CA2446795A1 - Sulfamide, sulfamate, sulfonamide, urea, amide, alpha, alpha-difluoro amide oxalyl diamide, and heterobicycles fkbp-binding ligands - Google Patents

Info

Publication number

CA2446795A1

CA2446795A1 CA002446795A CA2446795A CA2446795A1 CA 2446795 A1 CA2446795 A1 CA 2446795A1 CA 002446795 A CA002446795 A CA 002446795A CA 2446795 A CA2446795 A CA 2446795A CA 2446795 A1 CA2446795 A1 CA 2446795A1

Authority

CA

Canada

Prior art keywords

compound

mmol

pharmaceutically acceptable

acceptable salt

substituted

Prior art date

2001-05-10

Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)

Abandoned

Links

• Espacenet
• Global Dossier
• CIPO
• Discuss

• 229940124530 sulfonamide Drugs 0.000 title description 15
• 230000027455 binding Effects 0.000 title description 10
• 150000001408 amides Chemical class 0.000 title description 5
• NVBFHJWHLNUMCV-UHFFFAOYSA-N sulfamide Chemical compound NS(N)(=O)=O NVBFHJWHLNUMCV-UHFFFAOYSA-N 0.000 title description 4
• 150000003456 sulfonamides Chemical class 0.000 title description 4
• YIKSCQDJHCMVMK-UHFFFAOYSA-N Oxamide Chemical compound NC(=O)C(N)=O YIKSCQDJHCMVMK-UHFFFAOYSA-N 0.000 title description 3
• 239000003446 ligand Substances 0.000 title description 3
• XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 title 1
• 239000004202 carbamide Substances 0.000 title 1
• IIACRCGMVDHOTQ-UHFFFAOYSA-M sulfamate Chemical compound NS([O-])(=O)=O IIACRCGMVDHOTQ-UHFFFAOYSA-M 0.000 title 1
• 150000001875 compounds Chemical class 0.000 claims abstract description 545
• 208000012902 Nervous system disease Diseases 0.000 claims abstract description 10
• 208000025966 Neurological disease Diseases 0.000 claims abstract description 4
• -1 dimethoxymethyl Chemical group 0.000 claims description 80
• 150000003839 salts Chemical class 0.000 claims description 60
• 238000000034 method Methods 0.000 claims description 44
• 125000000217 alkyl group Chemical group 0.000 claims description 41
• 239000002207 metabolite Substances 0.000 claims description 37
• 229910052739 hydrogen Inorganic materials 0.000 claims description 31
• 239000001257 hydrogen Substances 0.000 claims description 31
• 239000012453 solvate Substances 0.000 claims description 30
• 239000000651 prodrug Substances 0.000 claims description 29
• 229940002612 prodrug Drugs 0.000 claims description 29
• IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 25
• 125000001072 heteroaryl group Chemical group 0.000 claims description 25
• 125000003118 aryl group Chemical group 0.000 claims description 23
• 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 21
• 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 20
• 229910052760 oxygen Inorganic materials 0.000 claims description 19
• 229910052799 carbon Inorganic materials 0.000 claims description 18
• OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 15
• QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 15
• 239000001301 oxygen Substances 0.000 claims description 15
• 239000008194 pharmaceutical composition Substances 0.000 claims description 15
• 150000001412 amines Chemical class 0.000 claims description 14
• 229910052757 nitrogen Inorganic materials 0.000 claims description 14
• 125000000753 cycloalkyl group Chemical group 0.000 claims description 11
• 125000003545 alkoxy group Chemical group 0.000 claims description 10
• 125000000623 heterocyclic group Chemical group 0.000 claims description 10
• 108010025020 Nerve Growth Factor Proteins 0.000 claims description 9
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 9
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 8
• 125000004433 nitrogen atom Chemical group N* 0.000 claims description 8
• 229910052717 sulfur Inorganic materials 0.000 claims description 8
• 125000003342 alkenyl group Chemical group 0.000 claims description 7
• 206010002026 amyotrophic lateral sclerosis Diseases 0.000 claims description 7
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 7
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 6
• NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 6
• 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 6
• 239000003937 drug carrier Substances 0.000 claims description 6
• 208000014674 injury Diseases 0.000 claims description 6
• 239000011593 sulfur Substances 0.000 claims description 6
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• 208000018737 Parkinson disease Diseases 0.000 claims description 5
• 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 claims description 5
• 230000006378 damage Effects 0.000 claims description 5
• 201000010099 disease Diseases 0.000 claims description 5
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 5
• 239000003900 neurotrophic factor Substances 0.000 claims description 5
• 201000004384 Alopecia Diseases 0.000 claims description 4
• 206010011878 Deafness Diseases 0.000 claims description 4
• 150000001721 carbon Chemical group 0.000 claims description 4
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 4
• 208000024963 hair loss Diseases 0.000 claims description 4
• 230000003676 hair loss Effects 0.000 claims description 4
• 230000010370 hearing loss Effects 0.000 claims description 4
• 231100000888 hearing loss Toxicity 0.000 claims description 4
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• 125000000040 m-tolyl group Chemical group [H]C1=C([H])C(*)=C([H])C(=C1[H])C([H])([H])[H] 0.000 claims description 4
• 206010027175 memory impairment Diseases 0.000 claims description 4
• QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 4
• 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 claims description 3
• 125000001917 2,4-dinitrophenyl group Chemical group [H]C1=C([H])C(=C([H])C(=C1*)[N+]([O-])=O)[N+]([O-])=O 0.000 claims description 3
• 125000006276 2-bromophenyl group Chemical group [H]C1=C([H])C(Br)=C(*)C([H])=C1[H] 0.000 claims description 3
• 125000004800 4-bromophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Br 0.000 claims description 3
• 125000000590 4-methylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 claims description 3
• 208000027418 Wounds and injury Diseases 0.000 claims description 3
• KPCZJLGGXRGYIE-UHFFFAOYSA-N [C]1=CC=CN=C1 Chemical group [C]1=CC=CN=C1 KPCZJLGGXRGYIE-UHFFFAOYSA-N 0.000 claims description 3
• 125000002252 acyl group Chemical group 0.000 claims description 3
• 125000004429 atom Chemical group 0.000 claims description 3
• 230000006931 brain damage Effects 0.000 claims description 3
• 231100000874 brain damage Toxicity 0.000 claims description 3
• 208000029028 brain injury Diseases 0.000 claims description 3
• 125000000392 cycloalkenyl group Chemical group 0.000 claims description 3
• 150000004820 halides Chemical class 0.000 claims description 3
• 229910052736 halogen Inorganic materials 0.000 claims description 3
• UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 claims description 3
• 125000004361 3,4,5-trifluorophenyl group Chemical group [H]C1=C(F)C(F)=C(F)C([H])=C1* 0.000 claims description 2
• 125000005809 3,4,5-trimethoxyphenyl group Chemical group [H]C1=C(OC([H])([H])[H])C(OC([H])([H])[H])=C(OC([H])([H])[H])C([H])=C1* 0.000 claims description 2
• 125000006275 3-bromophenyl group Chemical group [H]C1=C([H])C(Br)=C([H])C(*)=C1[H] 0.000 claims description 2
• 125000004207 3-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(OC([H])([H])[H])=C1[H] 0.000 claims description 2
• 125000004801 4-cyanophenyl group Chemical group [H]C1=C([H])C(C#N)=C([H])C([H])=C1* 0.000 claims description 2
• 125000004860 4-ethylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])C([H])([H])[H] 0.000 claims description 2
• GMPKIPWJBDOURN-UHFFFAOYSA-N Methoxyamine Chemical group CON GMPKIPWJBDOURN-UHFFFAOYSA-N 0.000 claims description 2
• 125000005843 halogen group Chemical group 0.000 claims description 2
• 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 claims description 2
• 125000000636 p-nitrophenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)[N+]([O-])=O 0.000 claims description 2
• 125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 2
• 150000002431 hydrogen Chemical class 0.000 claims 6
• ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical group C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 claims 2
• 235000010290 biphenyl Nutrition 0.000 claims 1
• 210000004556 brain Anatomy 0.000 claims 1
• 230000006735 deficit Effects 0.000 claims 1
• 230000004438 eyesight Effects 0.000 claims 1
• 208000027232 peripheral nervous system disease Diseases 0.000 claims 1
• 208000033808 peripheral neuropathy Diseases 0.000 claims 1
• 210000000278 spinal cord Anatomy 0.000 claims 1
• 230000000694 effects Effects 0.000 abstract description 21
• 239000003112 inhibitor Substances 0.000 abstract description 7
• 102000009658 Peptidylprolyl Isomerase Human genes 0.000 abstract description 5
• 108010020062 Peptidylprolyl Isomerase Proteins 0.000 abstract description 5
• 102000018679 Tacrolimus Binding Proteins Human genes 0.000 abstract description 5
• 108091011114 FK506 binding proteins Proteins 0.000 abstract description 3
• KTSZYXNHBVWNNV-UHFFFAOYSA-N 1,2-diazabicyclo[3.3.1]nonane Chemical class C1CNN2CCCC1C2 KTSZYXNHBVWNNV-UHFFFAOYSA-N 0.000 abstract 1
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 324
• 239000000047 product Substances 0.000 description 241
• 230000015572 biosynthetic process Effects 0.000 description 166
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 166
• 238000010183 spectrum analysis Methods 0.000 description 163
• 238000003786 synthesis reaction Methods 0.000 description 162
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 126
• 239000000203 mixture Substances 0.000 description 122
• 235000019439 ethyl acetate Nutrition 0.000 description 115
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 105
• 239000000243 solution Substances 0.000 description 97
• 238000000921 elemental analysis Methods 0.000 description 88
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 72
• HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 68
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 65
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 63
• 229910001868 water Inorganic materials 0.000 description 61
• 238000003820 Medium-pressure liquid chromatography Methods 0.000 description 53
• 239000000377 silicon dioxide Substances 0.000 description 53
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 51
• LVTJOONKWUXEFR-FZRMHRINSA-N protoneodioscin Natural products O(C[C@@H](CC[C@]1(O)[C@H](C)[C@@H]2[C@]3(C)[C@H]([C@H]4[C@@H]([C@]5(C)C(=CC4)C[C@@H](O[C@@H]4[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@@H](O)[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@H](CO)O4)CC5)CC3)C[C@@H]2O1)C)[C@H]1[C@H](O)[C@H](O)[C@H](O)[C@@H](CO)O1 LVTJOONKWUXEFR-FZRMHRINSA-N 0.000 description 49
• 238000005160 1H NMR spectroscopy Methods 0.000 description 48
• WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 48
• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 45
• 239000012044 organic layer Substances 0.000 description 45
• 229910052943 magnesium sulfate Inorganic materials 0.000 description 43
• 239000007787 solid Substances 0.000 description 42
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 42
• 238000001914 filtration Methods 0.000 description 38
• ZIXWTPREILQLAC-UHFFFAOYSA-N isoquinolin-8-ol Chemical compound C1=NC=C2C(O)=CC=CC2=C1 ZIXWTPREILQLAC-UHFFFAOYSA-N 0.000 description 38
• 239000012267 brine Substances 0.000 description 37
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