OA10794A - Metalloproteinase inhibitors pharmaceutical compositions containing them and their pharmaceutical uses and methods and intermediates useful for their preparation - Google Patents

Info

Publication number

OA10794A

OA10794A OA9800074A OA9800074A OA10794A OA 10794 A OA10794 A OA 10794A OA 9800074 A OA9800074 A OA 9800074A OA 9800074 A OA9800074 A OA 9800074A OA 10794 A OA10794 A OA 10794A

Authority

OA

OAPI

Prior art keywords

group

formula

compound

sait

solvaté

Prior art date

1995-12-08

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• 238000000034 method Methods 0.000 title claims abstract description 76
• 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 12
• 239000000543 intermediate Substances 0.000 title abstract description 17
• 239000003475 metalloproteinase inhibitor Substances 0.000 title description 2
• 238000002360 preparation method Methods 0.000 title description 2
• 150000001875 compounds Chemical class 0.000 claims abstract description 328
• 125000003118 aryl group Chemical group 0.000 claims abstract description 122
• 125000001072 heteroaryl group Chemical group 0.000 claims abstract description 87
• 229910052760 oxygen Inorganic materials 0.000 claims abstract description 46
• 229940002612 prodrug Drugs 0.000 claims abstract description 42
• 239000000651 prodrug Substances 0.000 claims abstract description 42
• 125000001424 substituent group Chemical group 0.000 claims abstract description 28
• 229910052717 sulfur Inorganic materials 0.000 claims abstract description 27
• 150000003839 salts Chemical class 0.000 claims abstract description 22
• 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 18
• 230000000694 effects Effects 0.000 claims abstract description 17
• 102000005741 Metalloproteases Human genes 0.000 claims abstract description 14
• 108010006035 Metalloproteases Proteins 0.000 claims abstract description 14
• 125000006413 ring segment Chemical group 0.000 claims abstract description 14
• 230000002401 inhibitory effect Effects 0.000 claims abstract description 7
• 125000005842 heteroatom Chemical group 0.000 claims abstract description 6
• 125000004432 carbon atom Chemical group C* 0.000 claims abstract description 5
• 125000000217 alkyl group Chemical group 0.000 claims description 118
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 78
• 125000000753 cycloalkyl group Chemical group 0.000 claims description 76
• -1 ethyi Chemical group 0.000 claims description 74
• 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 50
• 229910052799 carbon Inorganic materials 0.000 claims description 36
• 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 33
• 125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 claims description 32
• 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 27
• 229910052739 hydrogen Inorganic materials 0.000 claims description 24
• 239000001257 hydrogen Substances 0.000 claims description 23
• 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 22
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 21
• 239000000460 chlorine Substances 0.000 claims description 19
• OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 18
• 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 17
• 229910052710 silicon Inorganic materials 0.000 claims description 17
• 238000004519 manufacturing process Methods 0.000 claims description 14
• 125000002950 monocyclic group Chemical group 0.000 claims description 11
• 206010011416 Croup infectious Diseases 0.000 claims description 9
• 201000010549 croup Diseases 0.000 claims description 9
• 125000004429 atom Chemical group 0.000 claims description 8
• 125000005843 halogen group Chemical group 0.000 claims description 8
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 8
• 201000010099 disease Diseases 0.000 claims description 6
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 6
• 125000002962 imidazol-1-yl group Chemical group [*]N1C([H])=NC([H])=C1[H] 0.000 claims description 6
• 206010003246 arthritis Diseases 0.000 claims description 5
• 239000003085 diluting agent Substances 0.000 claims description 5
• 229910052736 halogen Inorganic materials 0.000 claims description 5
• 150000002367 halogens Chemical class 0.000 claims description 5
• 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 5
• 230000004614 tumor growth Effects 0.000 claims description 5
• 125000001376 1,2,4-triazolyl group Chemical group N1N=C(N=C1)* 0.000 claims description 4
• 125000003354 benzotriazolyl group Chemical group N1N=NC2=C1C=CC=C2* 0.000 claims description 4
• 150000001721 carbon Chemical group 0.000 claims description 4
• 239000000546 pharmaceutical excipient Substances 0.000 claims description 4
• 239000003981 vehicle Substances 0.000 claims description 4
• 206010027476 Metastases Diseases 0.000 claims description 3
• 239000003937 drug carrier Substances 0.000 claims description 3
• 230000009401 metastasis Effects 0.000 claims description 3
• 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 3
• 229910052731 fluorine Inorganic materials 0.000 claims description 2
• 125000002883 imidazolyl group Chemical group 0.000 claims description 2
• 125000004433 nitrogen atom Chemical group N* 0.000 claims description 2
• SGPGESCZOCHFCL-UHFFFAOYSA-N Tilisolol hydrochloride Chemical compound [Cl-].C1=CC=C2C(=O)N(C)C=C(OCC(O)C[NH2+]C(C)(C)C)C2=C1 SGPGESCZOCHFCL-UHFFFAOYSA-N 0.000 claims 10
• 230000009400 cancer invasion Effects 0.000 claims 2
• ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims 1
• PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims 1
• 229910006069 SO3H Inorganic materials 0.000 claims 1
• 241001504505 Troglodytes troglodytes Species 0.000 claims 1
• 229910052801 chlorine Inorganic materials 0.000 claims 1
• 125000000816 ethylene group Chemical group [H]C([H])([*:1])C([H])([H])[*:2] 0.000 claims 1
• 239000011737 fluorine Substances 0.000 claims 1
• 125000000020 sulfo group Chemical group O=S(=O)([*])O[H] 0.000 claims 1
• 239000012453 solvate Substances 0.000 abstract 5
• YMWUJEATGCHHMB-UHFFFAOYSA-N dichloromethane Substances ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 232
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 203
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 162
• 239000000243 solution Substances 0.000 description 145
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 114
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 77
• 238000006243 chemical reaction Methods 0.000 description 73
• 239000007787 solid Substances 0.000 description 72
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 70
• 239000000203 mixture Substances 0.000 description 66
• 235000019439 ethyl acetate Nutrition 0.000 description 63
• 229940093499 ethyl acetate Drugs 0.000 description 62
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 55
• 239000002253 acid Substances 0.000 description 55
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 52
• 239000002904 solvent Substances 0.000 description 51
• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 45
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 43
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 41
• 229910052938 sodium sulfate Inorganic materials 0.000 description 40
• 235000011152 sodium sulphate Nutrition 0.000 description 40
• PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 39
• 239000012044 organic layer Substances 0.000 description 38
• SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 36
• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 36
• 229960003010 sodium sulfate Drugs 0.000 description 36
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 32
• 238000007792 addition Methods 0.000 description 30
• 239000012267 brine Substances 0.000 description 30
• HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 30
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 27
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 27
• 239000002585 base Substances 0.000 description 27
• VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 24
• UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 23
• 238000001914 filtration Methods 0.000 description 23
• 239000010410 layer Substances 0.000 description 23
• 238000011282 treatment Methods 0.000 description 22
• DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 21
• 150000003254 radicals Chemical class 0.000 description 21
• 239000011541 reaction mixture Substances 0.000 description 21
• 238000005160 1H NMR spectroscopy Methods 0.000 description 20
• UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 20
• RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 18
• 235000011054 acetic acid Nutrition 0.000 description 18
• 229960000583 acetic acid Drugs 0.000 description 18
• QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 17
• 150000002148 esters Chemical class 0.000 description 17
• 229940086542 triethylamine Drugs 0.000 description 17
• 238000004587 chromatography analysis Methods 0.000 description 16
• 239000000725 suspension Substances 0.000 description 16
• WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 15
• 102000002274 Matrix Metalloproteinases Human genes 0.000 description 15
• 108010000684 Matrix Metalloproteinases Proteins 0.000 description 15
• CSKNSYBAZOQPLR-UHFFFAOYSA-N benzenesulfonyl chloride Chemical compound ClS(=O)(=O)C1=CC=CC=C1 CSKNSYBAZOQPLR-UHFFFAOYSA-N 0.000 description 15
• KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 15
• WBHQBSYUUJJSRZ-UHFFFAOYSA-M sodium bisulfate Chemical compound [Na+].OS([O-])(=O)=O WBHQBSYUUJJSRZ-UHFFFAOYSA-M 0.000 description 15
• 229910000342 sodium bisulfate Inorganic materials 0.000 description 15
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 14
• NHTMVDHEPJAVLT-UHFFFAOYSA-N Isooctane Chemical compound CC(C)CC(C)(C)C NHTMVDHEPJAVLT-UHFFFAOYSA-N 0.000 description 14
• QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 14
• JVSWJIKNEAIKJW-UHFFFAOYSA-N dimethyl-hexane Natural products CCCCCC(C)C JVSWJIKNEAIKJW-UHFFFAOYSA-N 0.000 description 14
• 239000003921 oil Substances 0.000 description 14
• 235000019198 oils Nutrition 0.000 description 14
• 229940100996 sodium bisulfate Drugs 0.000 description 14
• KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 13
• 206010028980 Neoplasm Diseases 0.000 description 13
• 239000000741 silica gel Substances 0.000 description 13
• 229910002027 silica gel Inorganic materials 0.000 description 13
• 229960001866 silicon dioxide Drugs 0.000 description 13
• 238000003756 stirring Methods 0.000 description 13
• RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 13
• IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 12
• AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 description 12
• WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 12
• BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 12
• KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 12
• QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 12
• IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 12
• 229910000041 hydrogen chloride Inorganic materials 0.000 description 12
• 102000004190 Enzymes Human genes 0.000 description 11
• 108090000790 Enzymes Proteins 0.000 description 11
• 150000002431 hydrogen Chemical class 0.000 description 11
• 230000005764 inhibitory process Effects 0.000 description 11
• 239000002244 precipitate Substances 0.000 description 11
• 239000000047 product Substances 0.000 description 11
• 238000000746 purification Methods 0.000 description 11
• GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 description 10
• XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 10
• JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 10
• 239000003153 chemical reaction reagent Substances 0.000 description 10
• 239000003960 organic solvent Substances 0.000 description 10
• BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 10
• 230000008569 process Effects 0.000 description 10
• YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 10
• FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 10
• 210000001519 tissue Anatomy 0.000 description 10
• 238000010626 work up procedure Methods 0.000 description 10
• 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 description 9
• KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 9
• 235000019441 ethanol Nutrition 0.000 description 9
• 229920006395 saturated elastomer Polymers 0.000 description 9
• 229910000030 sodium bicarbonate Inorganic materials 0.000 description 9
• 229960001407 sodium bicarbonate Drugs 0.000 description 9
• 235000017557 sodium bicarbonate Nutrition 0.000 description 9
• 102000008186 Collagen Human genes 0.000 description 8
• 108010035532 Collagen Proteins 0.000 description 8
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 8
• DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 8
• 230000015572 biosynthetic process Effects 0.000 description 8
• IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 description 8
• 229920001436 collagen Polymers 0.000 description 8
• 238000001816 cooling Methods 0.000 description 8
• 239000000706 filtrate Substances 0.000 description 8
• CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 8
• 239000008363 phosphate buffer Substances 0.000 description 8
• 125000006239 protecting group Chemical group 0.000 description 8
• 238000010992 reflux Methods 0.000 description 8
• KEQGZUUPPQEDPF-UHFFFAOYSA-N 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione Chemical compound CC1(C)N(Cl)C(=O)N(Cl)C1=O KEQGZUUPPQEDPF-UHFFFAOYSA-N 0.000 description 7
• IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 7
• XLYOFNOQVPJJNP-ZSJDYOACSA-N Heavy water Chemical compound [2H]O[2H] XLYOFNOQVPJJNP-ZSJDYOACSA-N 0.000 description 7
• DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 7
• UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 7
• 150000001412 amines Chemical class 0.000 description 7
• XTHPWXDJESJLNJ-UHFFFAOYSA-N chlorosulfonic acid Substances OS(Cl)(=O)=O XTHPWXDJESJLNJ-UHFFFAOYSA-N 0.000 description 7
• FAMRKDQNMBBFBR-BQYQJAHWSA-N diethyl azodicarboxylate Substances CCOC(=O)\N=N\C(=O)OCC FAMRKDQNMBBFBR-BQYQJAHWSA-N 0.000 description 7
• 239000011734 sodium Substances 0.000 description 7
• 229910052708 sodium Inorganic materials 0.000 description 7
• 229940032330 sulfuric acid Drugs 0.000 description 7
• 239000006188 syrup Substances 0.000 description 7
• 235000020357 syrup Nutrition 0.000 description 7
• WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 6
• CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
• WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 6
• VVNCNSJFMMFHPL-VKHMYHEASA-N D-penicillamine Chemical compound CC(C)(S)[C@@H](N)C(O)=O VVNCNSJFMMFHPL-VKHMYHEASA-N 0.000 description 6
• JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
• CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 6
• 125000003277 amino group Chemical group 0.000 description 6
• 238000003776 cleavage reaction Methods 0.000 description 6
• 210000002808 connective tissue Anatomy 0.000 description 6
• 238000000605 extraction Methods 0.000 description 6
• 238000002955 isolation Methods 0.000 description 6
• 239000007788 liquid Substances 0.000 description 6
• HSZCZNFXUDYRKD-UHFFFAOYSA-M lithium iodide Chemical compound [Li+].[I-] HSZCZNFXUDYRKD-UHFFFAOYSA-M 0.000 description 6
• 239000011159 matrix material Substances 0.000 description 6
• 229960001639 penicillamine Drugs 0.000 description 6
• 230000007017 scission Effects 0.000 description 6
• 239000000377 silicon dioxide Substances 0.000 description 6
• 239000000758 substrate Substances 0.000 description 6
• 229940124530 sulfonamide Drugs 0.000 description 6
• 238000003786 synthesis reaction Methods 0.000 description 6
• JABYJIQOLGWMQW-UHFFFAOYSA-N undec-4-ene Chemical compound CCCCCCC=CCCC JABYJIQOLGWMQW-UHFFFAOYSA-N 0.000 description 6
• LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 5
• BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 5
• FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 5
• 102000004318 Matrilysin Human genes 0.000 description 5
• 108090000855 Matrilysin Proteins 0.000 description 5
• 238000005481 NMR spectroscopy Methods 0.000 description 5
• MKUXAQIIEYXACX-UHFFFAOYSA-N aciclovir Chemical compound N1C(N)=NC(=O)C2=C1N(COCCO)C=N2 MKUXAQIIEYXACX-UHFFFAOYSA-N 0.000 description 5
• 125000003545 alkoxy group Chemical group 0.000 description 5
• 239000000010 aprotic solvent Substances 0.000 description 5
• 229910052786 argon Inorganic materials 0.000 description 5
• 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 5
• 239000000872 buffer Substances 0.000 description 5
• 238000007796 conventional method Methods 0.000 description 5
• 150000001987 diarylethers Chemical class 0.000 description 5
• 210000004072 lung Anatomy 0.000 description 5
• 229910000027 potassium carbonate Inorganic materials 0.000 description 5
• 229920005989 resin Polymers 0.000 description 5
• 239000011347 resin Substances 0.000 description 5
• 150000003456 sulfonamides Chemical class 0.000 description 5
• JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 5
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