 H), 7.70 (d, J = 6.6 Hz, 1 H).
Example 38 3-Fluorobenzylamide of l-benzyl-2-methyl-lH-indol-3-acid
carboxylic (Compound 38) R 1 H (Chloroform-d) d 2.73 (s, 3 H), 4.73 (d, J = 5.7 Hz, 2 H), 5.37 (s, 2 H), 6.32 (br s, 1 H) , 6.99 (br, d, 3 H), 7.12-7.36 (m, 9 H), 7.72 (d, J = 6.6 Hz, 1 H).
Example 39 3-Methoxybenzylamide of l-benzyl-2-methyl-lH-indole-3-carboxylic acid (Compound 39). R N1H (Chloroform-d) d 2.72 (s, 3 H), 3.82 (s, 3 H), 4.71 (d, J = 5.8 Hz, 2 H), 5.36 (s, 2 H), 6.27 (br, s , 1H), 6.85 (dd, J = 2.4, 8.8 Hz, 1 H), 7.00 (br d, 3 H), 7.17 (m, 2 H), 7.26-7.32 (m, 6 H), 7.72 (m, 1 HOUR) .
Reaction Scheme 2
Example 50 l-Benzyl-2-methyl-5-nitro-lH-indole-3-carboxaldehyde (Compound 50). General Procedure 4. To a solution of 2-methyl-5-nitro-lH-indole-3-carboxaldehyde (500 mg, 2.45 mmol) in DMF (5 mL) was added potassium carbonate (1.0 g, 7.35 mmol) and bromide of benzyl (0.44 ml, 3.68 mmol). The mixture was stirred at room temperature for 4 hours, diluted with EtOAc, washed with H20, brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was triturated with Et20-hexane to produce l-benzyl-2-methyl-5-nitro-lH-indole-3-carboxaldehyde (Compound 50) as a yellow solid (600 mg, 83%). RM 1H (ethanol-cL,) d 2.76 (s, 3 H), 5.60 (s, 2 H), 7.04-7.11 (m, 2 H), 7.26-7.37 (m, 3 H), 7.60 (d, J = 9.1 Hz, 1 H), 8.15 (dd, J = 8.9, 2.2 Hz, 1 H), 9.11 (d, J = 2.3 Hz, 1 H), 10.20 (s, 1 H).
Example 51 l-Benzyl-2-methyl-5-nitro-lH-indole-3-carboxylic acid
(Compound 51). General Procedure 5. To a suspension of 1-benzyl-2-methyl-5-nitro-lH-indole-3-carboxaldehyde (Compound 50, 150 mg, 0.51 mmol) in acetonitrile (6 ml), tert-butanol (6 ml) ) and H20 (6 mL) was added 2-methyl-2-butene (4 mL), potassium phosphate monobasic (1.4 g, 10.2 mmol), sodium chlorite (80%, 1.15 g, 10.2 mmol). The mixture was stirred at room temperature for 20 hours, more monobasic potassium phosphate (0.35 g, 2.6 mmol) and sodium chlorite (80%, 0.29 g, 2.6 mmol) were added and stirred at room temperature for 24 hours. The solvent was removed under reduced pressure. The solid residue was washed with H20 (x3) and filtered, dissolved in acetone and filtered to yield l-benzyl-2-methyl-5-nitro-lH-indole-3-carboxylic acid (Compound 51) as a powder yellow (160 mg, 100%). RMNXH (Acetone-d6) d 2.83 (s, 3 H), 5.68 (s, 2 H), 7.06-7.15 (m, 2 H), 7.25-7.41 (m, 3 H), 7.68 (d, J = 9.1 Hz, 1 H), 8.10 (dd, J = 9.1, 2.3 Hz, 1 H), 9.11 (d, J = 2.3 Hz, 1 H).
Example 45 3, 4-Difluorobenzylamide of l-benzyl-2-methyl-5-nitro-lH-indole-3-carboxylic acid (Compound 45). The title compound was prepared from l-benzyl-2-methyl-5-nitro-lH- acid
indole-3-carboxylic acid (Compound 51) by General Procedure 3. RM 1 H (DMSO-dg) d 2.60 (s, 3 H), 4.51 (d, J = 6.2 Hz, 2 H), 5.60 (s, 2 H) ), 7.01-7.08 (m, 2 H), 7.20-7.49 (m, 6 H), 7.74 (d, J = 8.8 Hz, 1 H), 8.05 (dd, J = 9.1, 2.3 Hz, 1 H), 8.57 (t, J = 5.7 Hz, 1 H), 8.71 (d, J = 2.1 Hz, 1 H).
Example 52 N- (3,4-difluorobenzyl) -l-benzyl-5- (benzyloxy) -lH-indole-3-carboxylic acid (Compound 52). The title compound was prepared from 5- (benzyloxy) -lH-indole-3-carboxaldehyde by, in order, General Procedures 4, 5, and 3. RMSfa (ethanol-d4) d 4.53 (s, 2H), 5.11 ( s, 2 H), 5.39 (s, 2 H), 6.92 (dd, J = 9.1, 2.3 Hz, 1 H), 7.14-7.39 (m, 12 H), 7.43-7.49 (m, 2 H), 7.79 (d, J = 2.3 Hz, 1 H), 7.91 (s, 1 H).
Example 46 3, 4-Diflurobenzylamide of 5-amino-1-benzyl-2-methyl-1H-indole-3-carboxylic acid (Compound 46). General Procedure 6. To a solution of 3,4-difluorobenzylamide of l-benzyl-2-methyl-5-nitro-lH-indole-3-carboxylic acid (Compound 45), 97 mg, 0.22 mmol) in MeOH (20 ml. ) and EtOAc (20 mL) was added Pd-C (10%, 47 mg, 0.045 mmol). The reaction was stirred under hydrogen for 24 hours, filtered through Celite,
was washed with MeOH-EtOAc (1: 1) to yield 3, 4-difluorobenzylamide of 5-amino-1-benzyl-2-methyl-1H-indole-3-carboxylic acid, (Compound 46) as a white solid (93 mg, 100%). RM XH (Methanol-cW d 2.54 (s, 3 H), 4.58 (s, 2 H), 5.35 (s, 2 H), 6.69 (dd, J = 8.5, 2.1 Hz, 1 H), 6.95-7.01 ( m, 2 H), 7.12 (d, J = 8.5 Hz, 1 H), 7.16-7.36 (m, 6 H).
Example 27 3,4-Difluorobenzylamide of l-benzyl-5-hydroxy-lH-indole-3-carboxylic acid (Compound 27). The title compound was prepared from 3,4-difluorobenzylamide of l-benzyl-5- (benzyloxy) -1H-indole-3-carboxylic acid (Compound 52) by General Procedure 6. RMT ^ H (Methanol-cL ,) d 4.52 (s, 2 H), 5.36 (s, 2 H), 6.74 (dd, J = 8.8, 2.6 Hz, 1 H), 7.12-7.36 (m, 9 H), 7.54 (d, J = 2.1 Hz, 1 H), 7.86 (s, 1 H).
Example 47 3, 4-Difluorobenzylamide of 5-acetamido-1-benzyl-2-methyl-1H-indole-3-carboxylic acid (Compound 47). General Procedure 7. To a solution of 3, 4-difluorobenzylamide of 5-amino-1-benzyl-2-methyl-1H-indole-3-carboxylic acid (Compound 46, 50 mg, 0.12 mmol) in pyridine (3 ml) acetic anhydride (120 μ ?, 1.23 mmol) was added. The reaction was stirred at room temperature for 72 hours, diluted with EtOAc, washed successively with 1M HC1, H20, brine, dried over
Na 2 SO 4 and concentrated under reduced pressure. The residue was crystallized from CH2Cl2-Et20 to yield 3-acetamidoyl-benzyl-2-methyl-1H-indole-3-carboxylic acid 3-difluorobenzylamide (Compound 47) as a white solid (37 mg, 68%). . R ^ H (Methanol-cL,) d 2.13 (s, 3 H), 2.58 (s, 3 H), 4.59 (s, 2 H), 5.44 (s, 2 H), 6.96-7.04 (m, 2 H) ), 7.14-7.37 (m, 9 H), 7.99 (d, J = 2.1 Hz. 1 H).
Reaction Scheme 3
Example 53 5-Benzyloxy-2-methyl-lH- ethyl ester
Indole-3-carboxylic acid (Compound 53). General Procedure 8. To a mixture of 5-hydroxy-2-methyl-1H-indole-3-carboxylic acid ethyl ester (0.76 g, 3.47 mmol) and potassium carbonate
(0.92 g, 6.67 mmol) in acetonitrile (10 mL) was added benzyl bromide (1.0 mL, 1.4 g, 8.4 mmol). The mixture was heated at 75-80 ° C for 18 hours. The reaction was cooled to room temperature, quenched with water, extracted with EtOAc, washed with brine, dried over Na 2 SO 4 and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (30% EtOAc-hexanes) to yield the 5-benzyloxy-2-methyl-1H-indole-3-carboxylic acid ethyl ester (Compound 53) as a solid. yellow (0.56 g, 52%). NMR1H (Methanol-d4) d 1.39 (t, J = 7.0 Hz, 3 H), 2.64
(s, 3 H), 4.32 (q, J = 7.0 Hz, 2 H), 5.10 (s, 2 H), 6.84 (d, J = 2.2, 8.8 Hz, 1 H), 7.20 (d, J = 8.8 Hz, 1 H), 7.23-7.40
(m, 5 H), 7.45 (2 br d, 2 H), 7.58 (d, 2.2 Hz, 1 H).
Example 54 5-Benzyloxy-2-methyl-1-phenyl-1H-indole-3-carboxylic acid ethyl ester (Compound 54) General Procedure 9. To a mixture of 5-benzyloxy-2-methyl-1H ethyl ester -indole-3-carboxylic acid (Compound 53, 0.14 g, 0.45 mmol) in toluene (6 mL) which has been degassed under argon for 15 minutes, added 2-
iodine-benzene (0.10 ml, 0.48 g, 0.88 mmol), potassium phosphate
(0.20 g, 0.94 mmol), copper (I) iodide (24 mg, 0.13 mmol) and then N, N '-dimethylethylenediamine (12 mg, 0.14 mmol) with continuous degassing. The tube was then sealed and the mixture was heated at 140 ° C for 24 hours. The reaction was then cooled and filtered. The filtrate was concentrated under reduced pressure and the residue of the crude product was purified by flash column chromatography on silica gel.
(30% EtOAc-hexanes) to produce the 5-benzyloxy-2-methyl-1-phenyl-1H-indole-3-carboxylic acid ethyl ester
(Compound 54) as an orange oil (0.13 g, 76%). MNXH (Chloroform-d) d 1.44 (t, J = 7.0 Hz, 3 H), 2.57 (s, 3 H), 4.42 (q, J = 7.0 Hz, 2 H), 5.16 (s, 2 H), 6.86
(dd, J = 2.7, 8.8 Hz, 1 H), 6.92 (d, J = 8.8 Hz, 1 H), 7.25-7.41 (m, 5 H), 7.48-7.60 (m, 5 H), 7.78 (d) , J = 2.7 Hz, 1 H).
Example 55 5-Benzyloxy-2-methyl-1-phenyl-1H-indole-3-carboxylic acid (Compound 55). The title compound was prepared from 5-benzyloxy-2-methyl-1-phenyl-1H-indole-3-carboxylic acid ethyl ester (Compound 54) by General Procedure 2. RMNXH (Methanol-d4) d 2.60 (s) , 3 H), 5.12 (s, 2 H), 6.84 (dd, J = 2.6, 8.8 Hz, 1 H), 6.90 (d, J = 8.8 Hz, 1 H), 7.26-7.63 (m,
H), 7.77 (d, J = 2.6 Hz, 1 H).
Example 56 3, 4-Difluorobenzylamide of 5-benzyloxy-2-methyl-1-phenyl-1H-indole-3-carboxylic acid (Compound 56). The title compound was prepared from 5-benzyloxy-2-methyl-1-phenyl-1H-indole-3-carboxylic acid (Compound 55) by General Procedure 3. RMt H (Methanol-d4) d 2.44 (s, 3 H), 4.60 (s, 2 H), 5.10 (s, 2 H), 6.85 (dd, J = 2.2, 8.8 Hz, 1 H), 6.90 (d, J = 8.8 Hz, 1 H), 7.21- 7.45 (m, 8 H), 7.54-7.66 (m, 3 H).
Example 29 3, 4-Difluorobenzylamide of 5-hydroxy-2-methyl-1-phenyl-1H-indole-3-carboxylic acid (Compound 29). General Procedure 10. To a mixture of 3-4-difluorobenzylamide of 5-benzyloxy-2-methyl-1-phenyl-1H-indole-3-carboxylic acid (Compound 56, 0.15 g, 0.31 mmol) in methanol (15 ml) , which was degassed with argon for 10 minutes, 10% palladium on carbon (0.17 g) was added, with continuous degassing. The reaction was placed in an even tube in the hydrogenator and hydrogenated at 45 psi for 18 hours. The reaction was then filtered, concentrated under reduced pressure and the residue of the crude product was purified by flash column chromatography on silica gel (30% EtOAc-hexanes) to yield 3.4-
-hydroxy-2-methyl-1-phenyl-β-indole-3-carboxylic acid difluorobenzylamide (Compound 29) as a solid (0.11 g, 92%) · RMNXH (Methanol-d4) d 2.42 (s, 3 H), 4.59 (s, 2 H), 6.66 (dd, J = 2.2, 8.8 Hz, 1 H), 6.82 (d, J = 8.8 Hz, 1 H), 7.21-7.26 (m, 3 H), 7.30 -7.40 (m, 3 H), 7.53-7.65 (m, 3 H).
Example 30 3, 4-Difluorobenzylamide of 5-hydroxy-2-methyl-l-pyridin-2-yl-lH-indole-3-carboxylic acid (Compound 30). The compound was prepared from 2-iodo-pyridine by following, in order, General Procedures 8, 9, 2, 3 and 10. RMt ^ H (Methanol-cL?) D 2.51 (s, 3 H), 4.59 (s) , 2 H), 6.70 (dd, J = 2.6, 8.8 Hz, 1 H), 7.03 (d, J = 8.8 Hz, 1 H), 7.20-7.26 (m, 3 H), 7.33 (m, 1 H) , 7.55 (m, 2 H), 8.10 (dt, J = 2.2, 8.8 Hz, H), 8.65 (dd, J = 2.2, 5.7 Hz, 1 H).
Example 31 3, 4-Diflurobenzylamide of 5-hydroxy-2-methyl-1-thiophen-2-yl-lH-indole-3-carboxylic acid (Compound 31). The title compound was prepared from 2-iodothiophene by following, in order, General Procedures 8, 9, 2, 3 and 10. RM 1 H (Methanol-d 4) d 2.45 (s, 3 H), 4.58 (s, 2 H),
6. 70 (dd, J = 2.6, 8.8 Hz, 1 H), 6.94 (d, J = 8.8 Hz, 1 H),
7. 12 J = 1.3, 3.5 Hz, 1 H), 7.16-7.46 (m, 5 H), 7.55 (dd, J = 1.4, 5.7 Hz, 1 H).
Example 35 3,5-Difluorobenzylamide of 5-methoxy-2-methyl-1-phenyl-1H-indole-3-carboxylic acid (Compound 35). The title compound was prepared from methyl iodide by following, in order General procedures 8, 9, 2 and 3. RMNXH (Chloroform-d) d 2.55 (s, 3 H), 3.85 (s, 3 H) , 4.72 (d, J = 6.1 Hz, 2 H), 6.25 (br s, 1 H), 6.73 (m, 1 H), 6.80 (dd, J = 2.2, 8.8 Hz, 1 H), 6.97 (2d, J = 8.8 Hz, 3 H), 7.26-7.33 (m, 3 H), 7.51-7.60 (m, 3 H).
Example 40 3,5-Difluorobenzylamide of 5-methoxy-1,2-dimethyl-1H-indole-3-carboxylic acid (Compound 40). The title compound was prepared from methyl iodide by following, in order, General Procedures 8, 9, 2 and 3. RMN1H (Chloroform-d) d 2.73 (s, 3 H), 3.69 (s, 3 H), 3.84 (s, 3 H), 4.69 (d, J = 6.1 Hz, 2 H), 6.19 (br s, 1 H), 6.71 (dt, J = 2.2, 8.8 Hz, 1 H), 6.91 (dd, J = 2.2, 8.8 Hz, 1 H), 6.95 (br, d, 2 H), 7.19 (d, J = 2.2 Hz, 1 H), 7.21-7.26 (m, 1 H).
Example 41 3-Fluorobericilamide of 5-methoxy-1,2-dimethyl-1H-indole-3-carboxylic acid (Compound 41). The title compound was prepared from methyl iodide by following, in order, General Procedures 8, 9, 2 and 3. RMI ^ H (Chloroform-d) d 2.73 (s, 3 H), 3.68 (s, 3 H) ), 3.81 (s, 3 H), 4.71 (d, J = 6.1 Hz, 2 H), 6.15 (br s, 1 H), 6.87 (dd, J = 2.2, 8.8 Hz, 1 H), 6.97 (m , 2 H), 7.13 (2 br d, 1 H), 7.18 (d, J = 2.6 Hz, 1 H), 7.22 (d, J = 8.4 Hz, 2 H).
Example 49 3, 4-Difluorobenzylamide of 5-benzyloxy-2-methyl-1-pyridin-2-yl-1H-indole-3-carboxylic acid (Compound 49). The title compound was prepared from 2-iodopyridine by following, in order, general procedures 8, 9, 2 and 3. R NXH (Chloroform-d) d 2.52 (s, 3 H), 4.60 (s, 2 H) , 5.10 (s, 2 H), 6.89 (dd, J = 2.6, 8.8 Hz, 1 H), 7.10 (d, J = 8.8 Hz, 1 H), 7.21-7.45 (m, 6 H), 7.55 (2 br d, 2 H), 8.10 (dt, J = 2.2, 7.9 Hz, 1 H), 8.65 (m, 1 H).
Reaction Scheme 4
Example 57 L-benzyl-2-methyl-lH-indole-3-carboxylic acid ethyl ester (Compound 57). General Procedure 11.- To a mixture of sodium hydride (0.28 g, 60% in mineral oil, 0.17 g, 7.0 mmol) in 10 ml of tetrahydrofuran stirring at 0 ° C under argon, 2-methyl ethyl ester was added. -IH-indole-3-carboxylic acid (1.17 g, 5.8 mmol) and the solution was stirred at 0 ° C for 15 minutes. Then benzyl bromide (0.80 ml, 1.15 g, 6.7 mmol) was added and the reaction was allowed to warm to room temperature and stirred for 24 hours. The reaction was cooled to 0 ° C, quenched with water, extracted with EtOAc, washed with brine, dried over a2SO4, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (40% EtOAc-hexane) to produce 1-benzyl-2-methyl-1H-indole-3-carboxylic acid ethyl ester (Compound 57) as a light brown color (1.13 g, 67%). RMT ^ H (Chloroform-d) d 1.46 (t, J = 7.0 Hz, 3H), 2.73 (s, 3H), 4.42 (q, J = 7.0 Hz, 2H), 5.36 (s, 2H), 6.97 (dd) , J = 2.1, 8.8 Hz, 2H), 7.15-7.30 (m, 6H), 8.17 (d, J = 8.5 Hz, 1H).
EXAMPLE 42 3,4-Difluorobenzylamide of 2-methyl-1-thiophen-2-ylmethyl-1H-indole-3-carboxylic acid (Corrigendum 42) .- The title was prepared from 2-bromomethylthiophene by following, in order, the Procedures General 11, 2 and 3. RMN ^ H (Chloroform-d) d 2.81 (s, 3H), 4.66 (s, 2H), 5.49 (s, 2H), 6.29 (br s, 1H), 6.83 (br d, 1H), 6.91 (m, 1H), 7.12-7.26 (m, 4H), 7.42 (m, 2H), 7.68 (m, 2H).
EXAMPLE 43 2-Methyl-1-thiophen-2-ylmethyl-1H-indole-3-carboxylic acid 3-methoxy-benzylamide (Code 43) .- the title compound was prepared from 2-bromomethylthiophene by following, in order, the Procedures General 11, 2 and 3. RMr ^ H (Chloroform-d) d 1.56 (s, 3H), 2.81 (s, 2H), 3.81 (s, 3H), 4.69 (d, J = 5.7 Hz, 1H), 5.48 (s, 2H), 6.25 (br t, 1H), 6.72 (dd, J = 2.6, 8.8 Hz, 1H), 6.88-6.95 (m, 3H), 7.00 (d, J = 8.0 Hz, 1H), 7.14 (d, J = 2.2 Hz, 1H), 6.84 (br d, 2H), 6.91 (m, 1H), 6.99 (m, 2H), 7.17-7.22 (m, 3H), 7.30 (d, J = 8.0 Hz , 1H), 7.39 (d, J = 7.0 Hz, 1H), 7.68 (d, J = 2.2 Hz, 1H).
Example 44 3.5-Difluorobenzylamide of 2-methyl-1-thiophen-2-ylmethyl-1H-indole-3-carboxylic acid (Corpro 44) .- The title was prepared from 2-bromomethylthiophene by following, in order, the
general procedures 11, 2 and 3. RN¾ (Methanol-cW d 2.63 (s, 3H), 4.58 (s, 2H), 5.53 2H), 6.72 (dd, J = 2.6, 8.8 Hz, 1H), 6.91 (2 br) d, 2H), 7.06 (t, J = Hz, 2H), 7.15 (d, J = 2.2 Hz, 1H), 7.25 (dd, J = 4.0, 6.6 Hz, 1H), 7 (d, J = 8.8 Hz , 1H), 7.35 (dd, J = 13.6, 8.4 Hz, 2H).
Reagents and conditions: (i) BnBr, K2C03, DMF; (ii) MeLi,
(iii) H2, Pd-C, EtOAc, EtOH, HCl-Et20; (iv) POCl3, D F; (v) NaC102, KH2PO4, isobutene, t-BuOH, CH3CN, H20; (vi) 3,4-difluorobenzylamine, EDC, DMAP, CH2C12; (vii) BBr3, CH2C12;
(viii) RX, K2C03, DMF; (ix) RCOC1, pyridine; (x) MOMC1, i-Pr2NEt, CH2C12; (xi) 2, 3-dihydrofuran, PPTS, CH2C12.
Example 102 Methyl l-Benzyl-6-methoxy-lH-indole-2-carboxylate (Compound 102). To a solution of methyl 6-methoxy-lH-indole-2-carboxylate (Compound 101 or Compound 1, Reaction Scheme 5), 1.0 g, 4.9 mmol) in DMF (10 mL) was added K2C03 (2.0 g, 14.6 mmol) and benzyl bromide (0.87 ml, 7.3 mmol). The mixture was stirred at room temperature for 40 hours and diluted with EtOAc, washed with H20, brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by crystallization from Et20 to produce the title compound as an off-white solid. NMR1H (500 MHz, Chloroform-d) d ppm 3.81 (s, 3H), 3.85 (s, 3H), 5.81 (s, 2H), 6.73 (d, J = 2.0 Hz, 1H), 6.84 (dd, J = 8.8, 2.0 Hz, 1H), 7.07 (d, J = 6.8 Hz, 2H), 7.19-7.29 (m, 3H), 7.33 (s, 1H), 7.58 (d, J = 8.8 Hz, 1H).
Example 103 2- (l-Benzyl-6-methoxy-lH-indol-2-yl) propan-2-o1 (Compound 103) .- To a solution of l-benzyl-6-methoxy-lH-
Methyl indole-2-carboxylate (Compound 102, 4.33 g, 14.7 mmol) in THF (50 ml) at 0 ° C under argon was added MeLi (3.0 M in diethoxymethane, 19.6 ml, 58.7 mmol) slowly. After 1 hour, the ice-water bath was stirred and the reaction was stirred at room temperature for 1 hour, cooled to -78 ° C, quenched with dry ice, diluted with EtOAc, washed with H20, brine , dried over Na2SO4, concentrated in vacuo to yield the crude title compound as a yellow solid. RMt ^ H (500 MHz, Chloroform-d) d ppm 1.69 (s, 3H),
3. 73 (s, 3 H), 5.76 (s, 2H), 6.42 (s, 1H), 6.55 (d, J = 2.4 Hz, 1H), 6.75-6.81 (m, 1H), 6.96 (d, J = 7.3 Hz, 2H), 7.22 (d, J = 7.3 Hz, 1H), 7.25-7.30 (m, 2H), 7.49 (d, J = 8.8 Hz, 1H).
EXAMPLE 104 l-Benzyl-2-isopropyl-6-methoxy-lH-indole (Compound 104). To a solution of 2- (1-benzyl-6-methoxy-1H-indol-2-yl) propan-2-ol (Compound 103, 1.05 g, 3.57 mmol) in EtOAc (35 mL) and EtOH (15 mL) was added. 10% Pd-C (190 mg, 0.18 mmol) and HCl-Et20 (1.0 M, 1.25 mL, 1.25 mmol). The mixture was stirred under hydrogen gas (atmospheric pressure) for 1 hour and filtered. To the filtrate was added NaHCO3 (0.5 g,) and H20 (0.5 ml), followed by NaSO4 and MgSO4. This was then filtered and concentrated in vacuo to yield the crude title compound as a yellow solid.
NMR1H (300 MHz, Chloroform-d) d ppm 1.31 (d, J = 6.7 Hz, 6H), 2.90-3.10 (m, 1H), 3.79 (s, 3H), 5.33 (s, 2H), 6.33 (s, 1H), 6.68 (d, J = 2.1 Hz, 1H), 6.79 (dd, J = 8.5, 2.3 Hz, 1H), 6.94-7.04 (m, 2H), 7.20-7.37 (m, 2H), 7.49 (d , J = 8.5 Hz, 1H).
Example 105 l-Benzyl-2-isorpopil-6-methoxy-lH-indole-3-carbaldehyde (Compound 105). POCl3 (0.48 mL, 5.23 mmol) was added to anhydrous DMF (2 mL) at 0 ° C under argon. After stirring for 30 minutes, this solution was added dropwise to a solution of l-benzyl-2-isopropyl-6-methoxy-1H-indole
(Compound 104, 583 mg, 2.09 mmol) in anhydrous DMF (8 mL) at 0 ° C under argon. The reaction was stirred for 1 hour at 0 ° C and 30 minutes at room temperature, diluted with EtOAc, washed with aqueous NaHCO3, brine, dried over Na2SC > 4, and concentrated in vacuo. The residue was purified by chromatography on silica gel (0 30% EtOAc-hexane) to yield the title compound as a light yellow syrup. RMIS ^ H (500 Hz, Chloroform-d) d ppm 1.45 (d, J = 7.3
Hz, 6H), 3.40-3.52 (m, 1H), 3.79 (s, 3H), 5.40 (s, 2H), 6.69 (d, J = 2.4 Hz, 1H), 6.94 (dd, J = 8.8, 2.0 Hz , 1H), 7.01 (d, J = 7.3 Hz, 2H), 7.25-7.35 (m, 3H), 8.28 (d, J = 8.8 Hz, 1H), 10.45 (s, 1H).
Example 106 l-Benzyl-2-isopropyl-6-methoxy-lH-indole-3-carboxylic acid (Compound 106) .- To a solution of l-benzyl-2-isopropyl-6-methoxy-lH-indol-3 carbaldehyde (Compound 105, 608 mg, 1.98 mmol) in t-BuOH (15 mL), CH3CN (15 mL), and 2-methyl-2-butene (10 mL) was added a solution of KH2P04 (5.4 g, 39.6 mmol. ) and NaC102 (80%, 4.5 g, 39.6 mmol) in H20 (50 mL). The mixture was stirred at room temperature and 2-methyl-2-butene, KH2P04 and additional NaC102 were added to the above ratio every 16-24 hours until the starting material was consumed. The reaction mixture was extracted with EtOAc (x3) and the combined organic layer was washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by chromatography on silica gel (0-25% EtOAc-hexane) to give the title compound as a yellow solid. RMN1! -! (500 MHz, Chloroform-d) d ppm 1.39 (d, J = 7.3 Hz, 6H), 3.75 (s, 3H), 3.99-4.17 (m, 1H), 5.45 (s, 2H), 6.62 (d, J = 2.4 Hz, 1H), 6.90 (dd, J = 8.8, 2.4 Hz, 1H), 6.99 (d, J = 7.3 Hz, 2H), 7.22-7.34 (m, 3H), 8.18 (d, J = 8.8 Hz , 1 HOUR) .
Example 107 1-Benzyl-N- (3,4-difluorobenzyl) -2-isopropyl-6-methoxy-1H-indole-3-carboxamide (Compound 107). To a solution of l-benzyl-2-isopropyl-6-methoxy-lH-indole-3-carboxylic acid (Compound 106, 226 mg, 0.70 mmol) in CH2C12 (7.0 ml) was
added EDC (202 mg, 1.05 mmol) and DMAP (128 mg, 1.05 mmol) followed by 3,4-difluorobenzylamine (0.25 mL, 2.1 mmol). The reaction was stirred at room temperature for 18 hours, diluted with EtOAc, washed with H20, brine, dried over a2SO4 and concentrated in vacuo. The residue was purified by chromatography on silica gel (0 30% EtOAc-hexane) to give the title compound as a yellow solid. RMIN ^ H (500 MHz, Chloroform-d) d ppm 1.37 (d, J = 7.3 Hz, 6H), 3.65-3.73 (m, 1H), 3.74 (s, 3H), 4.66 (d, J = 5.9 Hz, 2H), 5.40 (s, 2H), 6.30 (t, J = 6.3 Hz, 1H), 6.63 (d, J = 2.0 Hz, 1H), 6.82 (dd, J = 8.8, 2.4 Hz, 1H), 6.96 ( d, J = 6.8 Hz, 2H), 7.11-7.17 (m, 2H), 7.21-7.31 (m, 4H), 7.51 (d, J = 8.3 Hz, 1H).
Example 108 1-Benzyl-N- (3,4-difluorobenzyl) -6-hydroxy-2-isopropyl-1H-indole-3-carboxamide (Compound 108). To a solution of 1-benzyl-N- (3,4-difluorobenzyl) -2-isopropyl-6-methoxy-1H-indole-3-carboxamide (Compound 107, 452 mg, 1.0 mmol) in CH2C12 (20 mL) a 0 ° C BBr 3 (1.0 M in CH 2 Cl 2, 3.0 mL, 3.0 mmol) was added dropwise. The reaction was stirred for 1 hour at 0 ° C and one hour at room temperature, quenched with ice, extracted with EtOAc, the organic layer was washed with brine, dried over NaSO4, and concentrated in vacuo. The residue was purified by gel chromatography of
silica (0-50% EtOAc-hexane) to give the title compound as a yellow solid. R N1H (500 MHz, Chloroform-d) d ppm 1.37 (d, J = 7.3
Hz, 6H), 3.65-3.74 (m, 1H), 4.66 (d, J = 5.9 Hz, 2H), 4.78 (s, 1H), 5.37 (s, 2H), 6.27 (t, J = 5.6 Hz, 1H ), 6.60 (d, J = 2.4
Hz, 1H), 6.71 (dd, J = 8.5, 2.2 Hz, 1H), 6.95 (d, J = 6.8 Hz,
2H), 7.11-7.17 (m, 2H), 7.21-7.32 (m, 4H), 7.46 (d, J = 8.8 Hz, 1H).
Example 109 1-Benzyl-N- (3, -difluorobenzyl) -6-ethoxy-2-isopropyl-1H-indole-3-carboxamide (Compound 109). General Procedure A. To a solution of 1-benzyl-N- (3,4-difluorobenzyl) -6-hydroxy-2-isopropyl-1H-indole-3-carboxamide (Compound 108, 40 mg, 0.092 mmol) in DMF ( 2.0 ml) was added K2C03 (39 mg, 0.28 mmol) and iodoethane (22 μ ?, 0.28 mmol). The reaction was stirred at room temperature for 48 hours, diluted with EtOAc, washed with H20, brine, dried over Na2SC >4 and concentrated in vacuo. The residue was purified by PTLC on silica gel (30% EtOAc-hexane) to yield the title compound as an off-white solid. RM ^ H (500 MHz, Chloroform-d) d ppm 1.37 (t, J = 7.0 Hz, 3H), 1.38 (d, J = 7.3 Hz, 6H), 3.68-3.75 (m, 1H), 3.96 (q, J = 7.0 Hz, 2H), 4.67 (d, J = 6.3 Hz, 2H), 5.40 (s, 2H), 6.31 (t, J = 5.4 Hz, 1H), 6.64 (d, J = 2.4 Hz, 1H) , 6.82 (dd, J =
8. 8, 2.0 Hz, 1H), 6.97 (d, J = 6.8 Hz, 2H), 7.13-7.17 (m, 2H), 7.23-7.31 (m, 4H), 7.52 (d, J = 8.3 Hz, 1H).
Example 110 1-Benzyl-N- (3,4-difluorobenzyl) -2-isopropyl-6-propoxy-1H-indole-3-carboxamide (Compound 110). Following General A procedure, 1-benzyl-N- (3,4-difluorobenzyl) -6-hydroxy-2-isopropyl-1H-indole-3-carboxamide (Compound 108, 8.0 mg, 0.018 mmol) in DMF was reacted (1.0 ml) with K2C03 (8.0 mg, 0.055 mmol) and 1-iodopropane (9.0 μ ?, 0.092 mmol) to yield the title compound as a white solid. RM ^ H (500 MHz, Methanol-d4) d ppm 0.99 (t, J = 7.6 Hz, 3H), 1.32 (d, J = 7.3 Hz, 6H), 1.67-1.77 (m, 2H), 3.42-3.53 ( m, 1H), 3.84 (t, J = 6.6 Hz, 2H), 4.57 (s, 2H), 5.46 (s, 2H), 6.73 (d, J = 2.0 Hz, 1H), 6.78 (dd, J = 8.8 , 2.4 Hz, 1H), 6.95 (d, J = 6.8 Hz, 2H), 7.19-7.29 (m, 5H), 7.30-7.36 (m, 1H), 7.49 (d, J = 8.3 Hz, 1H).
Example 111 1-Benzyl-N- (3,4-difluorobenzyl) -6-isopropoxy-2-isopropyl-1H-indole-3-carboxamide (Compound 111). Following General Procedure A, 1-benzyl-N- (3,4-difluorobenzyl) -6-hydroxy-2-isopropyl-1H-indole-3-carboxamide (Compound 108, 8.0 mg, 0.018 mmol) in DMF was reacted (1.0 ml) with K2C03 (8.0 mg, 0.055 mmol) and 2-iodopropane (9.0 μ ?, 0.092 mmol) for
produce the title compound as a white solid. R N1H (500 MHz, Methanol-d4) d ppm 1.21 (d, J = 5.9 Hz, 6H), 1.33 (d, J = 7.3 Hz, 6H), 3.45-3.55 (m, 1H), 4.41-4.50 (m , 1H), 4.57 (s, 2H), 5.46 (s, 2H), 6.72 (d, J = 2.0 Hz, 1H), 6.74-6.79 (m, 1H), 6.96 (d, J = 7.3 Hz, 2H) , 7.18-7.29 (m, 5H), 7.30-7.37 (m, 1H), 7.49 (d, J = 8.8 Hz, 1H).
Example 112 l-Benzyl-6-butoxy-N- (3,4-difluorobenzyl) -2-isopropyl-1H-indole-3-carboxamide (Compound 112). Following General Procedure A, 1-benzyl-N- (3,4-difluorobenzyl) -6-hydroxy-2-isopropyl-1H-indole-3-carboxamide (Compound 108, 10.7 mg, 0.025 mmol) in DMF was reacted (1.0 ml) with K2CO3 (10.0 mg, 0.074 mmol) and 1-iodobutane (14.0 μ ?, 0.12 mmol) to yield the title compound as a white solid. NMR1H (500 MHz, Chloroform-d) d ppm 0.93 (t, J = 7.3 Hz, 3H), 1.37 (d, J = 7.3 Hz, 6H), 1.40-1.50 (m, 2H), 1.66-1.74 (m, 2H), 3.61-3.75 (m, 1H), 3.88 (t, J = 6.6 Hz, 2H), 4.66 (d, J = 6.3 HZ, 2H), 5.39 (s, 2H), 6.30 (t, J = 5.9 Hz, 1H), 6.63 (d, J = 2.0 Hz, 1H), 6.81 (dd, J = 8.5, 2.2 Hz, 1H), 6.96 (d, J = 6.8 Hz, 2H), 7.10-7.17 (m, 2H ), 7.21-7.32 (m, 4H), 7.50 (d, J = 8.8 Hz, 1H).
Example 113 1-Benzyl-N- (3,4-difluorobenzyl) -6-isobutoxy-2-
isopropyl-lH-indole-3-carboxamide (Compound 113). Following General Procedure A, 1-benzyl-N- (3,4-difluorobenzyl) -6-hydroxy-2-isopropyl-1H-indole-3-carboxamide (Compound 108, 10.7 mg, 0.025 mmol) in DMF was reacted (1.0 ml) with K2CO3 (10.0 mg, 0.074 mmol) and 2-iodobutane (14.0 μ ?, 0.12 mmol) to yield the title compound as a white solid. NMR ^ H (500 MHz, Chloroform-d) d ppm 0.98 (d, J = 6.8 Hz, 6H), 1.36 (d, J = 7.3 Hz, 6H), 1.96-2.08 (m, 1H), 3.65 (d, J = 6.8 Hz, 2H), 3.65-3.72 (m, 1H), 4.66 (d, J = 6.3 Hz, 2H), 5.39 (s, 2H), 6.29 (t, J = 5.6 Hz, 1H), 6.63 ( d, J = 2.0 Hz, 1H), 6.82 (dd, J = 8.8, 2.0 Hz, 1H), 6.96 (d, J = 6.8 Hz, 2H), 7.11-7.16 (m, 2H), 7.21-7.31 (m , 4H), 7.50 (d, J = 8.8 Hz, 1H).
Example 114 1-Benzyl-N- (3,4-difluorobenzyl) -6- (hexoxy) -2-isopropyl-1H-indole-3-carboxamide (Compound 114). Following General Procedure A, 1-benzyl-N- (3,4-difluorobenzyl) -6-hydroxy-2-isopropyl-1H-indole-3-carboxamide (Compound 108, 10.7 mg, 0.025 mmol) in DMF was reacted (1.0 ml) with K2C03 (10.0 mg, 0.074 mmol) and 1-iodohexane (18.0 μ ?, 0.12 mmol) to yield the title compound as a white solid. RM 1H (500 MHz, Chloroform-d) d ppm 0.85-0.93 (m, 3H), 1.24-1.33 (m, 4H), 1.37 (d, J = 6.8 Hz, 6H), 1.38-1.46 (m, 2H) , 1.66-1.77 (m, 2H), 3.63-3.75 (m, 1H), 3.87 (t, J =
6. 6 Hz, 2H), 4.66 (d, J = 5.9 Hz, 2H), 5.39 (s, 2H), 6.30 (t, J = 5.6 Hz, 1H), 6.63 (d, J = 2.4 Hz, 1H), 6.81 (dd, J = 8.8, 2.4 Hz, 1H), 6.96 (d, J = 6.8 Hz, 2H), 7.10-7.16 (m, 2H), 7.21-7.31 (m, 4H), 7.50 (d, J = 8.8 Hz, 1H).
Example 115 L-Benzyl-6- (benzyloxy) -N- (3,4-difluorobenzyl) -2-isopropyl-1H-indole-3-carboxamide (Compound 115). Following General Procedure A, 1-benzyl-N- (3,4-difluorobenzyl) -6-hydroxy-2-isopropyl-1H-indole-3-carboxamide (Compound 108, 10.7 mg, 0.025 mmol) in DMF was reacted (1.0 ml) and acetone (1.0 ml) with K2CO3 (10.0 mg, 0.074 mmol), benzyl bromide (14.0 μ ?, 0.12 mmol), and catalytic amount of Nal to produce the title compound as an off-white solid. NMR1H (500 MHz, Chloroform-d) d ppm 1.37 (d, J = 7.3 Hz, 6H), 3.65-3.75 (m, 1H), 4.66 (d, J = 6.3 Hz, 2H), 4.99 (s, 2H) , 5.37 (s, 2H), 6.28 (t, J = 6.3 Hz, 1H), 6.71 (d, J = 2.0 Hz, 1H), 6.89 (dd, J = 8.8, 2.0 Hz, 1H), 6.95 (d, J = 6.8 Hz, 2H), 7.11-7.18 (m, 2H), 7.22-7.30 (m, 5H), 7.31-7.39 (m, 4H), 7.51 (d, J = 8.8 Hz, 1H).
Example 116 l-Benzyl-6- (cyclopentoxy) -N- (3,4-difluorobenzyl) -2-isopropyl-1H-indole-3-carboxamide (Compound 116). Following the
General Procedure A, 1-benzyl-N- (3, -difluorobenzyl) -6-hydroxy-2-isopropyl-1H-indole-3-carboxamide (Compound 108, 40 mg, 0.092 mmol) in DMF (1.0 ml) was reacted ) with K2C03 (38 mg, 0.28 mmol), cyclopentyl iodide (53 μ ?, 0.46 mmol) to yield the title compound as a white solid. RM 1H (300 MHz, Chloroform-d) d ppm 1.37 (d, J = 7.0 Hz, 6H), 1.48-1.60 (m, 2H), 1.66-1.86 (m, 6H), 3.62-3.83 (m, 1H) , 4.56-4.77 (m, 3H), 5.38 (s, 2H), 6.32 (t, J = 5.9 Hz, 1H), 6.61 (d, J = 2.1 Hz, 1H), 6.78 (dd, J = 8.8, 2.1 Hz, 1H), 6.91-7.02 (m, 2H), 7.08-7.17 (m, 2H), 7.17-7.36 (m, 4H), 7.49 (d.J = 8.5 Hz, 1H).
Example 117 1-Benzyl-N- (3,4-difluorobenzyl) -2-isopropyl-6- (2-methoxyethoxy) -lH-indole-3-carboxamide (Compound 117). Following General Procedure A, 1-benzyl-N- (3,4-difluorobenzyl) -6-hydroxy-2-isopropyl-1H-indole-3-carboxamide (Compound 108, 17 mg, 0.039 mmol) in DMF was reacted (1.0 ml), with K2CO3 (28 mg, 0.20 mmol), 2-bromoethyl methyl ether (18 μl, 0.20 mmol) to yield the title compound (9 mg, 49%). NMR1H (300 MHz, CDC13) d ppm 1.37 (d, J = 7.04Hz, 6H), 3.40 (s, 3H), 3.60-3.78 (m, 3H), 4.04 (dd, J = 5.42, 3.96 Hz, 2H) , 4.66 (d, J = 5.86 Hz, 2H), 5.39 (s, 2H), 6.30 (t, J = 5.86 Hz, 1H), 6.68 (d, J = 2.35 Hz, 1H), 6.85 (dd, J = 8.65,
Hz, 1H), 6.89-7.01 (m, 2H), 7.10-7.18 (m, 2H), 7.17-7.35, 4H), 7.51 (d, J = 8.79 Hz, 1H).
EXAMPLE 118 1-Benzyl-N- (3,4-difluorobenzyl) -6- (2- (dimethylamino) -ethoxy) -2-isopropyl-1H-indole-3-carboxamide (Compound 118). Following General Procedure A, 1-benzyl-N- (3, -difluorobenzyl) -6-hydroxy-2-isopropyl-1H-indole-3-carboxamide (Compound 108, 17 mg, 0.039 mmol) was reacted in DMF ( 1.0 ml) with K2CO3 (28 mg, 0.20 mmol), 2-dimethylamino-ethyl chloride hydrochloride (20 mg, 0.20 mmol) to yield the title compound (10 mg, 53%). RM 1 H (300 MHz, CD 3 OD) d ppm 1.32 (d, J = 7.04 Hz, 6H), 2.30 (s, 6H), 2.71 (t, J = 5.42 Hz, 2H), 3.37-3.59 (m, 1H), 4.02 (t, J = 5.42 Hz, 2H), 4.57 (s, 2H), 5.48 (s, 2H), 6.73-6.88 (m, 2H), 6.89-7.02 (m, 2H), 7.12-7.40 (m, 6H), 7.50 (d, J = 8.50 Hz, 1H).
Example 119 1-Benzyl-N- (3,4-difluorobenzyl) -2-isopropyl-6- (tetrahydrofuran-3-yloxy) -lH-indole-3-carboxamide (Compound 119), To a solution of 1-benzyl N- (3,4-difluorobenzyl) -6-hydroxy-2-isopropyl-1H-indole-3-carboxamide (Compound 108, 8 mg, 0.039 mmol) in DMF (1.0 ml) was added K2C03 (13 mg, 0.092 mmol ) and catalytic amount of NaOH, 3-
iodohydrofuran (Compound 29, 120 mg, crude). The reaction was stirred at room temperature for 2 days, and purified by short column of silica gel to yield the title compound (8 mg, 86%). NMR1H (300 MHz, CDC13) d ppm 1.38 (d, J = 7.04 Hz,
6H), 1.95-2.14 (m, 2H), 3.59-4.01 (m, 5H), 4.66 (d, J = 6.16 Hz, 2H), 4.74-4.88 (m, 1H), 5.39 (s, 2H), 6.29 (t, J = 4.40 Hz, 1H), 6.57 (d, J = 2.05 Hz, 1H), 6.69-6.83 (m, 1H), 6.96 (d, J = 7.62 Hz, 2H), 7.08-7.19 (m, 2H), 7.18-7.35 (m, 4H), 7.51 (d, J = 8.79 Hz, 1H).
Example 120 1-Benzyl-N- (3,4-difluorobenzyl) -2-isopropyl-6- (2-oxotetrahydrofuran-3-yloxy) -lH-indole-3-carboxamide (Compound 120). Following General Procedure A, 1-benzyl-N- (3,4-difluorobenzyl) -6-hydroxy-2-isopropyl-1H-indole-3-carboxamide (Compound 108, 19 mg, 0.044 mmol) in DMF was reacted (1.0 ml) with K2CO3 (30 g, 0.22 mmol), 3-bromohydrofuran-2 (3 H) -one (20 mg, 0.22 mmol) to yield the title compound (16 mg, 71%). NMR1H (300 MHz, acetone-d6) d ppm 1.33 (d, J = 5.57 Hz, 6H), 2.21-2.42 (m, 1H), 2.68-2.88 (m, 1H), 3.43-3.65 (m, 1H), 4.21-4.53 (m, 2H), 4.66 (d, J = 6.16 Hz, 2H), 5.10-5.24 (m, 1H), 5.54 (s, 2H), 6.90 (dd, J = 8.65, 2.20 Hz, 1H) , 6.97-7.08 (m, 2H), 7.11 (d, J = 2.35 Hz, 1H), 7.17-7.35 (m, 5H),
7. 42 (dd, J = 12.31, 8.50 Hz, 1H), 7.62 (d, J = 8.79 Hz, 1H), 7.68-7.78 (m, 1H).
Example 121 L-Benzyl-3- (3,4-difluorobenzylcarbamoyl) -2-isopropyl-1H-indol-6-yl dimethylcarbamate (Compound 121) General Procedure B. To a solution of 1-benzyl-N- (3, -difluorobenzyl) -6-hydroxy-2-isopropyl-lH-indole-3-carboxamide (Compound 108, 18 mg, 0.041 mmol) in pyridine (1 mL) was added dimethylcarbamyl chloride (40 μ ?, 0.41 mmol) and stirred at room temperature overnight. The reaction was quenched with water, extracted with ethyl acetate. The combined organic layer was washed with water, brine was dried over a2SO4, and concentrated in vacuo. The residue was purified by chromatography on silica gel (0-50% EtOAc-hexane) to give the title compound as a white solid (17 mg, 82%). RMK ^ H (300 MHz, CD3OD) d ppm 1.32 (d, J = 7.04 Hz, 6H), 2.96 (s, 3H), 3.09 (s, 3H), 3.37-3.55 (m, 1H), 4.58 (s, 2H), 5.48 (s, 2H), 6.87 (dd, J = 8.65, 1.91 Hz, 1H), 6.91-6.99 (m, 2H), 7.02 (d, J = 2.05 Hz, 1H), 7.16-7.39 (m , 6H), 7.58 (d, J = 8.79 Hz, 1H).
Example 122 L-benzyl-3- Pivalate (3, 4-
difluorobenzylcarbamoyl) -2-isopropyl-1H-indol-6-yl (Compound 122). Following General Procedure B, 1-benzyl-N- (3,4-difluorobenzyl) -6-hydroxy-2-isopropyl-1H-indole-3-carboxamide (Compound 108, 18 mg, 0.041 mol) in pyridine was reacted (1 ml) with pivaloyl chloride (5.1 μ ?, 0.41 mmol) to yield the title compound (16 mg, 74%). NMR1H (300 MHz, CD3OD) d ppm 1.25-1.40 (m, 15H), 3.34-3.55 (m, 1H), 4.58 (d, J = 5.86 Hz, 2H), 5.49 (s, 2H), 6.73-6.88 ( m, 1H), 6.89-6.99 (m, 2H), 7.00 (d, J = 1.76 Hz, 1H). 7.14-7.41 (m, 6H), 7.60 (d, J = 8.50 Hz, 1H).
Example 123 L-Benzyl-3- (3,4-difluorobenzylcarbamoyl) -2-isopropyl-lH-indol-6-yl acetate (Compound 123). Following General Procedure B, 1-benzyl-N- (3,4-difluorobenzyl) -6-hydroxy-2-isopropyl-1H-indole-3-carboxamide (Compound 108, 7 mg, 0.016 mol) in pyridine was reacted (1 mL) with acetyl chloride (1.0 μ ?, 0.16 mmol) to yield the title compound (8 mg, 100%). NMR1H (300 MHz, CDC13) d ppm 1.37 (d, J = 7.04 Hz,
6H), 2.26 (s, 3H), 3.54-3.76 (m, 1H), 4.66 (d, J = 6.16 Hz, 2H), 5.41 (s, 2H), 6.28 (t, J = 6.01 Hz, 1H), 6.81-7.01 (m, 4H), 7.06-7.19 (m, 2H), 7.18-7.35 (m, 4H), 7.61 (d, J = 9.09 Hz, 1H).
Example 124 l-Benzyl-3- (3,4-difluorobenzylcarbamoyl) -2-isopropyl-lH-indol-6-yl propionate (Compound 124). Following General Procedure B, 1-benzyl-N- (3,4-difluorobenzyl) -6-hydroxy-2-isopropyl-1H-indole-3-carboxamide (Compound 108, 7 mg, 0.016 mol) in pyridine was reacted (1 mL) with propionyl chloride (1.4 μ ?, 0.16 mmol) to yield the title compound (8 mg, 100%). RM ^ H (300 MHz, CDC13) d ppm 1.23 (t, J = 7.48 Hz, 3H), 1.37 (d, J = 7.33 Hz, 6H), 2.55 (q, J = 7.43 Hz, 2H), 3.53-3.73 (m, 1H), 4.66 (d, J = 5.86 Hz, 2H), 5.41 (s, 2H), 6.30 (t, J = 5.72 Hz, 1H), 6.83-7.00 (m, 4H), 7.06-7.18 ( m, 2H), 7.18-7.35 (m, 4H), 7.60 (d, J = 8.50 Hz, 1H).
EXAMPLE 125 l-Benzyl-3- (3,4-difluorobenzylcarbamoyl) -2-isopropyl-lH-indol-6-yl isobutyrate (Compound 125). Following General Procedure B, 1-benzyl-N- (3,4-difluorobenzyl) -6-hydroxy-2-isopropyl-1H-indole-3-carboxamide (Compound 108, 9 mg, 0.021 mol) in pyridine was reacted (1 mL) with isobutyryl chloride (4.1 μ ?, 0.21 mmol) to yield the title compound (8 mg, 80%). NMR1H (300 MHz, CDC13) d ppm 1.13-1.42 (m, 12H), 2.47-2.85 (m, 1H), 3.50-3.74 (m, 1H), 4.66 (d, J = 6.16 Hz, 2H), 5.41 ( s, 2H), 6.20-6.44 (m, 1H), 6.74-7.00 (m, 4H), 7.07-
7. 18 (m, 2H), 7.17-7.35 (m, 4H), 7.60 (d, J = 8.50 Hz, 1H)
Example 126 1-Benzyl-N- (3,4-difluorobenzyl) -2-isopropyl-6- (methoxymethoxy) -lH-indole-3-carboxamide (Compound 126). To a solution of 1-benzyl-N- (3,4-difluorobenzyl) -6-hydroxy-2-isopropyl-1H-indole-3-carboxamide (Compound 108, 39 mg, 0.090 mmol) in CH2C12 (2.0 ml) was added i-Pr2NEt (47 μ ?, 0.27 mmol) and MOMC1 (35 μ ?, 0.45 mmol). The reaction was stirred at room temperature for 4 hours, and then directly purified by PTLC on silica gel (30% EtOAc-hexanes) to give the title compound as a white solid. RM 1 H (300 MHz, Chloroform-d) d ppm 1.37 (d, J = 7.0 Hz, 6H), 3.42 (s, 3H), 3.59-3.78 (m, 1H), 4.66 (d, J = 5.9 Hz, 2H ), 5.10 (s, 2H), 5.40 (s, 2H), 6.29 (t, J = 5.7 Hz, 1H), 6.85 (d, J = 2.1 Hz, 1H), 6.89-7.01 (m, 3H), 7.10 -7.17 (m, 2H), 7.20-7.34 (m, 4H), 7.52 (d, J = 8.5 Hz, 1H).
Example 127 1-Benzyl-N- (3,4-difluorobenzyl) -2-isopropyl-6- (tetrahydrofuran-2-yloxy) -lH-indole-3-carboxamide (Compound 127). To a solution of 1-benzyl-N- (3,4-difluorobenzyl) -6-hydroxy-2-isopropyl-1H-indole-3-carboxamide (Compound 108, 39 mg, 0.090 mmol) in CH2C12 (2.0 ml) was added 2, 3-hydrofuran (68 μ ?, 0.98 mmol and catalytic amounts of PPTS.
The reaction was stirred at room temperature for 4 hours, and purified directly by PTLC on silica gel (30% EtOAc-hexanes) to give the title compound as a white solid. NMR1H (300 MHz, Chloroform-d) d ppm 1.36 (d, J = 7.3
Hz, 6H), 1.85-1.98 (m, 1H), 2.01-2.19 (m, 3H), 3.58-3.73 (m, 1H), 3.85-3.95 (m, 1H), 3.96-4.07 (m, 1H), 4.66 (d, J = 5.9 Hz, 2H), 5.40 (s, 2H), 5.70 (d, J = 4.7 Hz, 1H), 6.29 (t, J = 5.7 Hz, 1H), 6.86 (d, J = 2.1 Hz, 1H), 6.89-6.99 (m, 3H), 7.11-7.17 (m, 2H), 7.19-7.32 (m, 4H), 7.51 (d, J = 8.5 Hz, 1H).
Reaction Scheme 6
Example 128 Tetrahydrofuran-3-yl 4-methylbenzenesulfonate
(Compound 128 or Compound 29, Reaction Scheme 6). To a solution of tetrahydrofuran-3-ol (500 mg, 5.67 mmol) in pyridine (10 mL) at 0 ° C was added 4-methylbenzene-1-sulfonyl chloride (1.08 g, 5.67 mmol). The reaction was stirred to
Room temperature during the night. The reaction was quenched with water, extracted with ethyl acetate. The organic layer was washed with water, brine, dried over Na2SO4 and concentrated in vacuo to yield a crude oil (1.2 g). NMR1H (300 MHz, CDC13) d ppm 1.91-2.23 (m, 2H),
3. 61-4.05 (m, 4H), 4.95-5.24 (m, 1H), 7.36 (d, J = 7.92 Hz, 2H), 7.80 (d, J = 8.50 Hz, 2H).
Example 129 3-iodotetrahydrofuran (Compound 129). To a solution of crude tetrahydrofuran-3-yl-4-methylbenzosulfonate (Compound 128, 1.2 g, 4.96 mmol) in dry acetone (50 ml) was added Nal (1.1 g, 7.44 mmol). The reaction was heated to 60 ° C for 2 days. The mixture was diluted with water and extracted with diethyl ether. The organic layer was washed with water, brine, dried over Na 2 SO 4 and concentrated in vacuo to yield the crude oil which was used directly without purification. 1 H NMR (300 MHz, CDC13) d ppm 2.23-2.55 (m, 2H), 3.81-4.08 (m, 3H), 4.08-4.43 (m, 2H). The foregoing description details specific methods and compositions that can be employed to practice the present invention, and represents the best mode contemplated. In this way, despite the detail of the previous thing that may appear in the text, it should not be considered as limiting the
full scope of it; rather, the scope of the present invention was that it be governed only by the legal construction of the appended claims. In particular, the compounds of the invention comprise an indole-3-carboxylic acid N-arylmethyl-amide
6-substituted having sphingosine-1-phosphate antagonist activity wherein the 6-substituent is represented by the formula (X1) r-A2-B wherein X1 is 0; r is 0 or 1; A2 is absent or is (0? 2) ?, where V is 1 or 2; B is OR6 or NR8R9, wherein R6, R8 and R9 are methyl; or B is CR10 = NO RnR10 wherein R10 is H and R11 is methyl or i-butyl; or B is CONR8R9, wherein R8 and R9 are selected from the group consisting of H, methyl, ethyl, and propyl or R8 and R9, together with
N, form a 5-membered ring; or B is OR6, wherein R6 is H; or B is COR10, wherein R10 is methyl.
It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.
Claims (6)
1-thiophen-2-ylmethyl-1H-indole-3-carboxylic acid; 3, 5-Difluorobenzylamide of 1-furan-2-ylmethyl-5-hydroxy-2-methyl-lH-indole-3-carboxylic acid; 3, 4-Difluorobenzylamide of l-benzyl-5-hydroxy-2-methyl-lH-indole-3-carboxylic acid; 3-Fluorobenzylamide of 5-hydroxy-2-methyl-1-thiophen-2-ylmethyl-1H-indole-3-carboxylic acid; 5-Hydroxy-2-methyl-1-thiophen-2-ylmethyl-1H-indole-3-carboxylic acid benzylamide; 3-Methoxy-benzylamide of 5-hydroxy-2-methyl-1-thiophen-2-ylmethyl-1H-indole-3-carboxylic acid; L-butyl-5-hydroxy-2-methyl-lH-indole-3-carboxylic acid 3-methoxy-benzylamide; 4-Fluorobenzylamide of 5-hydroxy-2-methyl-1-thiophen-2-ylmethyl-1H-indole-3-carboxylic acid; 4-Methylbenzylamide of 5-hydroxy-2-methyl-1-thiophen-2-ylmethyl-1H-indole-3-carboxylic acid; 3-Chlorobenzylamide of 5-hydroxy-2-methyl-1-thiophen-2-ylmethyl-1H-indole-3-carboxylic acid; 4-Chlorobenzylamide of 5-hydroxy-2-methyl-1-thiophen-2-ylmethyl-1H-indole-3-carboxylic acid; 2-Methoxy-2-methyl-1-thiophen-2-ylmethyl-1H-indole-3-carboxylic acid 2-methoxy-benzylamide; 3, 4-Difluorobenzylamide of l-benzyl-2-ethyl-5-hydroxy-lH-indole-3-carboxylic acid; L-benzyl-2-ethyl-5-hydroxy-lH-indole-3-carboxylic acid 3-methoxy-benzylamide; 3, 4-Difluorobenzamide of l-benzyl-5-hydroxy-2-isopropyl-lH-indol-3-carb.oxylic acid; 3-5-Hydroxy-2-methyl-1-phenyl-1H-indole-3-carboxylic acid difluorobenzylamide; 3, 4-Difluorobenzylamide of 5-hydroxy-2-methyl-l-pyridin-2-yl-lH-indole-3-carboxylic acid; 3,4-Difluorobenzylamide of 5-hydroxy-2-methyl-1-thiophen-2-yl-lH-indole-3-carboxylic acid; 3.5-Difluorobenzylamide of l-benzyl-2-ethyl-5-hydroxy-lH-indole-3-carboxylic acid; 3, 5-difluorobenzylamide of l-benzyl-5-hydroxy-2-isopropyl-lH-indole-3-carboxylic acid; 3-methoxybenzylamide of l-benzyl-5-hydroxy-2-isopropyl-lH-indole-3-carboxylic acid; and 3,5-Difluorobenzylamide of l-benzyl-5-hydroxy-2-phenyl-1H-indole-3-carboxylic acid. 14. Compound according to claim 13, characterized in that it is selected from the group consisting of: 3,5-difluorobenzylamide of l-benzyl-5-hydroxy-2-methyl-lH-indole-3-carboxylic acid; 3, 5-Difluorobenzylamide of 1-furan-2-ylmethyl-5-hydroxy-2-methyl-lH-indole-3-carboxylic acid; 3-Methoxy-benzylamide of 5-hydroxy-2-methyl-1-thiophen-2-ylmethyl-1H-indole-3-carboxylic acid; 3,4-Difluorobenzylamide of l-benzyl-2-ethyl-5-hydroxy-lH-indole-3-carboxylic acid; 3.5-Difluorobenzylamide of l-benzyl-2-ethyl-5-hydroxy-lH-indole-3-carboxylic acid; 3, 5-Difluorobenzylamide of l-benzyl-5-hydroxy-2-isopropyl-1H-indole-3-carboxylic acid; 3-methoxybenzylamide of l-benzyl-5-hydroxy-2-isopropyl-lH-indole-3-carboxylic acid; and 3,5-Difluorobenzylamide of l-benzyl-5-hydroxy-2-phenyl-1H-indole-3-carboxylic acid. 15. Use of a compound represented by the general formula: where X is NR, O, S; Z is O or S; n is 0 or an integer from 1 to 4 or is 0 or an integer from 1 to 3 p is 0 or an integer from 1 to 4
A is (C (R5) 2) m, where m is 0 or an integer from 1 to 6; R5 is selected from the group consisting of hydrogen, straight or branched chain alkyl having 1 to 12 carbon atoms, cycloalkyl having 3 to 6 carbons, alkenyl having 2 to 6 carbons and 1 or 2 double bonds, alkynyl having 2 to 6 carbons and 1 or 2 triple bonds, aryl, wherein the aryl is a carbocyclic aryl or heterocyclic aryl group wherein the carbocyclic aryl comprises from 6 to 20 atoms and the heterocyclic aryl comprises from 2 to 20 atoms of carbon and from 1 to 5 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, halo, Ci to Ci2 haloalkyl, hydroxyl, Ci to Ci2 alkoxy, Ci to Ci2 alkylcarbonyl, formyl, oxycarbonyl, carboxy, Ci to Ci2 alkyl- carboxylate, Ci to Ci2 alkyl amide, aminocarbonyl, amino, cyano, diazo, nitro, thio, sulfoxyl or sulfonyl groups; Y is a carbocyclic aryl or heterocyclic aryl group wherein the carbocyclic aryl comprises from 6 to 20 atoms and the heterocyclic aryl comprises from 2 to 20 carbon atoms and from 1 to 5 heteroatoms selected from the group consisting of nitrogen, sulfur and oxygen, and wherein the aryl can be attached to A in any position; R1, R2, R3, R4 are selected from the group consisting of hydrogen, straight or branched chain alkyl having from 1 to 12 carbons, cycloalkyl having from 3 to 6 carbons, alkenyl having from 2 to 6 carbons and 1 or 2 double bonds, aryl, wherein the aryl is a carbocyclic aryl or heterocyclic aryl group wherein the carbocyclic aryl comprises from 6 to 20 atoms and the heterocyclic aryl comprises from 2 to 20 carbon atoms and from 1 to 5 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur and can be substituted with Ci to Ci2 alkyl, C2 to C6 alkenyl, C2 to C6 alkynyl, halo, Ci to Ci2 haloalkyl, hydroxyl, Ci to Ci2 alkoxy, C2 to C20 arylalkyloxy, Cx to Ci2 alkylcarbonyl, formyl, oxycarbonyl, carboxy, Ci to Ci2 alkyl carboxylate, Ci to C12 alkyl amide, aminocarbonyl, amino, cyano, diazo, nitro, thio, sulfoxy, or sulfonyl groups, or a group selected from the group consisting of: wherein R is C02H or P03H2, p is an integer of 1 or 2 and q is 0 or an integer from 1 to 5, for the manufacture of a medicament for treating a disease or condition selected from the group consisting of glaucoma, eye dryness, angiogenesis, cardiovascular conditions and diseases, and wound healing in a patient in need of it. 16. Use according to claim 12, in where Z is 0. 17. Use according to claim 12, wherein Y is a phenyl group, or a heterocyclyl-aryl group selected from the group consisting of pyridyl, thienyl, furyl, pyrazinyl, pyrimidinyl, pyrazinium, thiazolyl, oxazolyl. , and imidazolium. 18. Use according to claim 16, wherein aryl is independently selected from the group consisting of phenyl, pyridine, pyrazine, pyridazine, pyrimidine, triazine, thiophene, thiazole furan, thiazole, isothiazole, oxazole, oxadiazole, isooxazole, naphthalene, quinoline, tetralin, chroman, thiochroman, tetrahydroquinoline, dihydronaphthalene, tetrahydronaphthalene, chromene, thiochromen, dihydroquinoline, indane, dihydrobenzofuran, dihydrobenzothiophene, indene, benzofuran, benzothiophene, coumarin and coumarinone, wherein the aryl is unsubstituted or substituted with one or two alkyl groups alkenyl, alkynyl, aryl, halo, haloalkyl, hydroxyl, alkoxy, alkylcarbonyl, formyl, oxycarbonyl, carboxyl, alkyl carboxylate, alkyl-amide, aminocarbonyl, amino, cyano, diazo, nitro, thio, sulfoxyl, or sulfonyl. 19. Use according to claim 16, wherein Y is phenyl. 20. Use according to claim 16, wherein A is CH2. 21. Use in accordance with claim 20, where X is NH. 22. Use according to claim 21, wherein n is 0 or an integer of 1 or 2 and R4 are selected from the group consisting of methyl, methoxy, fluoro and chloro. 23. Use according to claim 22, wherein R1 is selected from the group consisting of hydrogen, methyl, ethyl and i-propyl. 24. Use according to claim 20, wherein R3 is selected from the group consisting of methyl, butyl, phenyl, benzyl, pyridyl, furanylmethylene, thienyl and thienyl-methylenyl. 25. Use according to claim 24, wherein p is 0 or p is 1 and R2 is selected from the group consisting of hydroxyl, methoxy, nitro, amino, acetamide and benzyloxy. 26. Use according to claim 25, wherein p is 1 and R2 is a 5-hydroxy group; R1 is selected from the group consisting of methyl, ethyl, i-propyl and phenyl; R3 is selected from the group consisting of benzyl, thienylmethylene, and furanylmethylenyl; n is 1 or 2 and R 4 is selected from the group consisting of methoxy and fluoro. 27. Use according to claim 16, wherein it is selected from the group consisting of: 3,5-difluorobenzylamide of l-benzyl-5- acid hydroxy-2-methyl-lH-indole-3-carboxylic acid; 3,4-Difluorobenzylamide of 5-hydroxy-methyl-1-thiophen-2-ylmethyl-1H-indole-3-carboxylic acid; 3.5-Difluorobenzylamide of l-butyl-5-hydroxy-2-methyl-lH-indole-3-carboxylic acid; 3, 4-Difluorobenzylamide of 1-furan-2-ylmethyl 5-hydroxy-2-methyl-lH-indole-3-carboxylic acid; 3, 5-Difluorobenzylamide of 5-hydroxy-2-methyl-1-thiophen-2-ylmethyl-1H-indole-3-carboxylic acid; 3, 5-Difluorobenzylamide of 1-furan-2-ylmethyl acid 5-hydroxy-2-methyl-lH-indole-3-carboxylic acid; 3, 4-Difluorobenzylamide of l-benzyl-5-hydroxy-2-methyl-lH-indole-3-carboxylic acid; 3-Fluorobenzylamide of 5-hydroxy-2-methyl-1-thiophen-2-ylmethyl-1H-indole-3-carboxylic acid; 5-Hydroxy-2-methyl-1-thiophen-2-ylmethyl-1H-indole-3-carboxylic acid benzylamide; 3-Methoxy-benzylamide of 5-hydroxy-2-methyl-1-thiophen-2-ylmethyl-1H-indole-3-carboxylic acid; L-butyl-5-hydroxy-2-methyl-lH-indole-3-carboxylic acid 3-methoxy-benzylamide; 4-Fluorobenzylamide of 5-hydroxy-2-methyl-1-thiophen-2-ylmethyl-1H-indole-3-carboxylic acid; 4-Methylbenzylamide of 5-hydroxy-2-methyl-1-thiophen-2-ylmethyl-1H-indole-3-carboxylic acid;
3-Chlorobenzylamide of 5-hydroxy-2-methyl-1-thiophen-2-ylmethyl-1H-indole-3-carboxylic acid;
4-Chlorobenzylamide of
5-hydroxy-2-methyl-1-thiophen-2-ylmethyl-1H-indole-3-carboxylic acid; 2-Hydroxy-2-methyl-1-thiophen-2-ylmethyl-1H-indole-3-carboxylic acid 2-methoxy-benzylamide; 3-l-Benzyl-2-ethyl-5-hydroxy-lH-indole-3-carboxylic acid difluorobenzylamide; 3-methoxybenzylamide of l-benzyl-2-ethyl-5-hydroxy-lH-indole-3-carboxylic acid; 3-L-benzyl-5-hydroxy-2-isopropyl-lH-indole-3-carboxylic acid difluorobenzamide; 3, 4-Difluorobenzylamide of 5-hydroxy-2-methyl-1-phenyl-1H-indole-3-carboxylic acid; 3-5-Hydroxy-2-methyl-l-pyridin-2-yl-lH-indole-3-carboxylic acid difluorobenzylamide; 3.-5-Hydroxy-2-methyl-1-thiophen-2-yl-lH-indole-3-carboxylic acid difluorobenzylamide; 3.5-Difluorobenzylamide of l-benzyl-2-ethyl-5-hydroxy-lH-indole-3-carboxylic acid; 3, 5-Difluorobenzylamide of l-benzyl-5-hydroxy-2-isopropyl-lH-indole-3-carboxylic acid; 3-Methoxybenzylamide of l-benzyl-5-hydroxy-2-isopropyl-1H-indole-3-carboxylic acid; and 3, 5-difluorobenzylamide of l-benzyl-5 acid hydroxy-2-phenyl-lH-indole-3-carboxylic acid. 28. Use according to claim 27, wherein it is selected from the group consisting of: 3,5-difluorobenzylamide of l-benzyl-5-hydroxy-2-methyl-lH-indole-3-carboxylic acid; 3, 5-Difluorobenzylamide of l-furan-2-ylmethyl-5-hydroxy-2-methyl-lH-indole-3-carboxylic acid; 3-Methoxy-benzylamide of 5-hydroxy-2-methyl-1-thiophen-2-ylmethyl-1H-indole-3-carboxylic acid; 3-L-benzyl-2-ethyl-5-hydroxy-lH-indole-3-carboxylic acid difluoro-benzylamide; 3, 5-Difluoro-benzylamide of l-benzyl-2-ethyl-5-hydroxy-lH-indole-3-carboxylic acid; 3, 5-difluorobenzylamide of l-benzyl-5-hydroxy-2-isopropyl-lH-indole-3-carboxylic acid; 3-methoxybenzylamide of l-benzyl-5-hydroxy-2-isopropyl-lH-indole-3-carboxylic acid; and 3, 5-Difluoro-benzylamide of l-benzyl-5-hydroxy-2-phenyl-1H-indole-3-carboxylic acid. 29. Compounds represented by having biological agonist activity and / or sphingosine-1-phosphate receptor antagonist represented by the general formula: Formula I characterized in that R1, R2, R3 and R4 are selected from the group consisting of hydrogen, straight or branched chain alkyl having 1 to 12 carbons, alkenyl having 2 to 6 carbons and 1 or 2 double bonds, alkynyl having 2 to 6 carbons and 1 or 2 triple bonds, carbocyclic hydrocarbon groups having from 3 to 20 carbon atoms, heterocyclic groups having up to 20 carbon atoms and at least one oxygen, nitrogen and / or sulfur in the ring, halo, Ci to C12 haloalkyl, hydroxyl, Ci to C12 alkoxy, C3 to C2 or arylalkyloxy, Ci to C12 alkylcarbonyl, formyl, oxycarbonyl, carboxy, Ci to C12 alkyl carboxylate, Ci to Ci2 alkyl amide, aminocarbonyl, amino, cyano, diazo, nitro, thio, sulfoxyl and sulfonyl groups; X and X1 are independently selected from the group consisting of NR5, 0 and S; R5 is hydrogen, an alkyl group of 1 to 10 carbons, a cycloalkyl group of 5 to 10 carbons, phenyl or lower alkylphenyl; And it's a carbocyclic aryl or aryl group heterocyclic wherein the carbocyclic aryl comprises from 6 to 20 atoms and the heterocyclic aryl comprises from 2 to 20 carbon atoms and from 1 to 5 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, and wherein the aryl may be attached to A in any position; Z is O or S; n is 0 or an integer from 1 to 5; 0 is 0 or an integer from 1 to 3; p is 0 or an integer from 1 to 3; which is O or l; r is 0 or 1; A, A1 and A2 are independently selected from the group consisting of (CH2) V wherein v is 0 or an integer from 1 to 12, branched chain alkyl having from 3 to 12 carbons, cycloalkyl having from 3 to 12 carbons, alkenyl having 2 to 10 carbons and 1-3 double bonds and alkenyl having 2 to 10 carbons and 1 to 3 triple bonds; B is selected from the group consisting of hydrogen, OR6, COOR7, NR8R9, CONR8R9, COR10, CH = N0Rn, CH = NNR12R13 wherein R6, R7, R10 and R11 are independently selected from the group consisting of hydrogen, straight-chain alkyl or branched having 1 to 12 carbons, alkenyl having 2 to 6 carbons and 1 or 2 double bonds, alkynyl having 2 to 6 carbons and 1 or 2 triple bonds, a carbocyclic hydrocarbon group having 3 to 20 atoms of carbon, a heterocyclic group having up to 20 carbon atoms and at least one of oxygen, nitrogen and / or sulfur in the ring; R8, R9, R12 and R13 are independently selected from the group consisting of hydrogen, straight or branched chain alkyl having 1 to 12 carbons, alkenyl having 2 to 6 carbons and 1 or 2 double bonds, alkynyl having 2 to 6 carbons and 1 or 2 triple bonds, a carbocyclic hydrocarbon group having from 3 to 20 carbon atoms, a heterocyclic group having up to 20 carbon atoms and at least one oxygen, nitrogen and / or sulfur atom in the ring, or R8 and R9 and / or R12 and R13, together can form a divalent carbon radical of 2 to 5 carbons to form a heterocyclic ring with nitrogen, wherein any of R6, R7, R8, R9, R10, R11, R 12 or R 13 may be substituted with one or more halogen, hydroxy, alkyloxy, cyano, nitro, mechapto or thiol radicals; with the condition, however, that when v is 0, and r is 0, B is not hydrogen; or B is a carbocyclic hydrocarbon group having from 3 to 20 carbon atoms, or a heterocyclic group having up to 20 carbon atoms and at least one oxygen, nitrogen and / or sulfur in the ring, and wherein when B is a carbocyclic or heterocyclic group, B may be attached to A2 in any position, or a pharmaceutically acceptable salt of this compound. 30. Compound according to claim 29, characterized in that Z is O. 31. Compound according to claim 30, characterized in that Y is a phenyl group or a pyridyl group. 32. Compound according to claim 31, characterized in that A is CH2. 33. Compound in accordance with the claim 32, characterized in that X is NH. 34. Compound in accordance with the claim 33, characterized in that n is 0 or an integer of 1 or 2 and R4 is fluoro. 35. Compound in accordance with the claim 34, characterized in that R1 is i-propyl. 36. Compound in accordance with the claim 35, characterized in that R3 is selected from the group consisting of phenyl, which may be substituted with one or two fluoro groups, and pyridyl. 37. Compound in accordance with the claim 36, characterized in that p is 0. 38. Compound according to claim 37, characterized in that A1 and A2 are absent. 39. Compound according to claim 38, characterized in that B is OR6. 40. Compound according to claim 38, characterized in that B is COOR7. 41. Compound in accordance with the claim 38, characterized in that X1 is 0, r is 1, A1 is absent, A2 is (CH2) V, where v is 1 or 2, and B is OR6 or NR8R9. 42. Compound according to claim 41, characterized in that R6, R8 and R9 are methyl 43. Compound in accordance with claim 38, characterized in that B is CR10 = NORnR10 wherein R10 is H and R11 is methyl or i-butyl. 44. Compound according to claim 38, characterized in that B is CONR8R9 wherein R8 and R9 are selected from the group consisting of H, methyl, ethyl and propyl, or R8 and R9, together with N, form a 5-membered ring . 45. Compound, according to claim 38, characterized in that A1 is absent, r is 0, A2 is CH2 and B is OR6, wherein R6 is H. 46. Compound according to claim 38, characterized in that A1 is absent , X is O, r is 1 and B is COR10 where R10 is methyl. 47. N-arylmethylamide of
6-substituted indole-3-carboxylic acid having an espingosine-1-phosphate antagonist activity, characterized in that the 6-substituent is represented by the formula (X1) r-A2-B wherein X1 is 0; r is O or l; A2 is absent or is (CH2) V, where v is 1 or 2; B is OR6 or NR8R9, wherein R6, R8 and R9 are methyl; or B is CR10 = NOR10Rn wherein R10 is H and R11 is methyl or i-butyl; or B is CONR8R9, wherein R8 and R9 are selected from the group consisting of H, methyl, ethyl and propyl or R8 and R9, together with N, form a 5-membered ring; or B is OR6, wherein R6 is H; or B is COR10, wherein R10 is methyl. 48. Use of a compound having biological agonist activity and / or sphingosine-1-phosphate receptor antagonist represented by the general formula: Formula I wherein R1, R2, R3 and R4 are selected from the group consisting of hydrogen, straight or branched chain alkyl having 1 to 12 carbons, alkenyl having 2 to 6 carbons and 1 or 2 double bonds, alkynyl having 2 to 6 carbons and 1 or 2 triple bonds, carbocyclic hydrocarbon groups having from 3 to 20 carbon atoms, heterocyclic groups which have up to 20 carbon atoms and at least one oxygen, nitrogen and / or sulfur in the ring, halo, Ci to C12 haloalkyl, hydroxyl, Ci to C12 alkoxy, C3 to C20 arylalkyloxy, Ci to C12 alkylcarbonyl, formyl, oxycarbonyl, carboxy Ci to Ci2 alkyl carboxylate, Ci to C12 alkyl amide, aminocarbonyl, amino, cyano, diazo, nitro, thio, sulfoxyl and sulfonyl groups; X and X1 are independently selected from the group consisting of NR5, O and S; R5 is hydrogen, an alkyl group of 1 to 10 carbons, a cycloalkyl group of 5 to 10 carbons, phenyl or lower alkylphenyl; Y is a carbocyclic aryl or heterocyclic aryl group wherein the carbocyclic aryl comprises from 6 to 20 atoms and the heterocyclic aryl comprises from 2 to 20 carbon atoms and from 1 to 5 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, and wherein the aryl may be attached to A in any position; Z is 0 or S; n is 0 or an integer from 1 to 5; 0 is 0 or an integer from 1 to 3; p is 0 or an integer from 1 to 3; q is 0 or 1; r is 0 or 1; A, A1 and A2 are independently selected from the group consisting of (CH2) V where v is 0 or a number whole from 1 to 12, branched chain alkyl having from 3 to 12 carbons, cycloalkyl having from 3 to 12 carbons, alkenyl having from 2 to 10 carbons and 1-3 double bonds and alkenyl having from 2 to 10 carbons and 1 to 3 triple links; B is selected from the group consisting of hydrogen, OR6, COOR7, NR8R9, CONR8R9, COR10, CH = NORu, CH = NNR12R13 wherein R6, R7, R10 and R11 are independently selected from the group consisting of hydrogen, straight-chain alkyl or branched having 1 to 12 carbons, alkenyl having 2 to 6 carbons and 1 or 2 double bonds, alkynyl having 2 to 6 carbons and 1 or 2 triple bonds, a carbocyclic hydrocarbon group having 3 to 20 carbon atoms, a heterocyclic group having up to 20 carbon atoms and at least one oxygen, nitrogen and / or sulfur in the ring; R8, R9, R12 and R13 are independently selected from the group consisting of hydrogen, straight or branched chain alkyl having 1 to 12 carbons, alkenyl having 2 to 6 carbons and 1 or 2 double bonds, alkynyl having 2 to 6 carbons and 1 or 2 triple bonds, a carbocyclic hydrocarbon group having from 3 to 20 carbon atoms, a heterocyclic group having up to 20 carbon atoms and at least one oxygen, nitrogen and / or sulfur atom in the ring, or R8 and R9 and / or R12 and R13, together can form a divalent carbon radical of 2 to 5 carbons to form a heterocyclic ring with nitrogen, wherein any of R6, R7, R8, R9, R10, R11, R12 or R13 may be substituted with one or more halogen, hydroxy, alkyloxy, cyano, nitro, mechapto or thiol radicals; with the condition, however, that when B is 0, and r is 0, B is not hydrogen; or B is a carbocyclic hydrocarbon group having from 3 to 20 carbon atoms, or a heterocyclic group having up to 20 carbon atoms and at least one oxygen, nitrogen and / or sulfur in the ring, and wherein when B is a carbocyclic or heterocyclic group, B may be attached to A2 in any position, or a pharmaceutically acceptable salt of this compound, for the manufacture of a medicament for treating a disease or condition selected from the group consisting of glaucoma, dry eye, angiogenesis , conditions and cardiovascular diseases, and wound healing in a patient in need of it.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US60/774,102 | 2006-02-15 | ||
US60/884,470 | 2007-01-11 |
Publications (1)
Publication Number | Publication Date |
---|---|
MX2008010560A true MX2008010560A (en) | 2008-10-03 |
Family
ID=
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CA2642668C (en) | Indole-3-carboxylic acid amide and ester compounds bearing phenyl groups having sphingosine-1-phosphate (s1p) receptor antagonist biological activity | |
US8097644B2 (en) | Indole compounds having sphingosine-1-phosphate (S1P) receptor antagonist | |
AU2008347006B2 (en) | 6-substituted indole-3-carboxylic acid amide compounds having sphingosine-1-phosphate (S1P) receptor antagonist biological activity | |
KR20090101307A (en) | 6-substituted indole-3-carboxylic acid amide compounds having sphingosine-1-phosphate (s1p) receptor antagonist biological activity | |
US7737173B2 (en) | Indole-3-carboxylic acid amide, ester, thioamide and thiol ester compounds bearing aryl or heteroaryl groups having sphingosine-1-phosphate (S1P) receptor antagonist biological activity | |
KR100575944B1 (en) | Triamide-substituted indoles, benzofuranes and benzothiophenes as inhibitors of microsomal triglyceride transfer protein(mtp) and/or apolipoprotein b(apo b) secretion | |
JP5073149B2 (en) | Acylated indanylamine and its use as a medicament | |
JP2006528218A (en) | GFAT inhibitor | |
KR20000076428A (en) | Certain Cyclic Thio Substituted Acylaminoacid Amide Derivatives | |
JP2006514637A (en) | Substituted 3-carbonyl-1H-indol-1-ylacetic acid derivatives as inhibitors of plasminogen activator inhibitor-1 (PAI-1) | |
MX2008010560A (en) | Indole-3-carboxylic acid amide, ester, thioamide and thiol ester compounds bearing aryl or heteroaryl groups having sphingosine-1-phosphate (s1p) receptor antagonist biological activity | |
US4767865A (en) | 3'-pyridinylalkylinden- and 3'-pyridinylalkylindol-2-carboxylic acids and analogs | |
AU2006256857A1 (en) | Inhibitors of soluble adenylate cyclase | |
EP1259488A1 (en) | Ortho-sulfonamido aryl hydroxamic acids, process for their preparation and their use as matrix metalloproteinase inhibitors |