OA12288A - Protease inhibitors. - Google Patents

Info

Publication number

OA12288A

OA12288A OA1200200377A OA1200200377A OA12288A OA 12288 A OA12288 A OA 12288A OA 1200200377 A OA1200200377 A OA 1200200377A OA 1200200377 A OA1200200377 A OA 1200200377A OA 12288 A OA12288 A OA 12288A

Authority

OA

OAPI

Prior art keywords

methyl

oxo

azepan

butyl

amide

Prior art date

2000-06-14

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• 229940042399 direct acting antivirals protease inhibitors Drugs 0.000 title abstract description 8
• 239000000137 peptide hydrolase inhibitor Substances 0.000 title abstract description 8
• 150000001875 compounds Chemical class 0.000 claims abstract description 887
• 238000000034 method Methods 0.000 claims abstract description 475
• 201000010099 disease Diseases 0.000 claims abstract description 29
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 29
• 108090000625 Cathepsin K Proteins 0.000 claims abstract description 23
• 239000004365 Protease Substances 0.000 claims abstract description 16
• 108091005804 Peptidases Proteins 0.000 claims abstract description 14
• 150000003839 salts Chemical class 0.000 claims abstract description 14
• 208000001132 Osteoporosis Diseases 0.000 claims abstract description 8
• 150000004677 hydrates Chemical class 0.000 claims abstract description 8
• 210000000845 cartilage Anatomy 0.000 claims abstract description 7
• 208000007565 gingivitis Diseases 0.000 claims abstract description 7
• 201000001245 periodontitis Diseases 0.000 claims abstract description 7
• 206010065687 Bone loss Diseases 0.000 claims abstract description 5
• 201000008482 osteoarthritis Diseases 0.000 claims abstract description 5
• 206010039073 rheumatoid arthritis Diseases 0.000 claims abstract description 5
• 230000002401 inhibitory effect Effects 0.000 claims abstract description 4
• 102000004171 Cathepsin K Human genes 0.000 claims abstract 2
• OFFSPAZVIVZPHU-UHFFFAOYSA-N 1-benzofuran-2-carboxylic acid Chemical compound C1=CC=C2OC(C(=O)O)=CC2=C1 OFFSPAZVIVZPHU-UHFFFAOYSA-N 0.000 claims description 586
• -1 piperidinyl-ethyl Chemical group 0.000 claims description 262
• 239000002253 acid Substances 0.000 claims description 241
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 188
• 239000000203 mixture Substances 0.000 claims description 144
• 150000001408 amides Chemical class 0.000 claims description 120
• YMZTUCZCQMQFMK-UHFFFAOYSA-N 3-methyl-1-benzofuran-2-carboxylic acid Chemical compound C1=CC=C2C(C)=C(C(O)=O)OC2=C1 YMZTUCZCQMQFMK-UHFFFAOYSA-N 0.000 claims description 70
• 125000005605 benzo group Chemical group 0.000 claims description 67
• DYSJMQABFPKAQM-UHFFFAOYSA-N 1-benzothiophene-2-carboxylic acid Chemical compound C1=CC=C2SC(C(=O)O)=CC2=C1 DYSJMQABFPKAQM-UHFFFAOYSA-N 0.000 claims description 50
• XZELWEMGWISCTP-UHFFFAOYSA-N 5-methoxy-1-benzofuran-2-carboxylic acid Chemical compound COC1=CC=C2OC(C(O)=O)=CC2=C1 XZELWEMGWISCTP-UHFFFAOYSA-N 0.000 claims description 49
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 44
• 102000005927 Cysteine Proteases Human genes 0.000 claims description 39
• 108010005843 Cysteine Proteases Proteins 0.000 claims description 39
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 32
• LOAUVZALPPNFOQ-UHFFFAOYSA-N quinaldic acid Chemical compound C1=CC=CC2=NC(C(=O)O)=CC=C21 LOAUVZALPPNFOQ-UHFFFAOYSA-N 0.000 claims description 32
• UPUZGXILYFKSGE-UHFFFAOYSA-N quinoxaline-2-carboxylic acid Chemical compound C1=CC=CC2=NC(C(=O)O)=CN=C21 UPUZGXILYFKSGE-UHFFFAOYSA-N 0.000 claims description 25
• GVZXSZWCZGKLRS-UHFFFAOYSA-N thieno[3,2-b]thiophene-5-carboxylic acid Chemical compound S1C=CC2=C1C=C(C(=O)O)S2 GVZXSZWCZGKLRS-UHFFFAOYSA-N 0.000 claims description 25
• 125000001544 thienyl group Chemical group 0.000 claims description 25
• QERYCTSHXKAMIS-UHFFFAOYSA-N thiophene-2-carboxylic acid Chemical compound OC(=O)C1=CC=CS1 QERYCTSHXKAMIS-UHFFFAOYSA-N 0.000 claims description 25
• 125000002541 furyl group Chemical group 0.000 claims description 24
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 23
• ADRFTNFHVKVATK-UHFFFAOYSA-N 5-[3-(trifluoromethyl)phenyl]furan-2-carboxylic acid Chemical compound O1C(C(=O)O)=CC=C1C1=CC=CC(C(F)(F)F)=C1 ADRFTNFHVKVATK-UHFFFAOYSA-N 0.000 claims description 20
• 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 19
• 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 claims description 18
• 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 18
• 229910052736 halogen Inorganic materials 0.000 claims description 18
• 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 16
• JBVXXGSEMNXAMH-LSLKUGRBSA-N (2s)-2-amino-4-methyl-n-(3-oxo-1-pyridin-2-ylsulfonylazepan-4-yl)pentanamide Chemical compound C1C(=O)C(NC(=O)[C@@H](N)CC(C)C)CCCN1S(=O)(=O)C1=CC=CC=N1 JBVXXGSEMNXAMH-LSLKUGRBSA-N 0.000 claims description 15
• 125000000842 isoxazolyl group Chemical group 0.000 claims description 15
• 125000004076 pyridyl group Chemical group 0.000 claims description 15
• 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 claims description 14
• HITUZQPFDWNUHA-UHFFFAOYSA-N 5-fluoro-1-benzofuran-2-carboxylic acid Chemical compound FC1=CC=C2OC(C(=O)O)=CC2=C1 HITUZQPFDWNUHA-UHFFFAOYSA-N 0.000 claims description 14
• VCNGNQLPFHVODE-UHFFFAOYSA-N 5-methylthiophene-2-carboxylic acid Chemical compound CC1=CC=C(C(O)=O)S1 VCNGNQLPFHVODE-UHFFFAOYSA-N 0.000 claims description 14
• 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 14
• 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 claims description 13
• 230000001590 oxidative effect Effects 0.000 claims description 12
• OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical group [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 claims description 11
• 125000004159 quinolin-2-yl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C([H])C(*)=NC2=C1[H] 0.000 claims description 11
• 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 10
• BNYIQEFWGSXIKQ-UHFFFAOYSA-N 3-methylfuran-2-carboxylic acid Chemical compound CC=1C=COC=1C(O)=O BNYIQEFWGSXIKQ-UHFFFAOYSA-N 0.000 claims description 9
• 102000012479 Serine Proteases Human genes 0.000 claims description 9
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• 125000003118 aryl group Chemical group 0.000 claims description 9
• 239000003795 chemical substances by application Substances 0.000 claims description 9
• 239000007800 oxidant agent Substances 0.000 claims description 9
• 125000004262 quinoxalin-2-yl group Chemical group [H]C1=NC2=C([H])C([H])=C([H])C([H])=C2N=C1* 0.000 claims description 9
• UDYFLDICVHJSOY-UHFFFAOYSA-N sulfur trioxide-pyridine complex Substances O=S(=O)=O.C1=CC=NC=C1 UDYFLDICVHJSOY-UHFFFAOYSA-N 0.000 claims description 9
• 125000002941 2-furyl group Chemical group O1C([*])=C([H])C([H])=C1[H] 0.000 claims description 8
• 125000004244 benzofuran-2-yl group Chemical group [H]C1=C(*)OC2=C([H])C([H])=C([H])C([H])=C12 0.000 claims description 8
• 230000015572 biosynthetic process Effects 0.000 claims description 8
• 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 claims description 8
• 238000003786 synthesis reaction Methods 0.000 claims description 8
• 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 7
• 125000003261 o-tolyl group Chemical group [H]C1=C([H])C(*)=C(C([H])=C1[H])C([H])([H])[H] 0.000 claims description 7
• 125000001037 p-tolyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 claims description 6
• 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 claims description 6
• 125000004182 2-chlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(*)C([H])=C1[H] 0.000 claims description 5
• 125000004180 3-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(F)=C1[H] 0.000 claims description 5
• 238000004519 manufacturing process Methods 0.000 claims description 5
• 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 5
• PSJMNAIMOCVKGC-UHFFFAOYSA-N 3-ethyl-1-benzofuran-2-carboxylic acid Chemical compound C1=CC=C2C(CC)=C(C(O)=O)OC2=C1 PSJMNAIMOCVKGC-UHFFFAOYSA-N 0.000 claims description 4
• 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 4
• UOJBPVNHCNJBSQ-UHFFFAOYSA-N 4-methylfuran-2-carboxylic acid Chemical compound CC1=COC(C(O)=O)=C1 UOJBPVNHCNJBSQ-UHFFFAOYSA-N 0.000 claims description 4
• 239000003085 diluting agent Substances 0.000 claims description 4
• 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims description 4
• 239000000546 pharmaceutical excipient Substances 0.000 claims description 4
• 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 4
• NRKKLJOOPCBMLZ-UEWDXFNNSA-N (2S)-2-amino-4-methyl-N-(3-oxo-1-propylsulfonylazepan-4-yl)pentanamide Chemical compound CCCS(=O)(=O)N1CCCC(NC(=O)[C@@H](N)CC(C)C)C(=O)C1 NRKKLJOOPCBMLZ-UEWDXFNNSA-N 0.000 claims description 3
• YAEDTUJDAJKEEM-PXYINDEMSA-N (2S)-2-amino-N-(1-ethylsulfonyl-3-oxoazepan-4-yl)-4-methylpentanamide Chemical compound CCS(=O)(=O)N1CCCC(NC(=O)[C@@H](N)CC(C)C)C(=O)C1 YAEDTUJDAJKEEM-PXYINDEMSA-N 0.000 claims description 3
• CITKJMOBBHFQBZ-UHFFFAOYSA-N 3,5-dimethyl-1-benzofuran-2-carboxylic acid Chemical compound C1=C(C)C=C2C(C)=C(C(O)=O)OC2=C1 CITKJMOBBHFQBZ-UHFFFAOYSA-N 0.000 claims description 3
• MBJKFAUPYMUFOV-UHFFFAOYSA-N 4-methoxy-3-methyl-1-benzofuran-2-carboxylic acid Chemical compound COC1=CC=CC2=C1C(C)=C(C(O)=O)O2 MBJKFAUPYMUFOV-UHFFFAOYSA-N 0.000 claims description 3
• BKOHXOOAJNTFCM-UHFFFAOYSA-N 5-methoxy-3-methyl-1-benzofuran-2-carboxylic acid Chemical compound COC1=CC=C2OC(C(O)=O)=C(C)C2=C1 BKOHXOOAJNTFCM-UHFFFAOYSA-N 0.000 claims description 3
• TZAGITKJEGVENE-UHFFFAOYSA-N 6-fluoro-3-methyl-1-benzofuran-2-carboxylic acid Chemical compound FC1=CC=C2C(C)=C(C(O)=O)OC2=C1 TZAGITKJEGVENE-UHFFFAOYSA-N 0.000 claims description 3
• CQZZSFNTQLCLJF-UHFFFAOYSA-N 6-methoxy-3-methyl-1-benzofuran-2-carboxylic acid Chemical compound COC1=CC=C2C(C)=C(C(O)=O)OC2=C1 CQZZSFNTQLCLJF-UHFFFAOYSA-N 0.000 claims description 3
• VHRCHODSRLMXFM-UHFFFAOYSA-N furo[3,2-b]pyridine-2-carboxylic acid Chemical compound C1=CC=C2OC(C(=O)O)=CC2=N1 VHRCHODSRLMXFM-UHFFFAOYSA-N 0.000 claims description 3
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