CN1261276A - 蛋白酶抑制剂 - Google Patents

Info

Publication number

CN1261276A

CN1261276A CN98806641A CN98806641A CN1261276A CN 1261276 A CN1261276 A CN 1261276A CN 98806641 A CN98806641 A CN 98806641A CN 98806641 A CN98806641 A CN 98806641A CN 1261276 A CN1261276 A CN 1261276A

Authority

CN

China

Prior art keywords

thiazol

hydrazide

carbonyl

leucyl

methyl

Prior art date

1997-04-29

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.)

Pending

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• 239000000137 peptide hydrolase inhibitor Substances 0.000 title description 7
• 229940042399 direct acting antivirals protease inhibitors Drugs 0.000 title description 2
• 150000001875 compounds Chemical class 0.000 claims abstract description 420
• 238000000034 method Methods 0.000 claims abstract description 77
• 201000010099 disease Diseases 0.000 claims abstract description 48
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 48
• 102000035195 Peptidases Human genes 0.000 claims abstract description 15
• 108091005804 Peptidases Proteins 0.000 claims abstract description 15
• 239000004365 Protease Substances 0.000 claims abstract description 15
• 108090000625 Cathepsin K Proteins 0.000 claims abstract description 14
• 208000001132 Osteoporosis Diseases 0.000 claims abstract description 12
• 210000000845 cartilage Anatomy 0.000 claims abstract description 11
• 206010065687 Bone loss Diseases 0.000 claims abstract description 9
• 201000008482 osteoarthritis Diseases 0.000 claims abstract description 9
• 230000015556 catabolic process Effects 0.000 claims abstract description 8
• 238000006731 degradation reaction Methods 0.000 claims abstract description 8
• 201000001245 periodontitis Diseases 0.000 claims abstract description 8
• 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 8
• 206010039073 rheumatoid arthritis Diseases 0.000 claims abstract description 8
• 208000007565 gingivitis Diseases 0.000 claims abstract description 7
• 102000004171 Cathepsin K Human genes 0.000 claims abstract 4
• 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 385
• -1 C 1-6Alkyl Chemical group 0.000 claims description 250
• 238000002360 preparation method Methods 0.000 claims description 225
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 171
• 125000001637 1-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C(*)=C([H])C([H])=C([H])C2=C1[H] 0.000 claims description 145
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 90
• JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 70
• OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 claims description 58
• 229910052757 nitrogen Inorganic materials 0.000 claims description 58
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 57
• 239000002253 acid Substances 0.000 claims description 37
• 102000005927 Cysteine Proteases Human genes 0.000 claims description 35
• 108010005843 Cysteine Proteases Proteins 0.000 claims description 35
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Substances CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 28
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 24
• 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 23
• 229910052799 carbon Inorganic materials 0.000 claims description 20
• 102000004190 Enzymes Human genes 0.000 claims description 19
• 108090000790 Enzymes Proteins 0.000 claims description 19
• 125000002252 acyl group Chemical group 0.000 claims description 19
• 150000003839 salts Chemical class 0.000 claims description 19
• 125000004186 cyclopropylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C1([H])[H] 0.000 claims description 18
• 239000000758 substrate Substances 0.000 claims description 18
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 15
• 125000000623 heterocyclic group Chemical group 0.000 claims description 15
• 230000005764 inhibitory process Effects 0.000 claims description 15
• 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 claims description 15
• 230000015572 biosynthetic process Effects 0.000 claims description 14
• 229910052736 halogen Inorganic materials 0.000 claims description 14
• 150000002367 halogens Chemical class 0.000 claims description 14
• 229920006395 saturated elastomer Polymers 0.000 claims description 14
• NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 claims description 12
• FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical group Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 claims description 10
• 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 10
• 239000003814 drug Substances 0.000 claims description 10
• UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 10
• 235000019419 proteases Nutrition 0.000 claims description 9
• 239000002904 solvent Substances 0.000 claims description 9
• 229910052717 sulfur Inorganic materials 0.000 claims description 9
• FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 claims description 8
• 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 8
• 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 8
• 125000005842 heteroatom Chemical group 0.000 claims description 8
• 229910052760 oxygen Inorganic materials 0.000 claims description 7
• 239000000546 pharmaceutical excipient Substances 0.000 claims description 7
• VRJHQPZVIGNGMX-UHFFFAOYSA-N 4-piperidinone Chemical compound O=C1CCNCC1 VRJHQPZVIGNGMX-UHFFFAOYSA-N 0.000 claims description 6
• 238000006243 chemical reaction Methods 0.000 claims description 6
• 239000007822 coupling agent Substances 0.000 claims description 6
• 239000003085 diluting agent Substances 0.000 claims description 6
• 229910052739 hydrogen Inorganic materials 0.000 claims description 6
• RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 6
• 238000005897 peptide coupling reaction Methods 0.000 claims description 6
• XUWHAWMETYGRKB-UHFFFAOYSA-N piperidin-2-one Chemical compound O=C1CCCCN1 XUWHAWMETYGRKB-UHFFFAOYSA-N 0.000 claims description 6
• HNJBEVLQSNELDL-UHFFFAOYSA-N pyrrolidin-2-one Chemical compound O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 claims description 6
• 102000012479 Serine Proteases Human genes 0.000 claims description 5
• 108010022999 Serine Proteases Proteins 0.000 claims description 5
• 239000003937 drug carrier Substances 0.000 claims description 5
• 125000002757 morpholinyl group Chemical group 0.000 claims description 5
• 125000001624 naphthyl group Chemical group 0.000 claims description 5
• 125000005936 piperidyl group Chemical group 0.000 claims description 5
• 125000000335 thiazolyl group Chemical group 0.000 claims description 5
• MNCMBBIFTVWHIP-UHFFFAOYSA-N 1-anthracen-9-yl-2,2,2-trifluoroethanone Chemical group C1=CC=C2C(C(=O)C(F)(F)F)=C(C=CC=C3)C3=CC2=C1 MNCMBBIFTVWHIP-UHFFFAOYSA-N 0.000 claims description 4
• BUKITYALZCIHTM-UHFFFAOYSA-N 1-benzyl-5-methylimidazole Chemical compound CC1=CN=CN1CC1=CC=CC=C1 BUKITYALZCIHTM-UHFFFAOYSA-N 0.000 claims description 4
• 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 4
• 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 claims description 4
• 125000004432 carbon atom Chemical group C* 0.000 claims description 4
• 125000003630 glycyl group Chemical group [H]N([H])C([H])([H])C(*)=O 0.000 claims description 4
• 239000001257 hydrogen Substances 0.000 claims description 4
• 238000004519 manufacturing process Methods 0.000 claims description 4
• KAESVJOAVNADME-UHFFFAOYSA-N 1H-pyrrole Natural products C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 claims description 3
• 125000004638 2-oxopiperazinyl group Chemical group O=C1N(CCNC1)* 0.000 claims description 3
• LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 claims description 3
• CKDWPUIZGOQOOM-UHFFFAOYSA-N Carbamyl chloride Chemical compound NC(Cl)=O CKDWPUIZGOQOOM-UHFFFAOYSA-N 0.000 claims description 3
• 229910052786 argon Inorganic materials 0.000 claims description 3
• 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 claims description 3
• 125000002527 bicyclic carbocyclic group Chemical group 0.000 claims description 3
• 125000002618 bicyclic heterocycle group Chemical group 0.000 claims description 3
• 125000002541 furyl group Chemical group 0.000 claims description 3
• 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 3
• 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 3
• 125000005956 isoquinolyl group Chemical group 0.000 claims description 3
• 125000002911 monocyclic heterocycle group Chemical group 0.000 claims description 3
• WCPAKWJPBJAGKN-UHFFFAOYSA-N oxadiazole Chemical compound C1=CON=N1 WCPAKWJPBJAGKN-UHFFFAOYSA-N 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
• 125000004193 piperazinyl group Chemical group 0.000 claims description 3
• 150000003214 pyranose derivatives Chemical class 0.000 claims description 3
• 125000003072 pyrazolidinyl group Chemical group 0.000 claims description 3
• 125000003226 pyrazolyl group Chemical group 0.000 claims description 3
• 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 3
• 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 claims description 3
• 125000005493 quinolyl group Chemical group 0.000 claims description 3
• YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 3
• 125000001984 thiazolidinyl group Chemical group 0.000 claims description 3
• 125000002769 thiazolinyl group Chemical group 0.000 claims description 3
• 125000003762 3,4-dimethoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C(OC([H])([H])[H])C([H])=C1* 0.000 claims description 2
• 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 2
• UZOFELREXGAFOI-UHFFFAOYSA-N 4-methylpiperidine Chemical compound CC1CCNCC1 UZOFELREXGAFOI-UHFFFAOYSA-N 0.000 claims description 2
• 241000243328 Hydridae Species 0.000 claims description 2
• 102000011195 Profilin Human genes 0.000 claims description 2
• 108050001408 Profilin Proteins 0.000 claims description 2
• DPOPAJRDYZGTIR-UHFFFAOYSA-N Tetrazine Chemical compound C1=CN=NN=N1 DPOPAJRDYZGTIR-UHFFFAOYSA-N 0.000 claims description 2
• 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 2
• 125000004307 pyrazin-2-yl group Chemical group [H]C1=C([H])N=C(*)C([H])=N1 0.000 claims description 2
• 125000003373 pyrazinyl group Chemical group 0.000 claims description 2
• 125000002098 pyridazinyl group Chemical group 0.000 claims description 2
• 239000012453 solvate Substances 0.000 claims description 2
• 125000004213 tert-butoxy group Chemical group [H]C([H])([H])C(O*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
• 125000001113 thiadiazolyl group Chemical group 0.000 claims description 2
• WCNFFKHKJLERFM-UHFFFAOYSA-N thiomorpholinyl sulfone group Chemical group N1(CCSCC1)S(=O)(=O)N1CCSCC1 WCNFFKHKJLERFM-UHFFFAOYSA-N 0.000 claims description 2
• ZCAGUOCUDGWENZ-UHFFFAOYSA-N thiomorpholinyl sulfoxide group Chemical group N1(CCSCC1)S(=O)N1CCSCC1 ZCAGUOCUDGWENZ-UHFFFAOYSA-N 0.000 claims description 2
• 125000001425 triazolyl group Chemical group 0.000 claims description 2
• AWJUIBRHMBBTKR-UHFFFAOYSA-N iso-quinoline Natural products C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 claims 22
• SMWDFEZZVXVKRB-UHFFFAOYSA-N anhydrous quinoline Natural products N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 claims 20
• 229950003188 isovaleryl diethylamide Drugs 0.000 claims 18
• IWNWRLUUSPDATD-UHFFFAOYSA-N 2-naphthalen-1-ylthiophene Chemical compound C1=CSC(C=2C3=CC=CC=C3C=CC=2)=C1 IWNWRLUUSPDATD-UHFFFAOYSA-N 0.000 claims 8
• 125000003277 amino group Chemical group 0.000 claims 6
• 125000004495 thiazol-4-yl group Chemical group S1C=NC(=C1)* 0.000 claims 6
• LBUJPTNKIBCYBY-UHFFFAOYSA-N 1,2,3,4-tetrahydroquinoline Chemical compound C1=CC=C2CCCNC2=C1 LBUJPTNKIBCYBY-UHFFFAOYSA-N 0.000 claims 4
• NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims 4
• HZONRRHNQILCNO-UHFFFAOYSA-N 1-methyl-2h-pyridine Chemical compound CN1CC=CC=C1 HZONRRHNQILCNO-UHFFFAOYSA-N 0.000 claims 2
• 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims 2
• BFAKENXZKHGIGE-UHFFFAOYSA-N bis(2,3,5,6-tetrafluoro-4-iodophenyl)diazene Chemical compound FC1=C(C(=C(C(=C1F)I)F)F)N=NC1=C(C(=C(C(=C1F)F)I)F)F BFAKENXZKHGIGE-UHFFFAOYSA-N 0.000 claims 2
• ANCBHJKEYPZCTE-UHFFFAOYSA-N ethyl 5-carbamoyl-4-methyl-2-[(2,3,4,5,6-pentafluorobenzoyl)amino]thiophene-3-carboxylate Chemical compound CC1=C(C(N)=O)SC(NC(=O)C=2C(=C(F)C(F)=C(F)C=2F)F)=C1C(=O)OCC ANCBHJKEYPZCTE-UHFFFAOYSA-N 0.000 claims 2
• 125000004435 hydrogen atom Chemical group [H]* 0.000 claims 2
• 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims 2
• GSYSFVSGPABNNL-UHFFFAOYSA-N methyl 2-dimethoxyphosphoryl-2-(phenylmethoxycarbonylamino)acetate Chemical group COC(=O)C(P(=O)(OC)OC)NC(=O)OCC1=CC=CC=C1 GSYSFVSGPABNNL-UHFFFAOYSA-N 0.000 claims 2
• 229960000210 nalidixic acid Drugs 0.000 claims 2
• 125000002114 valyl group Chemical group 0.000 claims 2
• 208000037147 Hypercalcaemia Diseases 0.000 abstract description 4
• 206010028980 Neoplasm Diseases 0.000 abstract description 4
• 201000011510 cancer Diseases 0.000 abstract description 4
• 208000024693 gingival disease Diseases 0.000 abstract description 4
• 230000000148 hypercalcaemia Effects 0.000 abstract description 4
• 208000030915 hypercalcemia disease Diseases 0.000 abstract description 4
• 208000030136 Marchiafava-Bignami Disease Diseases 0.000 abstract description 3
• 208000029725 Metabolic bone disease Diseases 0.000 abstract description 3
• 206010003246 arthritis Diseases 0.000 abstract description 3
• 208000010191 Osteitis Deformans Diseases 0.000 abstract 1
• 208000027868 Paget disease Diseases 0.000 abstract 1
• 230000036210 malignancy Effects 0.000 abstract 1
• 208000027202 mammary Paget disease Diseases 0.000 abstract 1
• 239000011159 matrix material Substances 0.000 abstract 1
• 239000002585 base Substances 0.000 description 396
• 229940042795 hydrazides for tuberculosis treatment Drugs 0.000 description 368
• 239000007787 solid Substances 0.000 description 266
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 234
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 125
• 229960003136 leucine Drugs 0.000 description 78
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 78
• 239000004395 L-leucine Substances 0.000 description 77
• 239000000243 solution Substances 0.000 description 75
• 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 73
• 150000003254 radicals Chemical class 0.000 description 72
• CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 68
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 68
• ODKSFYDXXFIFQN-UHFFFAOYSA-N Arginine Chemical compound OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 55
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 54
• SIOXPEMLGUPBBT-UHFFFAOYSA-N picolinic acid Chemical compound OC(=O)C1=CC=CC=N1 SIOXPEMLGUPBBT-UHFFFAOYSA-N 0.000 description 53
• QRDZFPUVLYEQTA-UHFFFAOYSA-N quinoline-8-carboxylic acid Chemical compound C1=CN=C2C(C(=O)O)=CC=CC2=C1 QRDZFPUVLYEQTA-UHFFFAOYSA-N 0.000 description 53
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 42
• SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 42
• 239000000203 mixture Substances 0.000 description 41
• MDXGYYOJGPFFJL-QMMMGPOBSA-N N(alpha)-t-butoxycarbonyl-L-leucine Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)OC(C)(C)C MDXGYYOJGPFFJL-QMMMGPOBSA-N 0.000 description 40
• 239000012141 concentrate Substances 0.000 description 39
• 235000008504 concentrate Nutrition 0.000 description 39
• 238000003756 stirring Methods 0.000 description 39
• 125000001980 alanyl group Chemical group 0.000 description 38
• 229910052943 magnesium sulfate Inorganic materials 0.000 description 34
• 235000019341 magnesium sulphate Nutrition 0.000 description 34
• 238000005406 washing Methods 0.000 description 34
• 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 30
• 239000004475 Arginine Substances 0.000 description 28
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 28
• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 28
• 230000008569 process Effects 0.000 description 28
• 238000001914 filtration Methods 0.000 description 25
• UIIMBOGNXHQVGW-UHFFFAOYSA-M sodium bicarbonate Substances [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 25
• 239000000741 silica gel Substances 0.000 description 23
• 229910002027 silica gel Inorganic materials 0.000 description 23
• 229960001866 silicon dioxide Drugs 0.000 description 23
• 238000005481 NMR spectroscopy Methods 0.000 description 22
• KDSNLYIMUZNERS-UHFFFAOYSA-N 2-methylpropanamine Chemical compound CC(C)CN KDSNLYIMUZNERS-UHFFFAOYSA-N 0.000 description 21
• 239000007864 aqueous solution Substances 0.000 description 21
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 20
• 229940088598 enzyme Drugs 0.000 description 18
• 239000012044 organic layer Substances 0.000 description 18
• FFBHFFJDDLITSX-UHFFFAOYSA-N benzyl N-[2-hydroxy-4-(3-oxomorpholin-4-yl)phenyl]carbamate Chemical compound OC1=C(NC(=O)OCC2=CC=CC=C2)C=CC(=C1)N1CCOCC1=O FFBHFFJDDLITSX-UHFFFAOYSA-N 0.000 description 17
• 210000000988 bone and bone Anatomy 0.000 description 17
• WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 16
• ULHLTDXPKWELHQ-UHFFFAOYSA-N 5-methyl-imidazole-4-carboxylic acid Chemical compound CC=1NC=NC=1C(O)=O ULHLTDXPKWELHQ-UHFFFAOYSA-N 0.000 description 15
• JKXKKNSEXGPUEU-UHFFFAOYSA-N B(O)O.C1=CC=CC2=CC=CC=C12.CC1=C(C=C(C(=O)O)C=C1)C(=O)O Chemical class B(O)O.C1=CC=CC2=CC=CC=C12.CC1=C(C=C(C(=O)O)C=C1)C(=O)O JKXKKNSEXGPUEU-UHFFFAOYSA-N 0.000 description 15
• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 15
• 210000004027 cell Anatomy 0.000 description 15
• 238000000746 purification Methods 0.000 description 15
• 238000010992 reflux Methods 0.000 description 15
• RZOKQIPOABEQAM-UHFFFAOYSA-N 6-methylpyridine-3-carboxylic acid Chemical compound CC1=CC=C(C(O)=O)C=N1 RZOKQIPOABEQAM-UHFFFAOYSA-N 0.000 description 14
• 239000007788 liquid Substances 0.000 description 14
• TXNBSTNWVSFRLH-UHFFFAOYSA-N n-cyclopropyl-n-methylcyclopropanamine Chemical compound C1CC1N(C)C1CC1 TXNBSTNWVSFRLH-UHFFFAOYSA-N 0.000 description 14
• XDOKFEJMEJKVGX-UHFFFAOYSA-N ethyl 1,3-thiazole-4-carboxylate Chemical compound CCOC(=O)C1=CSC=N1 XDOKFEJMEJKVGX-UHFFFAOYSA-N 0.000 description 13
• 102100024940 Cathepsin K Human genes 0.000 description 12
• 108010033040 Histones Proteins 0.000 description 12
• 239000000460 chlorine Substances 0.000 description 12
• 238000004440 column chromatography Methods 0.000 description 12
• LZTBZQSQFMLGQH-UHFFFAOYSA-N naphthalen-1-yloxyboronic acid Chemical compound C1=CC=C2C(OB(O)O)=CC=CC2=C1 LZTBZQSQFMLGQH-UHFFFAOYSA-N 0.000 description 12
• 210000002997 osteoclast Anatomy 0.000 description 12
• BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 12
• DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 12
• CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical class CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 11
• ZDXPYRJPNDTMRX-UHFFFAOYSA-N Glutamine Chemical compound OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 11
• 239000003112 inhibitor Substances 0.000 description 11
• QKYWADPCTHTJHQ-UHFFFAOYSA-N n,2-dimethylpropan-1-amine Chemical compound CNCC(C)C QKYWADPCTHTJHQ-UHFFFAOYSA-N 0.000 description 11
• 239000010410 layer Substances 0.000 description 10
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