MXPA99012020A - Specific immunophilin ligands useful as anti-asthmatic, anti-allergic, anti-rheumatic, immunosuppressive, antipsoriatic and neuroprotective agents - Google Patents
Specific immunophilin ligands useful as anti-asthmatic, anti-allergic, anti-rheumatic, immunosuppressive, antipsoriatic and neuroprotective agentsInfo
- Publication number
- MXPA99012020A MXPA99012020A MXPA/A/1999/012020A MX9912020A MXPA99012020A MX PA99012020 A MXPA99012020 A MX PA99012020A MX 9912020 A MX9912020 A MX 9912020A MX PA99012020 A MXPA99012020 A MX PA99012020A
- Authority
- MX
- Mexico
- Prior art keywords
- groups
- indolin
- carbonyl
- phenylsulfonyl
- carbamide
- Prior art date
Links
- 230000027455 binding Effects 0.000 title claims abstract description 14
- 239000003446 ligand Substances 0.000 title claims abstract description 14
- 230000001506 immunosuppresive Effects 0.000 title claims abstract description 8
- 230000001088 anti-asthma Effects 0.000 title claims abstract description 7
- 230000003356 anti-rheumatic Effects 0.000 title claims abstract description 5
- -1 anti-allergic Substances 0.000 title claims description 41
- 239000000924 antiasthmatic agent Substances 0.000 title claims description 5
- 239000003435 antirheumatic agent Substances 0.000 title claims description 4
- 230000003266 anti-allergic Effects 0.000 title abstract description 3
- 230000002682 anti-psoriatic Effects 0.000 title abstract 2
- 239000004090 neuroprotective agent Substances 0.000 title 1
- 239000003814 drug Substances 0.000 claims abstract description 8
- 150000001875 compounds Chemical class 0.000 claims description 57
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 30
- 229910052717 sulfur Inorganic materials 0.000 claims description 24
- 229910052757 nitrogen Inorganic materials 0.000 claims description 20
- 125000005842 heteroatoms Chemical group 0.000 claims description 18
- RAXXELZNTBOGNW-UHFFFAOYSA-N Imidazole Chemical compound C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 16
- SIKJAQJRHWYJAI-UHFFFAOYSA-N indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 claims description 16
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 16
- 239000000126 substance Substances 0.000 claims description 15
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 14
- 229910052736 halogen Inorganic materials 0.000 claims description 14
- 150000002367 halogens Chemical group 0.000 claims description 14
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 14
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 14
- 239000002253 acid Substances 0.000 claims description 13
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 13
- 229910052760 oxygen Inorganic materials 0.000 claims description 13
- 125000003277 amino group Chemical group 0.000 claims description 12
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 12
- 125000000738 acetamido group Chemical group [H]C([H])([H])C(=O)N([H])[*] 0.000 claims description 11
- 125000000217 alkyl group Chemical group 0.000 claims description 11
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 10
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 10
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 10
- 238000002360 preparation method Methods 0.000 claims description 10
- 239000004202 carbamide Substances 0.000 claims description 9
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims description 9
- 229910052739 hydrogen Inorganic materials 0.000 claims description 9
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 claims description 8
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 8
- YLQBMQCUIZJEEH-UHFFFAOYSA-N furane Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 8
- 239000001257 hydrogen Substances 0.000 claims description 8
- 125000002950 monocyclic group Chemical group 0.000 claims description 8
- YNAVUWVOSKDBBP-UHFFFAOYSA-N morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 8
- 229940113083 morpholine Drugs 0.000 claims description 8
- 125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 claims description 8
- GLUUGHFHXGJENI-UHFFFAOYSA-N piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims description 8
- NQRYJNQNLNOLGT-UHFFFAOYSA-N piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 8
- YTPLMLYBLZKORZ-UHFFFAOYSA-N thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 claims description 8
- BAXOFTOLAUCFNW-UHFFFAOYSA-N 1H-indazole Chemical compound C1=CC=C2C=NNC2=C1 BAXOFTOLAUCFNW-UHFFFAOYSA-N 0.000 claims description 7
- 108010016648 Immunophilins Proteins 0.000 claims description 7
- 102000000521 Immunophilins Human genes 0.000 claims description 7
- 150000004702 methyl esters Chemical class 0.000 claims description 7
- 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims description 6
- 125000004200 2-methoxyethyl group Chemical group [H]C([H])([H])OC([H])([H])C([H])([H])* 0.000 claims description 6
- CZPWVGJYEJSRLH-UHFFFAOYSA-N 289-95-2 Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 claims description 6
- 206010061218 Inflammation Diseases 0.000 claims description 6
- AWJUIBRHMBBTKR-UHFFFAOYSA-N Isoquinoline Chemical compound C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 claims description 6
- CTAPFRYPJLPFDF-UHFFFAOYSA-N Isoxazole Chemical compound C=1C=NOC=1 CTAPFRYPJLPFDF-UHFFFAOYSA-N 0.000 claims description 6
- LFSXCDWNBUNEEM-UHFFFAOYSA-N Phthalazine Chemical compound C1=NN=CC2=CC=CC=C21 LFSXCDWNBUNEEM-UHFFFAOYSA-N 0.000 claims description 6
- 239000000203 mixture Substances 0.000 claims description 6
- WCPAKWJPBJAGKN-UHFFFAOYSA-N oxadiazole Chemical compound C1=CON=N1 WCPAKWJPBJAGKN-UHFFFAOYSA-N 0.000 claims description 6
- ZCQWOFVYLHDMMC-UHFFFAOYSA-N oxazole Chemical compound C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 claims description 6
- WTKZEGDFNFYCGP-UHFFFAOYSA-N pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 claims description 6
- KAESVJOAVNADME-UHFFFAOYSA-N pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 claims description 6
- SMWDFEZZVXVKRB-UHFFFAOYSA-N quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 claims description 6
- 239000000243 solution Substances 0.000 claims description 6
- 125000004400 (C1-C12) alkyl group Chemical group 0.000 claims description 5
- 239000004472 Lysine Substances 0.000 claims description 5
- 125000006615 aromatic heterocyclic group Chemical group 0.000 claims description 5
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 5
- 238000006243 chemical reaction Methods 0.000 claims description 5
- 230000004054 inflammatory process Effects 0.000 claims description 5
- NZNMSOFKMUBTKW-UHFFFAOYSA-N Cyclohexanecarboxylic acid Chemical compound OC(=O)C1CCCCC1 NZNMSOFKMUBTKW-UHFFFAOYSA-N 0.000 claims description 4
- NIXOWILDQLNWCW-UHFFFAOYSA-N acrylic acid group Chemical group C(C=C)(=O)O NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 claims description 4
- 150000001408 amides Chemical class 0.000 claims description 4
- 125000005418 aryl aryl group Chemical group 0.000 claims description 4
- 125000003118 aryl group Chemical group 0.000 claims description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-M chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 4
- 125000001072 heteroaryl group Chemical group 0.000 claims description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 4
- 125000004435 hydrogen atoms Chemical group [H]* 0.000 claims description 4
- 230000001861 immunosuppresant Effects 0.000 claims description 4
- 239000003018 immunosuppressive agent Substances 0.000 claims description 4
- 239000000825 pharmaceutical preparation Substances 0.000 claims description 4
- LSNNMFCWUKXFEE-UHFFFAOYSA-N sulfonic acid Chemical compound OS(O)=O LSNNMFCWUKXFEE-UHFFFAOYSA-N 0.000 claims description 4
- GOLMDYICQCEUEH-MRXNPFEDSA-N (2R)-1-(4-acetamidophenyl)sulfonyl-2,3-dihydroindole-2-carboxylic acid Chemical compound C1=CC(NC(=O)C)=CC=C1S(=O)(=O)N1C2=CC=CC=C2C[C@@H]1C(O)=O GOLMDYICQCEUEH-MRXNPFEDSA-N 0.000 claims description 3
- DCAXZAOOFCHFCB-VMPREFPWSA-N (2S)-N-(2-methoxyethyl)-1-[(2S)-1-naphthalen-2-ylsulfonyl-2,3-dihydroindole-2-carbonyl]-2,3-dihydroindole-2-carboxamide Chemical compound C1=CC=CC2=CC(S(=O)(=O)N3C4=CC=CC=C4C[C@H]3C(=O)N3C4=CC=CC=C4C[C@H]3C(=O)NCCOC)=CC=C21 DCAXZAOOFCHFCB-VMPREFPWSA-N 0.000 claims description 3
- QNRXNRGSOJZINA-UHFFFAOYSA-N 2,3-dihydro-1H-indole-2-carboxylic acid Chemical compound C1=CC=C2NC(C(=O)O)CC2=C1 QNRXNRGSOJZINA-UHFFFAOYSA-N 0.000 claims description 3
- 208000006673 Asthma Diseases 0.000 claims description 3
- 229960003444 IMMUNOSUPPRESSANTS Drugs 0.000 claims description 3
- ROHFNLRQFUQHCH-YFKPBYRVSA-N L-leucine Chemical compound CC(C)C[C@H](N)C(O)=O ROHFNLRQFUQHCH-YFKPBYRVSA-N 0.000 claims description 3
- 150000001412 amines Chemical class 0.000 claims description 3
- 235000001014 amino acid Nutrition 0.000 claims description 3
- 239000002775 capsule Substances 0.000 claims description 3
- 229910052799 carbon Inorganic materials 0.000 claims description 3
- JBDSSBMEKXHSJF-UHFFFAOYSA-N cyclopentanecarboxylic acid Chemical compound OC(=O)C1CCCC1 JBDSSBMEKXHSJF-UHFFFAOYSA-N 0.000 claims description 3
- 201000010099 disease Diseases 0.000 claims description 3
- 239000007788 liquid Substances 0.000 claims description 3
- 239000000829 suppository Substances 0.000 claims description 3
- 239000003826 tablet Substances 0.000 claims description 3
- CNMAQBJBWQQZFZ-LURJTMIESA-N (2S)-2-(pyridin-2-ylamino)propanoic acid Chemical compound OC(=O)[C@H](C)NC1=CC=CC=N1 CNMAQBJBWQQZFZ-LURJTMIESA-N 0.000 claims description 2
- ASJNQYMOHLRWQG-VXKWHMMOSA-N (2S)-N-(2-methoxyethyl)-1-[2-[(2S)-1-(4-methylphenyl)sulfonylpyrrolidin-2-yl]-2-oxoacetyl]-2,3-dihydroindole-2-carboxamide Chemical compound C([C@H]1C(=O)C(=O)N2C3=CC=CC=C3C[C@H]2C(=O)NCCOC)CCN1S(=O)(=O)C1=CC=C(C)C=C1 ASJNQYMOHLRWQG-VXKWHMMOSA-N 0.000 claims description 2
- OXFGRWIKQDSSLY-UHFFFAOYSA-N 1,2,3,4-tetrahydroisoquinolin-2-ium-1-carboxylate Chemical compound C1=CC=C2C(C(=O)O)NCCC2=C1 OXFGRWIKQDSSLY-UHFFFAOYSA-N 0.000 claims description 2
- IJVLVRYLIMQVDD-UHFFFAOYSA-N 1,3-thiazole-2-carboxylic acid Chemical compound OC(=O)C1=NC=CS1 IJVLVRYLIMQVDD-UHFFFAOYSA-N 0.000 claims description 2
- JJMDCOVWQOJGCB-UHFFFAOYSA-N 5-aminopentanoic acid zwitterion Chemical compound [NH3+]CCCCC([O-])=O JJMDCOVWQOJGCB-UHFFFAOYSA-N 0.000 claims description 2
- MDFFNEOEWAXZRQ-UHFFFAOYSA-N Amino radical Chemical compound [NH2] MDFFNEOEWAXZRQ-UHFFFAOYSA-N 0.000 claims description 2
- 239000004475 Arginine Substances 0.000 claims description 2
- 229960001230 Asparagine Drugs 0.000 claims description 2
- 210000001124 Body Fluids Anatomy 0.000 claims description 2
- 206010011224 Cough Diseases 0.000 claims description 2
- MTCFGRXMJLQNBG-UWTATZPHSA-N D-serine Chemical compound OC[C@@H](N)C(O)=O MTCFGRXMJLQNBG-UWTATZPHSA-N 0.000 claims description 2
- QIVBCDIJIAJPQS-SECBINFHSA-N D-tryptophane Chemical compound C1=CC=C2C(C[C@@H](N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-SECBINFHSA-N 0.000 claims description 2
- 229960002989 Glutamic Acid Drugs 0.000 claims description 2
- SRJOCJYGOFTFLH-UHFFFAOYSA-N Isonipecotic acid Chemical compound OC(=O)C1CCNCC1 SRJOCJYGOFTFLH-UHFFFAOYSA-N 0.000 claims description 2
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 claims description 2
- DCXYFEDJOCDNAF-REOHCLBHSA-N L-asparagine Chemical compound OC(=O)[C@@H](N)CC(N)=O DCXYFEDJOCDNAF-REOHCLBHSA-N 0.000 claims description 2
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 claims description 2
- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 claims description 2
- AHLPHDHHMVZTML-BYPYZUCNSA-N L-ornithine Chemical compound NCCC[C@H](N)C(O)=O AHLPHDHHMVZTML-BYPYZUCNSA-N 0.000 claims description 2
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 claims description 2
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 claims description 2
- AYFVYJQAPQTCCC-GBXIJSLDSA-N L-threonine Chemical compound C[C@@H](O)[C@H](N)C(O)=O AYFVYJQAPQTCCC-GBXIJSLDSA-N 0.000 claims description 2
- XJLSEXAGTJCILF-UHFFFAOYSA-N Nipecotic acid Chemical compound OC(=O)C1CCCNC1 XJLSEXAGTJCILF-UHFFFAOYSA-N 0.000 claims description 2
- 229960003104 Ornithine Drugs 0.000 claims description 2
- 229960005190 Phenylalanine Drugs 0.000 claims description 2
- HXEACLLIILLPRG-UHFFFAOYSA-N Pipecolic acid Chemical compound OC(=O)C1CCCCN1 HXEACLLIILLPRG-UHFFFAOYSA-N 0.000 claims description 2
- 239000004473 Threonine Substances 0.000 claims description 2
- 229960004799 Tryptophan Drugs 0.000 claims description 2
- 229960003121 arginine Drugs 0.000 claims description 2
- 235000009582 asparagine Nutrition 0.000 claims description 2
- 239000010839 body fluid Substances 0.000 claims description 2
- 150000002148 esters Chemical class 0.000 claims description 2
- 235000013922 glutamic acid Nutrition 0.000 claims description 2
- 239000004220 glutamic acid Substances 0.000 claims description 2
- 150000002366 halogen compounds Chemical class 0.000 claims description 2
- 239000007937 lozenge Substances 0.000 claims description 2
- 101700041618 nhr-4 Proteins 0.000 claims description 2
- IOQPZZOEVPZRBK-UHFFFAOYSA-N octan-1-amine Chemical compound CCCCCCCCN IOQPZZOEVPZRBK-UHFFFAOYSA-N 0.000 claims description 2
- 230000001717 pathogenic Effects 0.000 claims description 2
- 239000000843 powder Substances 0.000 claims description 2
- 201000004681 psoriasis Diseases 0.000 claims description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-M toluene-4-sulfonate Chemical compound CC1=CC=C(S([O-])(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-M 0.000 claims description 2
- 239000003085 diluting agent Substances 0.000 claims 2
- DKTIEDYFVONSKG-NSOVKSMOSA-N (2S)-N-(2-methoxyethyl)-1-[(2S)-1-naphthalen-1-ylsulfonyl-2,3-dihydroindole-2-carbonyl]-2,3-dihydroindole-2-carboxamide Chemical compound C1=CC=C2C(S(=O)(=O)N3C4=CC=CC=C4C[C@H]3C(=O)N3C4=CC=CC=C4C[C@H]3C(=O)NCCOC)=CC=CC2=C1 DKTIEDYFVONSKG-NSOVKSMOSA-N 0.000 claims 1
- 206010003816 Autoimmune disease Diseases 0.000 claims 1
- 206010009900 Colitis ulcerative Diseases 0.000 claims 1
- 206010021425 Immune system disease Diseases 0.000 claims 1
- 206010053643 Neurodegenerative disease Diseases 0.000 claims 1
- 206010072736 Rheumatic disease Diseases 0.000 claims 1
- 206010039083 Rhinitis Diseases 0.000 claims 1
- FDDDEECHVMSUSB-UHFFFAOYSA-N Sulfanilamide Chemical compound NC1=CC=C(S(N)(=O)=O)C=C1 FDDDEECHVMSUSB-UHFFFAOYSA-N 0.000 claims 1
- 125000005001 aminoaryl group Chemical group 0.000 claims 1
- 125000005605 benzo group Chemical group 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 claims 1
- 229960001663 sulfanilamide Drugs 0.000 claims 1
- 201000006704 ulcerative colitis Diseases 0.000 claims 1
- 230000003110 anti-inflammatory Effects 0.000 abstract description 2
- 230000000324 neuroprotective Effects 0.000 abstract description 2
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 48
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 42
- YMWUJEATGCHHMB-UHFFFAOYSA-N methylene dichloride Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 29
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Natural products CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 19
- 108010036949 Cyclosporine Proteins 0.000 description 13
- 239000011780 sodium chloride Substances 0.000 description 13
- PMATZTZNYRCHOR-CGLBZJNRSA-N (3S,6S,9S,12R,15S,18S,21S,24S,30S,33S)-30-ethyl-33-[(E,1R,2R)-1-hydroxy-2-methylhex-4-enyl]-1,4,7,10,12,15,19,25,28-nonamethyl-6,9,18,24-tetrakis(2-methylpropyl)-3,21-di(propan-2-yl)-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotritriacontane-2,5,8,11,14,17 Chemical compound CC[C@@H]1NC(=O)[C@H]([C@H](O)[C@H](C)C\C=C\C)N(C)C(=O)[C@H](C(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)N(C)C(=O)CN(C)C1=O PMATZTZNYRCHOR-CGLBZJNRSA-N 0.000 description 12
- 229960001265 ciclosporin Drugs 0.000 description 12
- 238000002844 melting Methods 0.000 description 12
- 230000000694 effects Effects 0.000 description 11
- 150000003839 salts Chemical class 0.000 description 11
- 108010002350 Interleukin-2 Proteins 0.000 description 10
- 102000000588 Interleukin-2 Human genes 0.000 description 10
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 230000002401 inhibitory effect Effects 0.000 description 8
- 102100001877 FKBP6 Human genes 0.000 description 6
- 108060002918 FKBP6 Proteins 0.000 description 6
- 210000001744 T-Lymphocytes Anatomy 0.000 description 6
- 239000007864 aqueous solution Substances 0.000 description 6
- 210000004027 cells Anatomy 0.000 description 6
- 238000000354 decomposition reaction Methods 0.000 description 6
- 238000000034 method Methods 0.000 description 6
- 230000035755 proliferation Effects 0.000 description 6
- 102000004631 Calcineurin Human genes 0.000 description 5
- 108010042955 Calcineurin Proteins 0.000 description 5
- QFJCIRLUMZQUOT-HPLJOQBZSA-N Sirolimus Chemical compound C1C[C@@H](O)[C@H](OC)C[C@@H]1C[C@@H](C)[C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@](O)(O2)[C@H](C)CC[C@H]2C[C@H](OC)/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C1 QFJCIRLUMZQUOT-HPLJOQBZSA-N 0.000 description 5
- 230000000875 corresponding Effects 0.000 description 5
- 229960002930 sirolimus Drugs 0.000 description 5
- 108010068682 Cyclophilins Proteins 0.000 description 4
- 102000001493 Cyclophilins Human genes 0.000 description 4
- 239000002585 base Substances 0.000 description 4
- VLKZOEOYAKHREP-UHFFFAOYSA-N hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 4
- 150000007522 mineralic acids Chemical class 0.000 description 4
- 150000007524 organic acids Chemical class 0.000 description 4
- 235000005985 organic acids Nutrition 0.000 description 4
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 102100006400 CSF2 Human genes 0.000 description 3
- 108010017213 Granulocyte-Macrophage Colony-Stimulating Factor Proteins 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- 102000004388 Interleukin-4 Human genes 0.000 description 3
- 108090000978 Interleukin-4 Proteins 0.000 description 3
- 102100009534 TNF Human genes 0.000 description 3
- 108010027179 Tacrolimus Binding Proteins Proteins 0.000 description 3
- 102000018679 Tacrolimus Binding Proteins Human genes 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 238000007792 addition Methods 0.000 description 3
- 230000000172 allergic Effects 0.000 description 3
- 201000008937 atopic dermatitis Diseases 0.000 description 3
- 230000005540 biological transmission Effects 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 125000004432 carbon atoms Chemical group C* 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 102000005962 receptors Human genes 0.000 description 3
- 108020003175 receptors Proteins 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- KAQMVSFROXTIET-DQEYMECFSA-N (2S)-1-[(2S)-1-(4-aminophenyl)sulfonyl-2,3-dihydroindole-2-carbonyl]-N-(2-methoxyethyl)-2,3-dihydroindole-2-carboxamide Chemical compound C([C@H]1C(=O)N2C3=CC=CC=C3C[C@H]2C(=O)NCCOC)C2=CC=CC=C2N1S(=O)(=O)C1=CC=C(N)C=C1 KAQMVSFROXTIET-DQEYMECFSA-N 0.000 description 2
- AJLDLTXTWKNDTC-SFTDATJTSA-N (2S)-1-[2-[(2S)-1-(4-aminophenyl)sulfonylpyrrolidin-2-yl]-2-oxoacetyl]-N-(2-methoxyethyl)-2,3-dihydroindole-2-carboxamide Chemical compound C([C@H]1C(=O)C(=O)N2C3=CC=CC=C3C[C@H]2C(=O)NCCOC)CCN1S(=O)(=O)C1=CC=C(N)C=C1 AJLDLTXTWKNDTC-SFTDATJTSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N (E)-but-2-enedioate;hydron Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- TYHYESDUJZRBKS-UHFFFAOYSA-N 2,3-dihydroindole-1-carboxylic acid Chemical compound C1=CC=C2N(C(=O)O)CCC2=C1 TYHYESDUJZRBKS-UHFFFAOYSA-N 0.000 description 2
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 2
- MJDVREQKNCSKIN-QGZVFWFLSA-N C([C@@H]1C(=O)OC)C2=CC=CC=C2N1S(=O)(=O)C1=CC=C(NC(C)=O)C=C1 Chemical compound C([C@@H]1C(=O)OC)C2=CC=CC=C2N1S(=O)(=O)C1=CC=C(NC(C)=O)C=C1 MJDVREQKNCSKIN-QGZVFWFLSA-N 0.000 description 2
- 102100005003 IL5 Human genes 0.000 description 2
- 108010002616 Interleukin-5 Proteins 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 108091008153 T cell receptors Proteins 0.000 description 2
- 102000016266 T-Cell Antigen Receptors Human genes 0.000 description 2
- 108010001801 Tumor Necrosis Factor-alpha Proteins 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 150000001335 aliphatic alkanes Chemical class 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- 201000005794 allergic hypersensitivity disease Diseases 0.000 description 2
- 239000012298 atmosphere Substances 0.000 description 2
- 239000011230 binding agent Substances 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- 125000005521 carbonamide group Chemical group 0.000 description 2
- 230000001413 cellular Effects 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 238000004821 distillation Methods 0.000 description 2
- 239000008079 hexane Substances 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 230000003993 interaction Effects 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000006011 modification reaction Methods 0.000 description 2
- 230000037361 pathway Effects 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 230000002194 synthesizing Effects 0.000 description 2
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- 230000035897 transcription Effects 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 239000003981 vehicle Substances 0.000 description 2
- FUSBZCGQMOAQGF-VXKWHMMOSA-N (2S)-1-[2-[(2S)-1-(4-aminophenyl)sulfonylpiperidin-2-yl]-2-oxoacetyl]-N-(2-methoxyethyl)-2,3-dihydroindole-2-carboxamide Chemical compound C([C@H]1C(=O)C(=O)N2C3=CC=CC=C3C[C@H]2C(=O)NCCOC)CCCN1S(=O)(=O)C1=CC=C(N)C=C1 FUSBZCGQMOAQGF-VXKWHMMOSA-N 0.000 description 1
- HNFMAICDNRRJNA-UHFFFAOYSA-N 1-(2-methoxyethyl)-2,3-dihydroindole-2-carboxamide Chemical compound C1=CC=C2N(CCOC)C(C(N)=O)CC2=C1 HNFMAICDNRRJNA-UHFFFAOYSA-N 0.000 description 1
- DCHRPVKVHPHOBG-UHFFFAOYSA-N 1-[1-(4-acetamidophenyl)sulfonyl-2,3-dihydroindole-2-carbonyl]-2,3-dihydroindole-2-carboxylic acid Chemical compound C1=CC(NC(=O)C)=CC=C1S(=O)(=O)N1C2=CC=CC=C2CC1C(=O)N1C2=CC=CC=C2CC1C(O)=O DCHRPVKVHPHOBG-UHFFFAOYSA-N 0.000 description 1
- IYVYLVCVXXCYRI-UHFFFAOYSA-N 1-propylimidazole Chemical compound CCCN1C=CN=C1 IYVYLVCVXXCYRI-UHFFFAOYSA-N 0.000 description 1
- ATEDHUGCKSZDCP-UHFFFAOYSA-N 2,3-dihydro-1H-indole-2-carboxamide Chemical compound C1=CC=C2NC(C(=O)N)CC2=C1 ATEDHUGCKSZDCP-UHFFFAOYSA-N 0.000 description 1
- ABFPKTQEQNICFT-UHFFFAOYSA-M 2-chloro-1-methylpyridin-1-ium;iodide Chemical compound [I-].C[N+]1=CC=CC=C1Cl ABFPKTQEQNICFT-UHFFFAOYSA-M 0.000 description 1
- HKJUOMPYMPXLFS-UHFFFAOYSA-N 4-(4-hydroxy-3,5-diiodophenoxy)-3,5-diiodobenzoic acid Chemical compound IC1=CC(C(=O)O)=CC(I)=C1OC1=CC(I)=C(O)C(I)=C1 HKJUOMPYMPXLFS-UHFFFAOYSA-N 0.000 description 1
- JVVRCYWZTJLJSG-UHFFFAOYSA-N 4-Dimethylaminophenol Substances CN(C)C1=CC=C(O)C=C1 JVVRCYWZTJLJSG-UHFFFAOYSA-N 0.000 description 1
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 1
- HVCNXQOWACZAFN-UHFFFAOYSA-N 4-ethylmorpholine Chemical compound CCN1CCOCC1 HVCNXQOWACZAFN-UHFFFAOYSA-N 0.000 description 1
- 125000006418 4-methylphenylsulfonyl group Chemical group 0.000 description 1
- 206010001897 Alzheimer's disease Diseases 0.000 description 1
- 101700067048 CDC13 Proteins 0.000 description 1
- 108090000317 Chymotrypsin Proteins 0.000 description 1
- 229940064701 Corticosteroid nasal preparations for topical use Drugs 0.000 description 1
- 229960001334 Corticosteroids Drugs 0.000 description 1
- 241001044073 Cypa Species 0.000 description 1
- 102000004127 Cytokines Human genes 0.000 description 1
- 108090000695 Cytokines Proteins 0.000 description 1
- IQFYYKKMVGJFEH-XLPZGREQSA-N DEOXYTHYMIDINE Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](CO)[C@@H](O)C1 IQFYYKKMVGJFEH-XLPZGREQSA-N 0.000 description 1
- DYHSDKLCOJIUFX-UHFFFAOYSA-N Di-tert-butyl dicarbonate Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 1
- 102100014139 FKBP1A Human genes 0.000 description 1
- 241000233866 Fungi Species 0.000 description 1
- 229940093912 Gynecological Sulfonamides Drugs 0.000 description 1
- JKMHFZQWWAIEOD-UHFFFAOYSA-N HEPES Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 1
- 239000007995 HEPES buffer Substances 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- 206010062016 Immunosuppression Diseases 0.000 description 1
- 102000004195 Isomerases Human genes 0.000 description 1
- 108090000769 Isomerases Proteins 0.000 description 1
- 210000003734 Kidney Anatomy 0.000 description 1
- KZSNJWFQEVHDMF-BYPYZUCNSA-N L-valine Chemical compound CC(C)[C@H](N)C(O)=O KZSNJWFQEVHDMF-BYPYZUCNSA-N 0.000 description 1
- 210000002540 Macrophages Anatomy 0.000 description 1
- 210000000138 Mast Cells Anatomy 0.000 description 1
- COTNUBDHGSIOTA-UHFFFAOYSA-N MeOH methanol Chemical compound OC.OC COTNUBDHGSIOTA-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-XIXRPRMCSA-N Mesotartaric acid Chemical compound OC(=O)[C@@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-XIXRPRMCSA-N 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- OKDQKPLMQBXTNH-UHFFFAOYSA-N N,N-dimethyl-2H-pyridin-1-amine Chemical compound CN(C)N1CC=CC=C1 OKDQKPLMQBXTNH-UHFFFAOYSA-N 0.000 description 1
- 102000002673 NFATC Transcription Factors Human genes 0.000 description 1
- 108010018525 NFATC Transcription Factors Proteins 0.000 description 1
- 239000007832 Na2SO4 Substances 0.000 description 1
- 206010029350 Neurotoxicity Diseases 0.000 description 1
- 210000004940 Nucleus Anatomy 0.000 description 1
- 102100010818 PPIB Human genes 0.000 description 1
- 101700009772 PPIC Proteins 0.000 description 1
- WLJNZVDCPSBLRP-UHFFFAOYSA-N Pamoic acid Chemical compound C1=CC=C2C(CC=3C4=CC=CC=C4C=C(C=3O)C(=O)O)=C(O)C(C(O)=O)=CC2=C1 WLJNZVDCPSBLRP-UHFFFAOYSA-N 0.000 description 1
- 206010061536 Parkinson's disease Diseases 0.000 description 1
- 102000009658 Peptidylprolyl Isomerase Human genes 0.000 description 1
- 108010020062 Peptidylprolyl Isomerase Proteins 0.000 description 1
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 1
- WROMPOXWARCANT-UHFFFAOYSA-N TFA trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.OC(=O)C(F)(F)F WROMPOXWARCANT-UHFFFAOYSA-N 0.000 description 1
- 101710040537 TNF Proteins 0.000 description 1
- QJJXYPPXXYFBGM-LFZNUXCKSA-N Tacrolimus Chemical compound C1C[C@@H](O)[C@H](OC)C[C@@H]1\C=C(/C)[C@@H]1[C@H](C)[C@@H](O)CC(=O)[C@H](CC=C)/C=C(C)/C[C@H](C)C[C@H](OC)[C@H]([C@H](C[C@H]2C)OC)O[C@@]2(O)C(=O)C(=O)N2CCCC[C@H]2C(=O)O1 QJJXYPPXXYFBGM-LFZNUXCKSA-N 0.000 description 1
- 229960001967 Tacrolimus Drugs 0.000 description 1
- 108010006877 Tacrolimus Binding Protein 1A Proteins 0.000 description 1
- 206010044221 Toxic encephalopathy Diseases 0.000 description 1
- 206010067584 Type 1 diabetes mellitus Diseases 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 125000005214 aminoheteroaryl group Chemical group 0.000 description 1
- 102000004965 antibodies Human genes 0.000 description 1
- 108090001123 antibodies Proteins 0.000 description 1
- 230000001363 autoimmune Effects 0.000 description 1
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 1
- 102000024070 binding proteins Human genes 0.000 description 1
- 108091007650 binding proteins Proteins 0.000 description 1
- 230000000903 blocking Effects 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 238000001516 cell proliferation assay Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 229960002376 chymotrypsin Drugs 0.000 description 1
- 238000007697 cis-trans-isomerization reaction Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000003246 corticosteroid Substances 0.000 description 1
- 108010048032 cyclophilin B Proteins 0.000 description 1
- PMATZTZNYRCHOR-UHFFFAOYSA-N cyclosporine A Chemical compound CCC1NC(=O)C(C(O)C(C)CC=CC)N(C)C(=O)C(C(C)C)N(C)C(=O)C(CC(C)C)N(C)C(=O)C(CC(C)C)N(C)C(=O)C(C)NC(=O)C(C)NC(=O)C(CC(C)C)N(C)C(=O)C(C(C)C)NC(=O)C(CC(C)C)N(C)C(=O)CN(C)C1=O PMATZTZNYRCHOR-UHFFFAOYSA-N 0.000 description 1
- 230000001086 cytosolic Effects 0.000 description 1
- 230000001419 dependent Effects 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 238000009510 drug design Methods 0.000 description 1
- 238000007876 drug discovery Methods 0.000 description 1
- 229940079593 drugs Drugs 0.000 description 1
- 238000000921 elemental analysis Methods 0.000 description 1
- 230000002255 enzymatic Effects 0.000 description 1
- 238000007824 enzymatic assay Methods 0.000 description 1
- 238000006911 enzymatic reaction Methods 0.000 description 1
- 238000001952 enzyme assay Methods 0.000 description 1
- 230000002349 favourable Effects 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 238000005755 formation reaction Methods 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N fumaric acid Chemical compound OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 239000001963 growth media Substances 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 1
- KJUGUADJHNHALS-UHFFFAOYSA-O hydron;2H-tetrazole Chemical class C1=NN=[NH+]N1 KJUGUADJHNHALS-UHFFFAOYSA-O 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
- 125000004246 indolin-2-yl group Chemical group [H]N1C(*)=C([H])C2=C([H])C([H])=C([H])C([H])=C12 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 229940079867 intestinal antiinfectives Sulfonamides Drugs 0.000 description 1
- 238000009114 investigational therapy Methods 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 238000006317 isomerization reaction Methods 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- URORFKDEPJFPOV-UHFFFAOYSA-N methyl 2,3-dihydro-1H-indole-2-carboxylate Chemical compound C1=CC=C2NC(C(=O)OC)CC2=C1 URORFKDEPJFPOV-UHFFFAOYSA-N 0.000 description 1
- 230000000051 modifying Effects 0.000 description 1
- 201000006417 multiple sclerosis Diseases 0.000 description 1
- 239000005445 natural product Substances 0.000 description 1
- 230000021616 negative regulation of cell division Effects 0.000 description 1
- 230000035771 neuroregeneration Effects 0.000 description 1
- 230000002887 neurotoxic Effects 0.000 description 1
- 231100000228 neurotoxicity Toxicity 0.000 description 1
- 229940005938 ophthalmologic antiinfectives Sulfonamides Drugs 0.000 description 1
- 230000003287 optical Effects 0.000 description 1
- 239000000546 pharmaceutic aid Substances 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 230000002035 prolonged Effects 0.000 description 1
- 235000018102 proteins Nutrition 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 239000012266 salt solution Substances 0.000 description 1
- 231100000486 side effect Toxicity 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 150000003456 sulfonamides Chemical class 0.000 description 1
- 150000003457 sulfones Chemical class 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 229960001367 tartaric acid Drugs 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 229940026752 topical Sulfonamides Drugs 0.000 description 1
- 229940083878 topical for treatment of hemorrhoids and anal fissures Corticosteroids Drugs 0.000 description 1
- 210000004881 tumor cells Anatomy 0.000 description 1
- 239000004474 valine Substances 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Abstract
New specific immunophilin ligands ofgeneral formula (I) have anti-asthmatic, anti-allergic, anti-rheumatic, anti-inflammatory, immunosuppressive, anti-psoriatic and neuroprotective effects and are suitable for preparing medicaments.
Description
IMMUNOFILIN SPECIFIC LIGANDS NOVEDOUS AS AGENTS
ANTIASMATICOS, ANTIALERGICOS, ANTIRREUMATICOS, IMMUNOSUPPRESSORS, ANTIPSORIASIS AND NEUROPROTECTORES Description of the invention The invention is related to new specific ligands of the immunofilina of the formula
The radicals R17 R2, R3, X, Y, Z, A, B and D have the following meaning: RL = hydrogen, (C1-C12) -alkyl or (C2-C6) -alkyloxy groups, the alkyl group being straight or branched chain and may be substituted by a mono or bicyclic heteroaryl with 1-4 heteroatoms, preferably N, S, O, such as morpholine, piperazine, piperidine, pyridine, isoquinoline, quinoline, pyrimidine, oxazole, oxadiazole, isoxazole, pyrazole, pyrrole, indole, indazole, phthalazine, thiophene, furan, imidazole, mono- or polysubstituted by a phenyl ring, this phenyl ring being in turn mono- or polysubstituted by halogen, (Ci-Cß) - alkyl, (C3-C) -cycloalkyl, by carboxyl groups, carboxyl groups esterified with straight or branched chain (Ci-Ce) -alkanols, carbamoyl groups, trifluoromethyl groups, hydroxyl groups, methoxy groups, ethoxy groups, benzyloxy groups, amino, being that these in turn are again replaced by benzyl, benzoyl, acetyl lo, Ri can also be the amino radical of the following amino acid methyl esters: histidine, leucine, valine, serine (Bzl), threonine, pipecolinic acid, 4-piperidinecarboxylic acid, 3-piperidinecarboxylic acid, e-NH2_lisin, 8_Z- NH2-lysine, e- (2C1Z) -NH-lysine, 2-pyridylalanine, phenylalanine, tryptophan, glutamic acid, arginine (Cough), asparagine, citroline, homocitroline, ornithine, thiazolecarboxylic acid, proline, 2-indoline-carboxylic acid, octahydrindolinecarboxylic acid, tetrahydroisoquinolinecarboxylic acid, 5-aminovaleric acid, 8-aminooctane acid, R2 = hydrogen, (C? -C? 2) -alkyl or (C2-C6) -alkyloxy groups, wherein the alkyl group is straight-chain or branched and may be substituted by a mono or bicyclic heteroaryl with 1-4 heteroatoms, preferably N, S, 0, such as morpholine, piperazine, piperidine, pyridine, isoquinoline, quinoline, pyrimidine, oxazole, oxadiazole, isoxazole, pyrazole, pyrrole, indole, indazole, ft alazine, thiophene, furan, imidazole, mono- or polysubstituted by a phenyl ring. This phenyl ring in turn may be mono- or polysubstituted by halogen, (C6C6) -alkyl, (C3-G7) -cycloalkyl, by carboxyl groups, carboxyl groups esterified with (Ci-Ce) -chain alkanes linear or branched, carbamoyl groups, trifluoromethyl groups, hydroxyl groups, methoxy groups, ethoxy groups, benzyloxy groups, amino groups, these being in turn again substituted by benzyl, benzoyl, acetyl, or may be substituted by aryl or heteroaryl mono , bi or tricyclic with 1-4 heteroatoms, preferably N, S, O, or by carboxy (C1-C2) -alkyl, carboxycyclopentane, carboxycyclohexane, benzoyl which may be mono- or polysubstituted by halogen, methoxy groups, amino groups , carbamoyl groups, trifluoromethyl groups, carboxyl groups, carboxyl groups esterified with straight or branched chain (Ci-Cß) -alkanols, amino- (C 1 -C 12) -alkyl or amino- (C 2 -C 6) -alkyloxy groups, being the alkyl group is straight chain or ram and can be substituted by a mono or bicyclic heteroaryl with 1-4 heteroatoms, preferably N, S, O, such as morpholine, piperazine, piperidine, pyridine, isoquinoline, quinoline, pyrimidine, oxazole, oxadiazole, isoxazole, pyrazole, pyrrole, indole, indazole, phthalazine, thiophene, furan, imidazole, mono- or polysubstituted by a phenyl ring. This phenyl ring in turn can be mono or polysubstituted by halogen, (C6C6) alkyl, (C3C7) cycloalkyl, by carboxyl groups, carboxyl groups esterified with (C6C6) chain alkanes linear or branched, carbamoyl groups, trifluoromethyl groups, hydroxyl groups, methoxy groups, ethoxy groups, benzyloxy groups, amino groups, these being in turn again substituted by benzyl, benzoyl, acetyl, or may be substituted by mono-aryl or mono-, bi- or tricyclic amino-heteroaryl with 1-4 heteroatoms, preferably N, S, O, or by carboxy (C 1 -C 12) -alkyl, carboxycyclopentane, carboxycyclohexane, benzoyl which may be mono- or polysubstituted by halogen, methoxy groups, amino groups, carbamoyl groups, trifluoromethyl groups, carboxyl groups, carboxyl groups esterified with straight or branched chain (C? -C6) -alkanols, R3 H; F, OR, Br, NHR4, R4 hydrogen, (C3-C) -cycloalkyl, (Ci-Cß) -alkyl or carboxy- (C? -C6) -alkyl, wherein the alkyl group can be straight or branched chain and it can be substituted by a carbonyl-aryl or mono, bi- or tricyclic carbonyl-heteroaryl with 1-4 heteroatoms, preferably N, S, O, whereby the aryl or heteroaryl itself can be mono- or polysubstituted by halogen, ( C? -C6) -alkyl, (C3-C7) -cycloalkyl, by carboxyl groups, carboxyl groups esterified with straight or branched chain (Ci-Cd) -alkanols, carbamoyl groups, trifluoromethyl groups, hydroxyl groups, methoxy groups, groups ethoxy, benzyloxy groups, amino groups, these being in turn again substituted by benzyl, benzoyl, acetyl, A = ring-free, aromatic, non-aromatic, aromatic heterocyclic with 1-2 heteroatoms, preferably N, S, O, non-aromatic heterocyclic with 1-2 heteroatoms, preferably N, S, 0, B = CH2 D = CH BD = CH = CX = O, S, H2 Y = S, C, single bond Z = S, 0, NR5 R5 = hydrogen, (C1-C12) -alkyl or (C2-C6) -alkyloxy groups, wherein the alkyl group is straight or branched chain and may be substituted by a mono or bicyclic heteroaryl with 1-4 heteroatoms, preferably N, S, 0, such as morpholine, piperazine, piperidine, indole, indazole, phthalazine, thiophene, furan, imidazole, mono- or polysubstituted by a phenyl ring. This phenyl ring in turn can be mono or polysubstituted by halogen, (Ci-Cß) -alkyl, (C3-C7) -cycloalkyl, by carboxyl groups, carboxyl groups esterified with straight-chain (C? -C6) -alkanols or branched, carbamoyl groups, trifluoromethyl groups, hydroxyl groups, methoxy groups, ethoxy groups, benzyloxy groups, amino groups, these being in turn again substituted by benzyl, benzoyl, acetyl. The invention also relates to physiologically compatible salts of the compounds according to formula I, to the compounds for the preparation of the compounds according to formula I, and to their pharmaceutical use. Cyclosporin A (CsA) or FK 506 are natural immunosuppressive substances that come from fungi, which inhibit the Ca + 2-dependent signal transmission pathway in some cell types. In T cells both agents inhibit the transcription of a series of genes, including the gene for IL-2, which is activated by the stimulation of T-cell receptors (TCR). Both FK 506 and CsA bind with high affinity to soluble receptor proteins (G. Fischer et al., Nature 337, 476-478, 1989, M.W. Harding et al., Nature 341, 755-760, 1989). The FK 506 receptor was named FKBP, the CsA cyclophilin (CyP) receptor. Both proteins catalyze the isomerization of rotamers of cis and trans amide ligands of peptides, and are often specified as immunophilins. The supermolecule of CsA-CyP or of FK 506-FKBP binds calcineurin (CN) and inhibits. its phosphatase activity. As the target molecule of the transcription factor NF-AT, the cytosolic cellular phosphorylated component of CN was identified, which in the case of the absence of CN activity is not dephosphorylated for the activity in the nucleus of the cell, therefore it can not be activated. active transcription complex to the IL-2 promoter. (MK Rosen, SL Schreiber, Angew, Chem. 104 (1992), 413-430, G. Fischer, Angew. Chem. 106 (1994), 1479-1501; Allergic asthmatic diseases are based on an inflammatory reaction that is controlled T cells and their mediators Corticosteroids remain the agent of choice for the treatment of many allergic diseases, and CsA and FK 506 proved to be a favorable therapeutic agent in the case of bronchial asthma and the inflammations on which it is based, both in animal experiments as well as in clinical studies In animal experiments it was possible to demonstrate the blocking of various cytosines such as IL-2, IL-4 and IL-5, which cause inflammations induced by allergy. Despite the multitude of approaches to identify new active inhibitors of the immunophilin, to date it was not possible to prepare or isolate more effective structures than CsA, FK 506, rapamycin or derivatives of these natural substances. However, the high level of inhibition of CsA, FK 506, rapamycin is greatly reduced due to the multitude of side effects, in particular kidney toxicity and neurotoxicity. (N.H. Sigal et al., J. Exp. Med. 173, 619-628, 1991). The background of this fact is that the interaction between the immunophilin ligands and the specific binding proteins of the cells is not specific. Due to this, the known medicinal-therapeutic effect of these immunosuppressants is considerably limited. In addition, the lack of selectivity of the compounds proves to be problematic precisely during the prolonged therapies. Another compound with immunosuppressive properties was discovered when exploring mixtures of combinatorial substances (G. Quinkert, H. Bang and D. Reichert, Helv.Chim, Acta 1996, 79, 1260). In the case of the structure published therein, it is an amide of indolin-2-carboxylic acid which presented at 10 μmol an inhibition of IL-2 proliferation of 77%, at 1 μmol an inhibition of the proliferation of IL-2. of 29%. New measurements resulted in an inhibition of 29% proliferation as a function of IL-2 at a concentration of 10 μmol. The compounds described in this invention clearly stand out from the structure mentioned in the publication for their optical purity of the indolincarboxylic acid in the C-terminal, and furthermore demonstrate an anti-asthmatic, antiallergic, antirheumatic, anti-inflammatory, anti-psoriasis and immunosuppressant activity clearly better. A class of substances that also has indolincarboxylic acid as a central component, and demonstrate immunosuppressive as well as antiasthmatic properties, was described in DE 196 16 509.1. These substances that are described there differ significantly in the N-terminus of the substances described in the invention. The object of the invention is to find new substances with valuable pharmacological characteristics, and to provide them by means of a specific synthesis. By the compounds of the formula I according to the invention a class of substances is constituted that surprisingly binds specifically the immunophilins, inhibits the proliferation in function of IL-2, as well as the liberation of TNF-a and GM-CSF, and surprisingly blocks a signal transmission path based on Ca ++. This class of compounds and their pharmaceutically acceptable salts shows a high affinity to immunophilins such as CyPA, CyPB, CyPC and FKBP12. In addition, the substances of the formula I inhibit various cytokine synthesis, as well as a signal transmission pathway as a function of Ca ++. Those compounds of the formula I that contain asymmetric carbon atoms and therefore as a rule are obtained as racemates can be separated in a manner known per se from the optically active isomers, for example by means of an optically active acid. However, it is also possible to use optically active starting substances from the start, whereby the corresponding optically active compounds or diastereoisomers are obtained as a final product.
That is, the invention comprises compounds of the formula I containing an asymmetric carbon atom, the R form, the S form and R, S mixtures, as well as the diastereomeric forms in the case of several asymmetric carbon atoms. Depending on the process conditions and the starting substances, the compounds of the formula I can be obtained as isolated compounds or in the form of their salts. The salts obtained can be converted in a manner known per se into free bases or acids, for example with acids, alkali or ion exchangers. The compounds of formula I thus isolated can be converted into corresponding physiologically acceptable acid addition salts with inorganic or organic acids or alkalis. Both the free bases and their salts are biologically active. The compounds of the formula I can be administered in the isolated form or as a salt with a physiologically compatible acid or base. The application can be carried out in peroral, parenteral, intravenous, transdermal or inhalation form. The invention also relates to pharmaceutical preparations containing at least one compound of the formula I or its salts with physiologically acceptable inorganic or organic acids or bases, and optionally pharmaceutically usable carriers and auxiliaries. Suitable forms of application are, for example, tablets or dragees, capsules, solutions or else ampoules, suppositories, patches, powder preparations applicable by inhalers. The dosage of the aforementioned pharmaceutical preparations is a function of the condition of the patient and the manner of application. The daily dose of active substance is between 0.01-100 mg / day per kg of body weight. As an example of the compounds of the formula I, we will mention: Example 1 (2S) -l- [. { (2S) -1- (4-acetylamino) -phenylsulfonyl) -indolin-2-yl) -carbonyl] -N- (2-methoxyethyl) -indoline-2-carbamide Example 2 (2R) -l - [((2S ) -1- (4-acetylamino) -phenylsulfonyl) -indolin-2-yl) -carbonyl] -N- (2-methoxyethyl) -indoline-2-carbamide Example 3 (2S) -l - [((2R) - 1- (4-acetylamino) -phenylsulfonyl) -indolin-2-yl) -carbonyl] -N- (2-methoxyethyl) -indoline-2-carbamide Example 4 (2R) -l - [((2R) -1- (4-acetylamino) -phenylsulfonyl) -indolin-2-yl) -carbonyl] -N- (2-methoxyethyl) -indoline-2-carbamide Example 5 (2R, S) -l - [((2R, S) - l ~ (4-acetylamino-phenylsulfonyl) -indolin-2-yl) -carbonyl] -N- (2-methoxyethyl) -indolin-2-carbamide Example 6 (2S) -l - [((2S) -1 - (4-Amino-phenylsulfonyl) -indolin-2-yl) -carbonyl] -N- (2-methoxyethyl) -indolin-2-carbamide Example 7 (2S) -l - [((2S) -1- ( 4-amino-phenylsulfonyl) -prolyl) -carbonyl] -N- (2-methoxyethyl) -indolin-2-carbamide
Example 8 (2S) -l - [((2S) -l- (4-amino-phenylsulfonyl) -ppecolyl) -carbonyl] -N- (2-methoxyethyl) -indolin-2-carbamide Example 9 (2S) -! - [((2S) -l- (4-methyl-phenylsulfonyl) -prolyl) -carbonyl] -N- (2-methoxyethyl) -indolin-2-carbamide Example 10 (2S) -l- [(8-quinolinyl -sulfonyl) -N- (2-methoxy-ethyl) -indoline-carbamide Example 11 1 - [(2S) -1- (4-acetylamino-phenylsulfonyl) -indolin-2-yl) -carbonyl] -N-leucine Example 12 Methyl ester of (S) -Na-. { (2S) -l- [4- (acetylamino) phenylsulfonyl] -indolin-2-yl} -carbonyl-Ns- (benzyloxycarbonyl) -lysine Example 13 (E) (. {(2S) -l- [4- (Acetylamino) phenylsulfonyl] -indolin-2-yl} -carbonyl methyl ester -4- (aminophenyl) acrylic Example 14 (2S) -l - [((2S) -l- (1-naphthalynylsulfonyl) -indolin-2-yl) -carbonyl] -N- (2-methoxyethyl) -indolin-2 Carbamide Example 15 (2S) -l - [((2S) -1- (2-naphthalylsulfonyl) -indolin-2-yl) -carbonyl] -N- (2-methoxyethyl) -indolin-2-carbamide Example 16 ( 2S) -l - [((2S) -1- (4-methyl-phenylsulfonyl) -indolin-2-yl) -carbonyl] -N3- (N-propylimidazole) -indolin-2-carba ida Example 17 (2S) -l - [((2S) -1- (4-Methyl-phenylsulfonyl) -indolin-2-yl) -carbonyl] -N2- (N-ethylmorpholin) -indolin-2-s-carbamide Example 18 (2S) - l - [((2S) -1- (4-methyl-phenylsulfonyl) -indolin-2-yl) -carbonyl] -N 2 - (ethyl-pyridin) -indolin-2-carbamide Example 19 (2S) -l- [ ((2S) -1- (4-Methyl-phenylsulfonyl) -indolin-2-yl) -carbonyl] - (-4-pyridin) -indolin-2-carbamide
Example 20 (2R) - [4- (Acetylamino) -phenylsulfonyl] -indoline-2-carboxylic acid methyl ester Example 21 (2R) - [4- (Acetylamino) -phenylsulfonyl] -indoline-2-carboxylic acid Example 22 (2RS) -1- (. {(2RS) -l- [4- (acetylamino) phenylsulfonyl] -indolin-2-yl}. -carbonyl) -indoline-2-carboxylic acid ester Example 23 acid (2RS) ) -1- ( { (2RS) -l- [4- (acetylamino) -phenylsulfonyl] -indolin-2-yl} .carbonyl) -indoline-2-carboxylic acid.
According to the present invention, the compounds of the formula I can be prepared according to the following processes: ler Process:
í s "< -t
In the first process, the compounds of the formula I according to the invention in which Ri, R2 / Rz, A, B, D, X, Y and Z have the meaning mentioned are prepared by reacting a carboxylic acid derivative of the formula II in which R3, A, B, D, X, Y and Z have the aforementioned meaning, with an amine, an alkanol, a halogen compound or a tosylate III to obtain an amide, an ester or an ether IV wherein R 1 f R 3, A, B, D, X, Y and Z have the meaning mentioned, by reacting this IV derivative after deprotection with acid to obtain an intermediate product V wherein R x, R 3, A, B, D , X, Y and Z have the meaning mentioned and, continuing with the reaction, reacting with a compound VI in which R2 has the aforementioned meaning, or with a compound VIII (see the 2nd Process) in "that R2, R3» A , B, D, X, Y and Z have the meaning mentioned to obtain compound I of the title.
VII VIII
In the second process the compounds of the formula I according to the invention in which Ri, R2, R3 / A, B, D, X, Y and Z have the meaning mentioned are prepared by reacting a carboxylic acid derivative of the Formula VI? , wherein R3, A, B, D, X, Y and Z have the meaning mentioned, with sulfonic acid chloride VI in which R2 has the aforementioned meaning and, continuing with the reaction, reacting with a compound III in which Ri has the aforementioned meaning, or with a compound V in which Ri, R3, A, B, D, X, Y and Z have the aforementioned meaning to obtain compound I of the title. For the preparation of the physiologically compatible salts, the compounds of the formula I are reacted in known manner with inorganic or organic acids, such as, for example, hydrochloric acid. hydrobromic acid, phosphoric acid, sulfuric acid, acetic acid, tartaric acid, citric acid, fumaric acid, maleic acid, lactic acid or embonic acid, or with inorganic or organic alkalis. The pharmaceutical compositions contain at least one compound of the general formula I or its salts with physiologically compatible inorganic or organic acids or alkalis, and optionally pharmaceutically acceptable carriers and excipients. The compounds of the formula I can be applied in peroral, parenteral, intravenous, transdermal or inhalative form, in their pure form or as a salt with a physiologically compatible acid or alkali. Suitable forms of application are, for example, tablets or lozenges, capsules, solutions and ampoules, suppositories, patches or powdered preparations which can be introduced into inhalers. The dosage of these pharmaceutical preparations mentioned above in terms of the state of the patient and the manner of application. The daily dose of active substance is between 0.01-100 mg per kg of body weight. The compounds of the formula (I) according to the invention are distinguished as immunophilin ligands and inhibit their isomerase activity. This prolyl isomerase activity is verified according to a worldwide enzymatic assay: G. Fischer, H. Bang, A. Schellenberger, Biochim. Biophys. Acta, 791, 87-97, 1984; D.H. Rich et al., J. Med. Chem. 38, 4164-4170, 1995). Without in each case influencing the peptidyl-cis-trans-isomerase activity of the immunophilins, these compounds surprisingly inhibit the proliferation of
TNF-α, GM-CSF, IL-2, IL-4 and IL-5 of mast cells, macrophages, and activate T cells. The compounds according to the invention can be applied as cyclosporin A (Sandimmun®, CsA ), FK 506 or well Rapamycin
(Tacrolimus) as immunosuppressants (R.Y. Calne et al., Br.
Med. J. 282, 934-936, 1981), for the treatment of diseases, autoimmune (RH Wiener et al., Hepatology 7, 1025, paragraph 9, 1987; L. Fry, J. Autoiramun., 5, 231-240. , 1992, GJ Feutren J, Autoimmun., 5, 183-195, 1992, EP 610,743), of allergic inflammations (P. Zabel et al., Lancet 343, 1984), as antiasthmatics (C. Bachert, Ate w.-Lungenkrkh 20, 59, 1994), the treatment of insulin-dependent diabetes mellitus (CR Stiller, Science, 223, 1362-1367, 1984), of sepsis, as neuroprotective or also for neuroregeneration in the case of multiple sclerosis , of Alzheimer's and Parkinson's diseases (US 5 614 547, JP 08 333 334, Nature Medicine, 3,4, 1997), as antirheumatics, the treatment of psoriasis (SANDORMA, 4, 1995), and also in combination with known ligands of the immunophilin such as CsA, FK 506 or Rapamycin. (M.J. Wyvratt, N.H. Sigal, Perspectives in Drug Discovery and Design, Immunosuppression, 2,1, 1994, WO 92/21313, US 5 330 993). In the following, the invention is explained in more detail based on exemplary embodiments. The abbreviations used for this are: AcOEt ethyl acetate Boc tert-butyloxycarbonyl (Boc) 20 tert-butoxycarbonyl anhydride CN calcineurin CsA cyclosporin A Cyp cyclophilin DMAP N, N-dimethylaminopyridine EA elemental analysis EE ethyl acetate FKBP protein binder FK 506 HPLC High Performance Liquid Chromatography i. OPV vacuum oil pump Lsg. Solution MeOH methanol PPlase peptidyl-prolin-cis-trans-isomerase i. RV. in the rotary evaporator i. V. in the vacuum RT ambient temperature rae racemic enantio TFA trifluoroacetic acid z benzyloxycarbonyl General instruction for the preparation of carbonamides of the general formula IV: (3.3 mmoles) of Boc protected carboxylic acid, 1 eq (3.3 mmoles) of the amine corresponding and 1.5 eq
(4.9 moles) of 2-chloro-l-methylpyridiniumiodide and 2.5 eq (8.1 mmol, 1.13 ml) of TEA were dissolved or suspended together in DCM, stirred for 30 minutes and refluxed for 6 hours. The solvent was removed by distillation in the rotary evaporator, the residue was absorbed in AcOEt. This suspension was washed in each case twice with an aqueous solution of KHS0 and an aqueous solution of NaOH, and once with a saturated aqueous solution of NaCl, dried over Na2SO and purified by chromatography on silica gel with AcOEt mixtures. / Hexane or CH2Cl2 / MeOH. General instruction for the preparation of sulfonamides of the general formula VIII: 100 mmoles of the amino acid were suspended in water and mixed with 300 mmoles of NaOH and with 110 mmoles of sulfonic acid chloride, and heated for 4 hours at 90 ° C. After cooling it is acidified with HCl
2N aqueous, the precipitated product is separated by suction and dried at 40 ° C. General instruction for the preparation of compounds of the general formula I: 4.7 mmoles of the carbonamides of the general formula IV protected from Boc were stirred for 2 hours at room temperature in DCM / TFA 4: 1. The solvent and the excess TFA were removed in vacuo. The oily residue was stirred for 24 hours at 35 ° C with one (7 mmoles) sulfone ida of the general formula VI, 11.7 mmoles of TEA and
7. 7 mmoles of Mukaiyama reagent in 120 ml of DCM. The solvent was removed by distillation in the rotary evaporator, the residue was absorbed in AcOEt. This suspension was washed in each case twice with an aqueous solution of
KHS0 and an aqueous solution of NaOH, and once with a saturated aqueous solution of NaCl, dried over Na2SO4 and purified by chromatography on silica gel with AcOEt / Hexane or CH2Cl2 / MeOH mixtures.
In accordance with these general instructions, the following compounds of the general formula I were prepared: Example 1 (2S) -l - [((2S) -1- (4-acetylamino) -phenylsulfonyl) -indolin-2-yl) -carbonyl] -N- (2-methoxyethyl) -indoline-2-carbamide. Melting point: 224-227 ° C (decomposition) (AcOEt / PE). DC: DCM / MeOH 95: 5, Rf 0.35 ^ -RMN (270 MHz, (D6) DMSO): 2.01 (s, 3H); 3.08 (s, 3H); 3.09-3.83 (m, 8H); 4.70-5.45 (m, 2H); 6.93-7.41 (m,
7H); 7.62-8.16 (m, 5H); 8.45-8.73 (m, 1H); 10.44 (s, 1H). EA: calculated for C29H3oN406S calculated C 61.91 H 5.37 N 9.96; found C 60.42 H 5.15 N 9.64. Example 2 (2R) -l- [((2S) -1- (4-acetylamino) -phenylsulfonyl) -indolin-2-yl) -carbonyl] -N- (2-methoxyethyl) -indoline-2-carbamide. melting: 223-227 ° C (decomposition) (AcOEt / PE). DC: DCM / MeOH 95: 5, Rf 0.35 ^ -R (270 MHz, (D6) DMSO): 2.0 (s, 3H); 3.09 (s, 3H); 3.10-3.70 (m, 8H); 4.77-5.51 (m, 2H); 6.89-7.39 (m, 7H); 7.60-8.21 (m, 5H); 8.31-8.59 (m, 1H); 10.39 (s, 1H). MS (ESI +): calculated for C29H30 4O6S, M = 562.65; found: M + = 563.72 Example 3 (2S) -l - [((2R) -1- (4-acetylamino) -phenylsulfonyl) -indolin-2-yl) -carbonyl] -N- (2-methoxyethyl) -indoline- 2-carbamide Melting point: 224-227 ° C (decomposition) (AcOEt / PE). DC: DCM / MeOH 95: 5, Rf 0.35 XH-NMR (270 MHz, (D6) DMSO): 2.02 (s, 3H); 3.00 (s, 3H); 3.15-3.80 (m, 8H); 4.72-5.40 (m, 2H); 6.98-7.44 (m, 7H); 7.66-8.22 (m, 5H); 8.48-8.70 (m, 1H); 10.52 (s, 1H). MS (ESI +): calculated for C29H3oN406S, M = 562.65; found: M + = 563.71 Example 4 (2R) -l - [((2R) -1- (4-acetylamino) -phenylsulfonyl) -indolin-2-yl) -carbonyl] -N- (2-methoxyethyl) -indoline- 2-carbamide Melting point: 221-225 ° C (decomposition) (AcOEt / PE). DC: DCM / MeOH 95: 5, Rf 0.35 XH-NMR (270 MHz, (D6) DMSO): 2.08 (s, 3H); 3.00 (s, 3H); 3.11-3.76 (m, 8H); 4.72-5.39 (, 2H); 6.88-7.47 (m, -7H); 7.62-8.17 (, 5H); 8.41-8.68 (m, 1H); 10.43
(s, 1H). MS (ESI +): calculated for C29H3oN406S, M = 562.65; found: M + = 563.7 Example 5 (2R, S) -l - [((2R, S) -1- (4-acetylamino-phenylsulfonyl) -indolin-2-yl) -carbonyl] -N- (2- methoxyethyl) -indolin-2-carbamide Melting point: 220-225 ° C (decomposition) (AcOEt / PE). DC: DCM / MeOH 95: 5, Rf 0.35 XH-NMR (270 MHz, (D6) DMSO): 2.05 (s, 3H); 3.10 (s, 3H); 3.06-3.75 (m, 8H); 4.72-5.40 (m, 2H); 6.91-7.41 (m,
7H); 7.68-8.26 (m, 5H); 8.46-8.79 (m, 1H); 10.41 (s, 1H). EA: calculated for C29H3o 406S x 1/4 H20 (567.15) calculated C 61.41 H 5.42 N 9.87; found C 61.23 H 5.51 N 9.63. Example 6 (2S) -l- [((2S) -1- (4-amino-phenylsulfonyl) -indolin-2-yl) -carbonyl] -N- (2-methoxyethyl) -indolin-2-carbamide DC: DCM / MeOH 95: 5, Rf 0.16 ^ -RMN (270 MHz, (D6) DMSO): 2.0 (s, 3H); 3.02-3.8 (m, 8H); 4.72-5.35 (m, 2H); 6.15 (s, NH2); 6.91-7.41 (m, 7H); 7.68-8.26 (m, 5H); 8.3-8.7 (m, 1H). Example 7 (2S) -l - [((2S) -1- (4-amino-phenylsulfonyl) -prolyl) -carbonyl] -N- (2-methoxyethyl) -indolin-2-carbamide DC: DCM / MeOH 95 : 5, Rf 0.12 XH-NMR (270 MHz, (D6) DMSO): 1.7 (m, 2H); 1.9 (m, 2H); 2.05 (s, 3H); 3.0-3.74 (, 6H); 4.5 (, 1H); 5.1 (m, 1H); 6.05 (s, NH2); 7.0-7.65 (m, 7H); 8.2 (m, 1H). Example 8 (2S) -l - [((2S) -1- (4-amino-phenylsulfonyl) -pipecolyl) -carbonyl] -N- (2-methoxyethyl) -indolin-2-carbamide DC: DCM / MeOH 95: 5, Rf 0.14 XH-NMR (270 MHz, (D6) DMSO): 1.55 (m, 2H); 1.85 (m, 2H); 2.03 (s, 3H); 2.3-2.4 (m, 2H); 2.85-3.65 (m, 6H);
4. 1 (m, 1H); 5.15 (m, 1H); 6.05 (s, NH2); 7.0-7.65 (m, 8H); 8.4 (m, 1H). Example 9 (2S) -l - [((2S) -1- (4-methyl-phenylsulfonyl) -prolyl) -carbonyl] -N- (2-methoxyethyl) -indolin-2-carbamide DC: DCM / MeOH 95: 5, Rf 0.42 XH-NMR (270 MHz, (D6) DMSO): 1.7 (m, 2H); 1.9 (m, 2H); 2.05 (s, 3H); 3.0-3.74 (m, 6H); 4.54 (m, 1H); 5.1 (m, 1H); 7.0-7.65 (, 8H); 8.25 (m, 1H). Example 10 (2S) -l - [(8-quinolinyl-sulfonyl) -N- (2-methoxy-ethyl) -indoline-carbamide DC: DCM / MeOH 95: 5, Rf 0.46 XH-NMR (270 MHz, (D6 DMSO): 3.08 (s, 3H); 3.09-3.83 (m, 4H); 6.15 (m, 1H); 6.65-6.85 (m, 10H); 9.15 (s, 1H). Example 11 1 - [(2S) -1- (4-acetylamino-phenylsulfonyl) -indolin-2-yl) -carbonyl] -N-leucine MS (ESI +): calculated for C23H27N 05S, M = 471.56; found: M + - 471.9, M + + Na + = 495.3 Example 12 Methyl ester of (S) -Na-. { (2S) -l- [4- (acetylamino) phenylsulfonyl] -indolin-2-yl} -carbonyl-Ne- (benzyloxycarbonyl) -lysine Melting point: 189-192 ° C (AcOEt / PE). DC: DCM / MeOH 95: 5, Rf 0.3 XH-NMR (270 MHz, DMSO): 1.2-1.45 (m, 4H); 1.6-1.76 (m, 2H); 2.08 (s, 3H); 2.78-3.21 (s, 5H); 3.63 (s, 3H);
4. 25 (m, 1H); 4.8-4.92 (m, 1H); 5.02 (s, 2H); 6.93-7.45 (m, 9H); 7.65-7.75 (m, 4H); 8.40 (m, 1H); 10.33 (s, 1H). EA: calculated for C32H36N408S (636.83) calculated C 60.36 H 5.70 N 8.8; found C 60.27 H 5.93 N 8.92. EXAMPLE 13 (E) (. {(2S) -l- [4- (Acetylamino) phenylsulfonyl] -indolin-2-yl} .carbonyl-4- (aminophenyl) acrylic acid methyl ester Melting point; -171 ° C (AcOEt) DC: DCM / MeOH 95: 5, Rf 0.63 XH-NMR (270 MHz, DMSO): 2.11 (s, 3H); 3.05-3.11 (m, 1H); 3.27-3.36 (m , 1H), 3.71 (s, 3H), 4.95 (dd, Ji = 4.1, J2 = 13, 1H), 6.68 (d, J «16.1, 1H), 7.00-7.83 (m, 12H), 10.37 (s, 1H); 10.48 (s, 1H) EA: calculated for C27H25N306S x 1/8 H20 (521.83) calculated C 62.14 H 4.87 N 8.01, found C 62.28 H 5.10 N 7.72 Example 14 (2S) -l - [(( 2S) -1- (1-naphthalynesulfonyl) -indolin-2-yl) -carbonyl] -N- (2-methoxyethyl) -indolin-2-carbamide DC: DCM / MeOH 95: 5, Rf 0.35 XH-NMR (270 MHz, (D6) DMSO): 2.05 (s, 3H), 3.10 (s, 3H), 3.0-3.07 (m, 8H), 4.8-5.2 (m, 2H), 6.93-7.41 (, 7H), 7.7- 8.4 (m, 9H) Example 15 (2S) -l - [((2S) -1- (2-naphthalylsulfonyl) -indolin-2-yl) -carbonyl] -N- (2-methoxyethyl) -indolin-2 - carbamide Melting point: 224-227 ° C (decomposition) (AcOEt / P E) DC: DCM / MeOH 95: 5, Rf 0.35 ^ -RM (270 MHz, (D6) DMSO): 2.0 (s, 3H); 3.06 (s, 3H); 3.1-3.8 (m, 8H); 4.75-5.5 (m, 2H); 6.93-7.41 (,
7H); 7.7-8.4 (, 9H). Example 16 (2S) -l- [((2S) -1- (4-methyl-phenylsulfonyl) -indolin-2-yl) -carbonyl] -N3- (N-propylimidazole) -indolin-2-carbamide DC: DCM / MeOH 95: 5, Rf 0.26 ^ -RM (270 MHz, (D6) DMSO): 1.95 (m, 2H); 2.3 (s, 3H); 3.1 (m, 2H); 4.5 (, 2H); 4.64 (m, 1H); 5.1 (, 1H); 6.9-7.85 (m, 15H); 8.2 (m, 1H). Example 17 (2S) -l - [((2S) -1- (4-methyl-phenylsulfonyl) -indolin-2-yl) -carbonyl] -N2- (N-ethylmorpholin) -indolin-2-carbamide DC: DCM / MeOH 95: 5, Rf 0.24 XH-NMR (270 MHz, (D6) DMSO): 1.5-1.7 (m, 4H); 1.9 (m, 4H);
2. 25 (s, 3H); 2.75 (m, 2H); 3.65 (m, 2H); 4.72-5.35 (m, 2H); 6.91-7.71 (m, 12H); 8.4 (m, 1H). Example 18 (2S) -l- [. { (2S) -1- (4-Methyl-phenylsulfonyl) -indolin-2-yl) -carbonyl] -N2- (ethyl-pyridine) -indolin-2-carbamide DC: DCM / MeOH 95: 5, Rf 0.19 ^ - RM (270 MHz, (D6) DMSO): 2.2 (s, 3H); 2.6 (m, 2H); 3.4 (m, 2H); 4.72-5.35 (m, 2H); 6.85-7.9 (m, 12H); 8.4 (m, 1H). Example 19 (2S) -l- [((2S) -1- (4-methyl-phenylsulfonyl) -indolin-2-yl) -carbonyl] - (4-pyridin) -indolin-2-carbamide DC: DCM / MeOH 95: 5, Rf 0.24 XH-NMR (270 MHz, (D6) DMSO): 2.4 (s, 3H); 3.25 (m, 2H); 4.72-5.35 (m, 2H); 6.85-8.1 (m, 16H); 8.4 (m, 1H). EXAMPLE 20 (2R) - [4- (Acetylamino) -phenylsulfonyl] -indoline-2-carboxylic acid methyl ester Melting point: 172-176 ° C (AcOEt / PE). DC: DCM / MeOH 95: 5, Rf 0.44 ^ -R N (270 MHz, (D6) DMSO): 2.22 (s, 3H); 3.0-3.22 (m, 1H); 3.83 (s, 3H); 4.63 (dd, Jx = 15.2, J2 = 5.3,
1 HOUR); 6.88-7.31 (m, 4H); 7.52-7.70 (dd, Ji = 8.9, J2 = 8.9, 4H); 7.93 (s, 1H). EA: calculated for C18Hi8 2? 5S x 1/4 H20 (374.42) calculated C 57.74 H 4.84 N 7.48; found C 56.82 H 4.99 N 7.15.
Example 21 (2R) - [4- (Acetylamino) -phenylsulfonyl] -indoline-2-carboxylic acid Melting point: 198-202 ° C. DC: DCM / MeOH 95: 5, 1% HoAc; Rf 0.20 ^? - NMR (270 MHz, CDC13): 2.08 (s, 3H); 2.97-3.34 (m, 2H); 3.78 (s, 3H); 4.86-4.92 (dd, J = 15.5, 5.4, 1H); 6.95-7.36 (m, 4H); 7.67-7.78 (dd, J = 9.0, 9.0, 4H); 10.33 (s, 1H); 12.97 (s, 1H). EXAMPLE 22 (2RS) -1- ( { (2RS) -l- [4- (Acetylamino) phenylsulfonyl] -indolin-2-yl.} - carbonyl) indoline-2-carboxylic acid methyl ester Melting point : 213-215 ° C (AcOEt / PE). DC: DCM / MeOH 95: 5, 1% HoAc; Rf 0.31 ^ -RM (270 MHz, DMSO): 2.07 (s, 3H); 3.02-3.46 (m, 4H); 3.76 (s, 3H); 5.18-5.69 (m, 2H); 6.95-7.40 (m, 7H); 7.71 (s, 4H); 10.33 (s, 1H). EA: calculated for C27H25 3? 6S x 1 H20 (537.59) calculated C 60.32 H 5.09 N 7.82; found C 60.13 H 4.89 N 7.62. EXAMPLE 23 (2RS) -1- ( { (2RS) -l- [4- (acetylamino) -phenylsulfonyl] -indolin-2-yl} -carbonyl) -indoline-2-carboxylic acid. Melting point: 190-192 ° C. DC: DCM / MeOH 95: 5, Rf 0.23 XH-NMR (270 MHz, DMSO): 2.07 (s, 3H); 3.03-3.70 (m, 4H);
. 05-5.70 (m, 2H); 6.96-7.53 (m, 7H); 7.72 (4H); 7.95-8.09 (m, 1H); 10.35 (s, 1H). EA: calculated for C26H23N3? 6S x 1/2 H20 (514.56) calculated C 60.69 H 4.70 N 8.17; found C 60.64 H 4.81 N 8.03. The examples 1-23 surprisingly exposed turned out to be powerfully binding immunophilin modulators, which are suitable as fixed formula to a vehicle and have the ability to bind immunophilins of pathogenic activity from liquids, in particular from body fluids. To find ligands Cyp B or FKBP strongly binding agents of the formula I, the immobilized ligands were subjected to a SDS-PAGE- with cell homogenate. Ligands fixed to a vehicle that show a particular affinity with respect to the immunophilins specifically bind them with high affinity. The compounds according to formula (I) according to the invention are characterized by immunofilin ligation and inhibit the peptidyl-prolyl-cis-trans-isomerase (PPlase) activity thereof. The inhibition of human cyclophilin B in the PPlase test is determined for the input scan (1 μmol / 1 substance). This PPlase activity is verified according to a worldwide common enzyme assay: G. Fischer, H. Bang, A. Schellenberger, Biochim. Biophys. Acta, 791, 87-97, 1984; D.H. Rich et al., J. Med. Chem. 38, 4164-4170, 1995). The compounds of the general formula I according to the invention are pre-incubated together with 10 nmol of Cyp B for 15 minutes at 4 ° C. The enzymatic reaction is initiated after the addition of chymotrypsin and HEPES regulator with the Suc-Ala-Ala-Pro-Phe-Nan test peptide. The modification of the extinction at 390 nm is then observed and evaluated. The modification of the photoelectrically determined extinction is the result of two partial reactions: a) the rapid chymotryptic splitting of the trans peptide; b) non-enzymatic cis-trans isomerization that is catalyzed by cyclophilins. The corresponding PPlase activity of the compounds of the general formula I > according to the invention is shown in table 1.
Table 1: Compound (10 μmoles) Inhibition (%)
Example 1 (2S) -l - [((2S) -l- (4-acetylamino) -phenylsulfonyl) -indolin-2-yl) -40-carbonyl] -N- (2-methoxyethyl) -indolin-2-carbamide Example 9 (2S) -l - [((2S) -1- (4-methyl-phenylsulphonyl) -prolyl) -carbonyl] -N- (2- 40-60-methoxyethyl) -indolin-2-carbam a Example 10 (2S) -l - [(8-quinolinyl-sulfonyl) -N- 20-40 (2-methoxy-ethyl) -indoline-carbamide Example 11 1 - [(2S) -1- (4-acetylamino-phenylsulfonyl ) -indolin-2-yl) -carbonyl] -N ~ 40 leucine Example 12 methyl ester of (S) -Na-. { (2S) -1- [4- (acetylamino) phenylsulfonyl] -60-indolin-2-yl} -carbonyl-N8- (benzyloxycarbonyl) -lysine Example 13 (E) (. {(2S) l- [4- (acetylamino) phenylsulfonyl] -0-20 indolin-2-yl} methyl ester. -carbonyl-4- (aminophenyl) acrylic Example 14 (2S) -l - [((2S) -1- (1-naphthalynylsulphonyl) -indolin-2-yl) -carbonyl] -N- 20 (2-methoxyethyl) ) -indolin-2-carbamide Example 15 (2S) -l - [((2S) -1- (2-naphthalinyl-sulfonyl) -indolin-2-yl) -carbonyl] -N- 20 (2-methoxyethyl) - indolin-2-carbamide Example 16 (2S) -l - [((2S) -1- (4-methyl-phenylsulphonyl) -indolin-2-yl) -carbonyl] -N3- (N- 20-40 propylimidazole -indolin-2-carbamide
It seems that the formation of the supercellula of CsA-Cyp B-calcineurin (phosphatase as a function of Ca + 2) is responsible for the immunosuppressive effects of known CsA. For the investigation with respect to the interaction with this CsA-Cyp B or CsA-Cyp B-calcineurin supermolecule, the compounds of the general formula I according to the invention were incubated with cell homogenates of a human T-cell line with 3H-CsA (100 nols). After filtering the gel with superose 12, the radioactivity of the eluted fractions was measured and compared with the control without treatment. The corresponding expulsion of 3H-CsA from the supermolecule Cyp B-CsA and Cyp-CsA-calcineurin by the compounds of the general formula I according to the invention is shown in table 2:
Table 2
Example 8 (2S) -l - [((2S) -1- (4-amino-phenylsulphonyl) -pipecolyl) 42 -81 carbonyl] -N- (2-methoxyethyl) indolin-2-carbamide Example 9 (2S) ) -l - [((2S) -1- (4-methyl-phenyl-sulfonyl) -prolyl) -39-64 carbonyl] -N- (2-methoxyetii; indolin-2-carbamide Example 10 (2S) -l - [(8-quinolinyl-sulfonyl) -N- (2-methoxy-ethyl) -15 -54-indolin-carbamide Example 11 1 - [(2S) -1- (4-acetylamino-phenyl-sulfonyl) -indolin-2- il) - 12 carbonyl] -N-leucine Example 12 methyl ester of (S) -N0. { (2S) -l- [4- (Asethylamino) -phenylsulfonyl] -indolin-2-yl} - 27 14 carbonyl-Ng- (benzyloxycarbonyl) -lysine Example 13 (E) (. {(2S) -l- [4- (acetylamino) -phenylsulfonyl] -indolin-2-yl) methyl ester .}. - 19 carbonyl-4- (aminophenyl) - acrylic
The proliferation assay of IL-2 is based on the incorporation of 3H-thymidine in T cells stimulated with 0KT-3 (human anti-CD-3 antibodies), and is carried out as follows: 100000 T cells are seeded in 150 μl of culture medium per well in microtiter plates are stimulated by the addition of 0KT-3 (1 μg / ml) and incubated for 45 hours with respectively one of the compounds of the general formula I according to the invention. After this incubation interval, 10 μl of the 3 H-thymidine solution (0.5 μCi) is added to each well by pipette. It is then incubated for 6 hours at 37 ° C in a 5% C02 atmosphere. After collecting the cells, the radioactivity is quantified in a β-counter. The inhibition of induced CD3 proliferation of the compounds of the general formula I according to the invention is shown in Table 3: Table 3
Example 11 1 - [(2S) -1- (4-acetylamino-phenylsulfonyl) -indolin-2-yl) -61 carbonyl] -N-leucine
Example 12 Methyl ester of (S) -Na-. { (2S) -l- [4- (acetylamino) phenyl-79-sulfonyl] -indolin-2-yl} -carbonyl- Ne- (benzyloxycarbonyl) -lysine Example 13 (E) (. {(2S) -l- [4- (acetylamino) -4-phenylsulfonyl] -indolin-2-yl} methyl ester. - carbohydr-4- (aminophenyl) acrylic Example 14 (2S) -l - [((2S) -1- (1-naphthalynylsulphonyl) -indolin-2-yl) -48 carbonyl] -N- (2-methoxyethyl) ) - indolin-2-carbamide Example 15 (2S) -l- [((2S) -1- (2-naphthalenylsulfonyl) -indolin-2-yl) -56 carbonyl] -N- (2-methoxyethyl) - indolin-2-carbamide Example 16 (2S) -l - [((2S) -1- (4-methyl-phenylsulfo-nyl) -indolin-2-yl) -54-carbonyl] -N3- (N-propylimidazole) indoline -2-carbamide The compounds of the general formula I according to the invention show how CsA, FK 506 or rapamycin cause blockage of cytokines such as TNF-α, GM-CSF, IL-2, IL-4 and IL -5 in experiments with animals, which in the case of disease cause allergic induction inflammations.To determine the inhibition of cell division of the compounds of the gene formula In accordance with the invention, 50000 human tumor cells were cultured for 48 hours in the presence of the compounds of the general formula I according to the invention, 10 μl of a yellow tetrazolium salt solution (MTT) were added thereto, and they were continued incubating other 4 hours at 37 ° C in a C02 atmosphere. The resulting violet coloration was analyzed photometrically at 570 nm. After adding 100 μl of SDS solution in each case, the coloration was quantified photometrically after incubation overnight. No general cellular toxicity of the compounds of the general formula I according to the invention could be verified.
Claims (1)
- CLAIMS New specific ligands of the immunophilin of the formula I wherein the radicals Ri, R2, R3, X, Y, Z, A, B and D have the following meaning: Ri hydrogen, (C1-C12) -alkyl or (C2-Cß) -alkyloxy groups, wherein the alkyl group is straight or branched chain and may be substituted by a mono or bicyclic heteroaryl with 1-4 heteroatoms, preferably N, S, 0, such as morpholine, piperazine, piperidine, pyridine, isoquinoline, quinoline, pyrimidine, oxazole, oxadiazole , isoxazole, pyrazole, pyrrole, indole, ± ndazole, phthalazine, thiophene, furan, imidazole, mono- or polysubstituted by a phenyl ring, this phenyl ring being in turn mono- or polysubstituted by halogen, (Ci- Cß) -alkyl, (C3-C7) -cycloalkyl, by carboxyl groups, carboxyl groups esterified with straight or branched chain (Ci-Ce) -alkanols, carbamoyl groups, trifluoromethyl groups, hydroxyl groups, methoxy groups, ethoxy groups, groups benzyloxy, amino groups, being that these in turn are again replaced by benzyl, benzo ilo, acetyl; Ri may also be the amino radical of the following amino acid methyl esters: histidine, leucine, haze, serine (Bzl), threonine, pipecolinic acid, 4-piperidinecarboxylic acid, 3-piperidinecarboxylic acid, 8_ NH2-lysine, e_Z-NH2-lysine , e_ (2C1Z) -NH-lysine, 2-pyridylalanine, phenylalanine, tryptophan, glutamic acid, arginine (Cough), asparagine, citroline, homocitroline, ornithine, thiazolecarboxylic acid, proline, 2-indolino-carboxylic acid, octahydrindolinecarboxylic acid, tetrahydro-isoquinolinecarboxylic acid, 5-amino-valeric acid, 8-amino-octane acid, R 2 = hydrogen, (C 1 -C 12) -alkyl or (C 2 -C 6) -alkyloxy groups, wherein the alkyl group is straight or branched chain and may be substituted by a mono or bicyclic heteroaryl with 1-4 heteroatoms, preferably N, S, 0, such as morpholine, piperazine, piperidine, pyridine, isoquinoline, quinoline, pyrimidine, oxazole, oxadiazole, isoxazole, pyrazole, pyrrole, indole , indazol, ft alazine, thiophene, furan, imidazole, mono- or polysubstituted by a phenyl ring. This phenyl ring in turn can be mono or polysubstituted by halogen, (Ci-Ce) -alkyl, (C3-C) -cycloalkyl, by groups Carboxyl, carboxyl groups esterified with (C? -C6) -alkanols of straight or branched chain, carbamoyl groups, trifluoromethyl groups, hydroxyl groups, methoxy groups, ethoxy groups, benzyloxy groups, amino groups, these being at their They are again substituted by benzyl, benzoyl, acetyl, or can be substituted by mono, bi or tricyclic aryl or heteroaryl with 1-4 heteroatoms, preferably N, S, 0, or by carboxy (C? -C 2) -alkyl, 20 carboxrcyclopentane, carboxycyclohexane, benzoyl which may be mono- or polysubstituted by halogen, methoxy groups, amino groups, carbamoyl groups, trifluoromethyl groups, carboxyl groups, carboxyl groups esterified with 25 (C? -C6) -alkanols of straight or branched chain; R2 = amino- (C1-C12) -alkyl or amino- CC2-C6 groups} - alkyloxy, wherein the alkyl group is straight or branched chain and can be substituted by a mono or bicyclic heteroaryl with 1-4 heteroatoms, preferably N, S, 0, such as morpholine, piperazine, piperidine, pyridine, isoquinoline, quinoline , pyrimidine, oxazole, oxadiazole, isoxazole, pyrazole, pyrrole, indole, indazole, phthalazine, thiophene, furan, 10 imidazole, mono- or polysubstituted by a phenyl ring. This phenyl ring in turn can be mono or polysubstituted by halogen, (Ci-Cß) -alkyl, (C3-C7) -cycloalkyl, by carboxyl groups, carboxyl groups esterified with 15 (Ci-Cβ) -stranched or branched chain alkanols, carbamoyl groups, trifluoromethyl groups, hydroxyl groups, methoxy groups, ethoxy groups, benzyloxy groups, amino groups, these being in turn again substituted by benzyl, Benzoyl, acetyl, or may be substituted by amino-aryl or mono, bi or tricyclic ino-heteroaryl with 1-4 heteroatoms, preferably N, S, O, or by carboxy (C? ~ C12) -alkyl, carboxycyclopentane, Carboxycyclohexane, benzoyl which may be mono or polysubstituted by halogen, methoxy groups, amino groups, carbamoyl groups, trifluoromethyl groups, carboxyl groups, carboxyl groups esterified with straight or branched chain (Ci-Cß) -alkanols; R3 = H, F, OR4, Br, NHR4; R4 = hydrogen, (C3-C7) -cycloalkyl, (Ci-Cβ) -alkyl or carboxy- (Ci-Ce) -alkyl, wherein the alkyl group may be straight or branched chain and may be substituted by a carbonyl group; aril or carbonyl-heteroaryl mono, bi or tricyclic with 1-4 heteroatoms, preferably N, S, O, whereby the aryl or heteroaryl itself can be mono- or polysubstituted by halogen, (C? -C6) -alkyl, (C3) -C7) -cycloalkyl, by carboxyl groups, carboxyl groups esterified with straight or branched chain (Ci-Ce) -alkanols, carbamoyl groups, trifluoromethyl groups, hydroxyl groups, methoxy groups, ethoxy groups, benzyloxy groups, amino groups, being these in turn are again replaced by benzyl, benzoyl, acetyl; A = without ring, aromatic, non-aromatic, aromatic heterocyclic with 1-2 heteroatoms, preferably N, S, O, non-aromatic heterocyclic preference N, S, O, non-aromatic heterocyclic with 1-2 heteroatoms, preferably N, S, 0; B = CH2; D = CH; B-D = CH = C; X = O, S, H2; Y = S, C, simple league; Z = S, O, NR5; R5 = hydrogen, (C1-C12) -alkyl or (C2-C6) -alkyloxy groups, wherein the alkyl group is straight or branched chain and may be substituted by a mono or bicyclic heteroaryl with 1-4 heteroatoms, preferably N, S, 0, "as morpholine, piperazine, piperidine, indole, indazole, phthalazine, thiophene, furan, imidazole, mono- or polysubstituted by a phenyl ring.This phenyl ring in turn may be mono or polysubstituted by halogen , (Ci-Cß) -alkyl, (C3-O7) -cycloalkyl, by carboxyl groups, carboxyl groups esterified with straight or branched chain (Ci-Cg) -alkanols, carbamoyl groups, trifluoromethyl groups, hydroxyl groups, methoxy groups, ethoxy groups, benzyloxy groups, amino groups, these being in turn again substituted by benzyl, benzoyl, acetyl. (2S) -l - [((2S) -1- (4-acetylamino) -phenylsulfonyl) -indoun ~ 2-yl) -carbonyl] -N- (2-methoxyethyl) -indolin-2-carbamide (2R) -l - [((2S) -1- (4-acetylamino) -phenylsulfonyl) -indol n-2-yl) -carbonyl] -N- (2-methoxyethyl) -indolin-2-carbamide (2S) -l - [((2R) -l- (4-acetylamino) -phenylsulfonyl) -indolin-2- il) -carbonyl] -N- (2-methoxyethyl) -indolin-2-carbamide (2R) -l - [((2R) -1- (4-acetylamino) -phenylsulfonyl) -indolin-2-yl) -carbonyl ] -N- (2-methoxyethyl) -indolin-2-carbamide (2R, S) -l - [((2R, S) -l- (4-acetylamino-phenylsulfonyl) -indolin-2-yl) - carbonyl] -N- (2-methoxyethyl) -indolin-2-carbamide (2S) -l - [((2S) -1- (4-amino-phenylsulfonyl) -indolin-2-yl) -carbonyl] -N- (2-methoxyethyl) -indolin-2-carbamide (2S) -l- [. { (2S) -1- (4-Amino-phenylsulfonyl) -prolyl) -carbonyl] -N- (2-methoxyethyl) -indolin-2-carbamide (2S) -l - [((2S) -l- (4- amino-phenylsulfonyl) -pipecolyl) -carbonyl] -N- (2-methoxyethyl) -indolin-2-carbamide (2S) -l - [((2S) -l- (4-methyl-phenylsulfonyl) -prolyl) -carbonyl ] -N- (2-methoxyethyl) -indolin-2-carbamide 11, (2S) -l - [(8-quinolinyl-sulfonyl) -N- (2-methoxy-ethyl) -indoline-carbamide at 12, l- [(2S) -1- (4-acetylamino-phenylsulfonyl) -indolin-2-yl) -carbonyl] -N-leucine 13. Methyl ester of (S) -Na-. { (2S) -l- [4- (acetylamino) phenylsulfonyl] -indolin-2-yl} -carbonyl-Ne- (benzyloxycarbonyl) -lysine 14. (E) (. {(2S) -l- [4- (Acetylamino) phenylsulfonyl] -indolin-2-yl} -carbonyl-4-methyl ester - (aminophenyl) acrylic 15, (2S) -l - [((2S) -1- (1-naphthalylsulfonyl) -indolin-2-yl) -carbonyl] -N- (2-methoxyethyl) -indolin-2-carbamide 16. (2S) -l - [((2S) -l- (2-naphthalylsulfonyl) -indolin-2-yl) -carbonyl] -N- (2-methoxyethyl) -indolin-2-carbamide 17. (2S) -l - [((2S) -1- (4-methyl-phenylsulfonyl) -indolin-2-yl) -carbonyl] -N3- (N-propylimidazole) -indolin-2-carbamide 18. (2S) -l - [((2S) -1- (4-methyl-phenylsulfonyl) -indolin-2-yl) -carbonyl] -N2- (N-ethylmorpholin) -indolin-2-carbamide 19, (2S) -l - [((2S) -1- (4-methyl-phenylsulfonyl) -indolin-2-yl) -carbonyl] -N2- (ethyl-pyridine) -indolin-2-carbamide 20, (2S) -l - [((2S) -1- (4-methyl-phenylsulfonyl) -indolin-2-yl) -carbonyl] - (4-pyridin) -indolin-2-carbamide 21. Methyl ester (2R) - [4- (Acetylamino) -phenylsulfonyl] -indoline-2-carboxylic acid 2-carboxylic acid 23. (2RS) -1- ( { (2RS) -l- [4- ( acetylamino) phenylsulfonyl] -indolin-2-yl.} - carbonyl) indoline-2-carboxylic acid 24. Acid (2RS) -1- ( { (2RS) -l- [4- (acetylamino) -phenylsulphonyl) ] -indolin-2-yl.}. -carbonyl) -indoline-2-carboxylic acid. 25. Use of the compounds according to one of claims 1 to 24 for preparing a finished medicament. 26. Use of the compounds of the general formula I according to claims 1 to 24 for preparing a medicament with anti-asthmatic, anti-psoriasis and immunosuppressive activity for the treatment of immunological, autoimmune as well as neurodegenerative diseases, as well as diseases accompanied by inflammations, such as asthma, rhinitis, psoriasis, rheumatism, avoiding the rejection reaction in the case of transplants and ulcerative colitis, or in combination with anti-asthmatics, antirheumatics and therapeutically known immunosuppressants. 27. Fixed forms to vehicles containing compounds according to one of claims 1 to 24 for being used to bind immunophilins of pathogenic activity of liquids, in particular of body fluids. bodily Medicament containing at least one of the compounds according to one of claims 1 to 24 together with vehicles and / or diluents or auxiliary substances. Method for the manufacture of a medicament, characterized in that a compound according to one of claims 1 to 24 is processed to obtain pharmaceutical preparations or is transformed into a therapeutically applicable form, with vehicles or diluents or other pharmaceutically usual auxiliary substances. Medicament according to claims 1 to 29, in the form of tablets or lozenges, capsules, solutions or else ampoules, suppositories, patches liquid or powder preparations introduced in inhalers. Method for the preparation of new specific ligands of the immunofilin of the formula I according to claim 1, wherein Ri, R2, R3, X, Y, Z, A, B and D have the meaning mentioned in claim 1 , characterized in that a carboxylic acid derivative of the formula II is reacted wherein R3, A, B, D, X and Y have the aforementioned meaning, with an amine, an alkanol, a halogen compound or a tosylate III, in which Ri and Z have the aforementioned meaning H ._. R, III to obtain an amide, ester or ether IV, in which Ri, R3, A, B, D, X, Y and Z have the meaning mentioned, IV the IV derivative is reacted to obtain a compound V, in which Ri, R3, A, B, D, X, Y and Z have the aforementioned meaning, V this compound V is then reacted with a sulphonic acid chloride VI in which R2 has the aforementioned meaning SAW to obtain the title compound. Method for the preparation of new immunofilin specific ligands of the formula I according to claim 1, wherein Ri, R2, R3, X, Y, Z, A, B and D have the meaning mentioned in claim 1 , characterized in that a carboxylic acid derivative of the formula II is reacted wherein R3, A, B, D, X and Y have the aforementioned meaning, One thousand with a sulfonic acid chloride VI in which R2 has the aforementioned meaning SAW to obtain a sulfonamide of formula VIII, wherein R2, A, B, D, X and Y have the aforementioned meaning IH and continuing the reaction by reacting it with a compound III in which Ri and Z have the aforementioned meaning, H .Z.R, III or with a compound V in which Ri, R3, X, Y, Z, A, B and D have the aforementioned meaning, to obtain the title compound.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19742263.2 | 1997-09-25 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| MXPA99012020A true MXPA99012020A (en) | 2000-09-04 |
Family
ID=
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Martin et al. | 1, 2, 3-trisubstituted cyclopropanes as conformationally restricted peptide isosteres: application to the design and synthesis of novel renin inhibitors | |
| AU2001264977B2 (en) | Melanocortin receptor agonists | |
| RU2237661C2 (en) | N-substituted indole-3-glyoxylamides and medicinal preparation eliciting anti-asthmatic, anti-allergic and immunodepressive/immunomodulating effect, method for preparing compounds (variants) and method for preparing medicinal preparation | |
| US6410548B2 (en) | Spiropiperidine derivatives as melanocortin receptor agonists | |
| AU2001249281B2 (en) | Spiropiperidine derivatives as melanocortin receptor agonists | |
| EP0610743B1 (en) | Aminomethylene-peptides as immunosuppressants | |
| US6251932B1 (en) | Immunophilin ligands | |
| AU4680199A (en) | Spiropiperidine derivatives as melanocortin receptor agonists | |
| JP2001517653A (en) | Specific immunophilin ligands as anti-asthmatic, anti-allergic, anti-rheumatic, immunosuppressive, anti-psoriatic, and neuroprotective drugs | |
| EP0753004A1 (en) | Antagonists of endothelin receptors | |
| CA2364178C (en) | N-benzenesulfonyl l-proline compounds as bradykinin antagonists | |
| KR20150065718A (en) | Indolines | |
| JP3102895B2 (en) | Specific immunophilin-ligand as anti-asthmatic and immunosuppressant | |
| KR20190027877A (en) | Inhibitors of Tryptophan 2,3-dioxygenase (Tryptophan 2,3-dioxygenase) | |
| IL107133A (en) | Piperidine derivatives, their preparation and pharmaceutical compositions containing them | |
| MXPA99012020A (en) | Specific immunophilin ligands useful as anti-asthmatic, anti-allergic, anti-rheumatic, immunosuppressive, antipsoriatic and neuroprotective agents | |
| AU617224B2 (en) | Pyrrolidone-2-carboxylic acid derivatives having a psychotropic action | |
| US7767645B2 (en) | SH2 domain binding inhibitors | |
| RU2172743C2 (en) | Immunofylline-specific ligands as antiasthmatic and immuno-depressant agents and method of their synthesis, pharmaceutically ready form, medicinal agent and method of its preparing | |
| WO2008148279A1 (en) | Cyclobutyl-fused pyrrolidine derivatives, their preparation methods and their medical use | |
| EP1087981B1 (en) | Prenyl transferase inhibitors | |
| MXPA98008546A (en) | Specific binders of immunophylin as antimatic, immunosupreso | |
| JPH08500116A (en) | Piperidinyl / quinolinyl-terminated alkylaminoethynylalanine aminodiol compounds for the treatment of hypertension | |
| JP2003171377A (en) | N-benzenesulfonyl-l-proline compound as bradykinin antagonist |