CA2206532C - Novel amidinonaphthyl derivative or salt thereof - Google Patents

Info

Publication number

CA2206532C

CA2206532C CA002206532A CA2206532A CA2206532C CA 2206532 C CA2206532 C CA 2206532C CA 002206532 A CA002206532 A CA 002206532A CA 2206532 A CA2206532 A CA 2206532A CA 2206532 C CA2206532 C CA 2206532C

Authority

CA

Canada

Prior art keywords

group

piperidyl

oxy

methyl

phenyl

Prior art date

1994-12-02

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.)

Expired - Fee Related

Links

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• -1 amidinonaphthyl Chemical class 0.000 title claims abstract description 562
• 150000003839 salts Chemical class 0.000 title claims abstract description 41
• 125000004453 alkoxycarbonyl group Chemical group 0.000 claims abstract description 69
• 125000003545 alkoxy group Chemical group 0.000 claims abstract description 52
• 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims abstract description 50
• 125000000217 alkyl group Chemical group 0.000 claims abstract description 46
• 125000005843 halogen group Chemical group 0.000 claims abstract description 42
• 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims abstract description 40
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 34
• 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 30
• 108010074860 Factor Xa Proteins 0.000 claims abstract description 19
• 208000007536 Thrombosis Diseases 0.000 claims abstract description 8
• 125000002947 alkylene group Chemical group 0.000 claims abstract description 8
• 229910052717 sulfur Inorganic materials 0.000 claims abstract description 8
• 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 6
• 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims abstract description 5
• 125000004430 oxygen atom Chemical group O* 0.000 claims abstract description 5
• 125000004434 sulfur atom Chemical group 0.000 claims abstract description 5
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 239
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 206
• 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 claims description 84
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 81
• 125000004432 carbon atom Chemical group C* 0.000 claims description 40
• 125000003277 amino group Chemical group 0.000 claims description 38
• 125000002252 acyl group Chemical group 0.000 claims description 34
• 125000003282 alkyl amino group Chemical group 0.000 claims description 31
• 125000003118 aryl group Chemical group 0.000 claims description 29
• 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 26
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 23
• 230000023555 blood coagulation Effects 0.000 claims description 22
• 239000003814 drug Substances 0.000 claims description 22
• 125000004457 alkyl amino carbonyl group Chemical group 0.000 claims description 21
• 229940079593 drug Drugs 0.000 claims description 21
• 125000004691 alkyl thio carbonyl group Chemical group 0.000 claims description 15
• 125000004414 alkyl thio group Chemical group 0.000 claims description 15
• 125000002102 aryl alkyloxo group Chemical group 0.000 claims description 15
• 125000004104 aryloxy group Chemical group 0.000 claims description 15
• 125000003396 thiol group Chemical group [H]S* 0.000 claims description 15
• 125000000753 cycloalkyl group Chemical group 0.000 claims description 14
• 125000001072 heteroaryl group Chemical group 0.000 claims description 12
• 229910052757 nitrogen Inorganic materials 0.000 claims description 12
• 239000002253 acid Substances 0.000 claims description 11
• KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 claims description 10
• 125000004670 alkyl amino thio carbonyl group Chemical group 0.000 claims description 7
• WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 7
• 239000005711 Benzoic acid Substances 0.000 claims description 6
• 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 6
• 235000010233 benzoic acid Nutrition 0.000 claims description 6
• 238000011282 treatment Methods 0.000 claims description 6
• 239000003112 inhibitor Substances 0.000 claims description 5
• DHMQDGOQFOQNFH-UHFFFAOYSA-M Aminoacetate Chemical compound NCC([O-])=O DHMQDGOQFOQNFH-UHFFFAOYSA-M 0.000 claims description 4
• DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 claims description 4
• 125000004471 alkyl aminosulfonyl group Chemical group 0.000 claims description 4
• 125000005842 heteroatom Chemical group 0.000 claims description 4
• 230000002265 prevention Effects 0.000 claims description 4
• 201000010099 disease Diseases 0.000 claims description 3
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 3
• 208000005189 Embolism Diseases 0.000 claims description 2
• 239000004471 Glycine Substances 0.000 claims description 2
• 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 2
• 239000003130 blood coagulation factor inhibitor Substances 0.000 claims description 2
• 125000006254 cycloalkyl carbonyl group Chemical group 0.000 claims description 2
• 239000003937 drug carrier Substances 0.000 claims description 2
• 125000001038 naphthoyl group Chemical group C1(=CC=CC2=CC=CC=C12)C(=O)* 0.000 claims description 2
• 125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 claims description 2
• 125000005400 pyridylcarbonyl group Chemical group N1=C(C=CC=C1)C(=O)* 0.000 claims description 2
• 229910052760 oxygen Inorganic materials 0.000 claims 3
• 239000003795 chemical substances by application Substances 0.000 abstract description 11
• 230000002401 inhibitory effect Effects 0.000 abstract description 8
• 208000010110 spontaneous platelet aggregation Diseases 0.000 abstract 1
• 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 156
• 238000004949 mass spectrometry Methods 0.000 description 154
• 239000007858 starting material Substances 0.000 description 140
• 150000001875 compounds Chemical class 0.000 description 135
• IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 98
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 81
• 239000000243 solution Substances 0.000 description 79
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 75
• 238000006243 chemical reaction Methods 0.000 description 75
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 63
• 101150041968 CDC13 gene Proteins 0.000 description 51
• HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 51
• 239000000203 mixture Substances 0.000 description 49
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 39
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 38
• 238000000034 method Methods 0.000 description 34
• 235000019441 ethanol Nutrition 0.000 description 33
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 33
• 239000002904 solvent Substances 0.000 description 33
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 32
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 26
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 26
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 25
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 21
• KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 21
• PECNQHUAAPIQQO-UHFFFAOYSA-N tert-butyl 4-[4-[(7-cyanonaphthalen-2-yl)methylamino]phenoxy]piperidine-1-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCC1OC(C=C1)=CC=C1NCC1=CC=C(C=CC(=C2)C#N)C2=C1 PECNQHUAAPIQQO-UHFFFAOYSA-N 0.000 description 21
• HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 20
• UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 19
• IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 19
• 125000002490 anilino group Chemical group [H]N(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 19
• 239000003480 eluent Substances 0.000 description 19
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 18
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 18
• 239000002585 base Substances 0.000 description 17
• CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 15
• 239000007864 aqueous solution Substances 0.000 description 15
• QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 14
• 238000004519 manufacturing process Methods 0.000 description 14
• 150000001412 amines Chemical class 0.000 description 13
• 230000015271 coagulation Effects 0.000 description 13
• 238000005345 coagulation Methods 0.000 description 13
• 238000012360 testing method Methods 0.000 description 13
• YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 13
• SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 12
• JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 12
• 238000004440 column chromatography Methods 0.000 description 12
• 238000005259 measurement Methods 0.000 description 12
• 239000002504 physiological saline solution Substances 0.000 description 12
• 125000001424 substituent group Chemical group 0.000 description 12
• GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 12
• MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 10
• XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 10
• PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 10
• 238000001816 cooling Methods 0.000 description 10
• 239000000499 gel 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
• 238000010898 silica gel chromatography Methods 0.000 description 10
• VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 10
• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
• 108090000190 Thrombin Proteins 0.000 description 9
• 238000010992 reflux Methods 0.000 description 9
• 229960004072 thrombin Drugs 0.000 description 9
• KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 8
• 238000005804 alkylation reaction Methods 0.000 description 8
• 238000004108 freeze drying Methods 0.000 description 8
• 239000012312 sodium hydride Substances 0.000 description 8
• 229910000104 sodium hydride Inorganic materials 0.000 description 8
• 238000003756 stirring Methods 0.000 description 8
• 229940124530 sulfonamide Drugs 0.000 description 8
• RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 7
• IOVCWXUNBOPUCH-UHFFFAOYSA-M Nitrite anion Chemical compound [O-]N=O IOVCWXUNBOPUCH-UHFFFAOYSA-M 0.000 description 7
• YIKSCQDJHCMVMK-UHFFFAOYSA-N Oxamide Chemical compound NC(=O)C(N)=O YIKSCQDJHCMVMK-UHFFFAOYSA-N 0.000 description 7
• UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 7
• XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Natural products NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 7
• 229910021529 ammonia Inorganic materials 0.000 description 7
• 235000015165 citric acid Nutrition 0.000 description 7
• 238000010438 heat treatment Methods 0.000 description 7
• 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 7
• 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 7
• DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 6
• QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 6
• NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 6
• BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 6
• KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
• QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 6
• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
• 235000011054 acetic acid Nutrition 0.000 description 6
• 230000009471 action Effects 0.000 description 6
• 230000010100 anticoagulation Effects 0.000 description 6
• 210000004369 blood Anatomy 0.000 description 6
• 239000008280 blood Substances 0.000 description 6
• 239000007924 injection Substances 0.000 description 6
• 238000002347 injection Methods 0.000 description 6
• UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 6
• ODZPKZBBUMBTMG-UHFFFAOYSA-N sodium amide Chemical compound [NH2-].[Na+] ODZPKZBBUMBTMG-UHFFFAOYSA-N 0.000 description 6
• 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 6
• NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 description 6
• SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 5
• USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 5
• 239000005695 Ammonium acetate Substances 0.000 description 5
• BMTAFVWTTFSTOG-UHFFFAOYSA-N Butylate Chemical compound CCSC(=O)N(CC(C)C)CC(C)C BMTAFVWTTFSTOG-UHFFFAOYSA-N 0.000 description 5
• XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 5
• 230000029936 alkylation Effects 0.000 description 5
• 235000019257 ammonium acetate Nutrition 0.000 description 5
• 229940043376 ammonium acetate Drugs 0.000 description 5
• WXBLLCUINBKULX-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1.OC(=O)C1=CC=CC=C1 WXBLLCUINBKULX-UHFFFAOYSA-N 0.000 description 5
• 230000015572 biosynthetic process Effects 0.000 description 5
• UKAWXALBBYVEGN-UHFFFAOYSA-N carbamic acid;dihydrochloride Chemical compound Cl.Cl.NC(O)=O UKAWXALBBYVEGN-UHFFFAOYSA-N 0.000 description 5
• NKDDWNXOKDWJAK-UHFFFAOYSA-N dimethoxymethane Chemical compound COCOC NKDDWNXOKDWJAK-UHFFFAOYSA-N 0.000 description 5
• QKIUAMUSENSFQQ-UHFFFAOYSA-N dimethylazanide Chemical compound C[N-]C QKIUAMUSENSFQQ-UHFFFAOYSA-N 0.000 description 5
• 230000000694 effects Effects 0.000 description 5
• IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 5
• 229910000041 hydrogen chloride Inorganic materials 0.000 description 5
• 239000012046 mixed solvent Substances 0.000 description 5
• 210000002381 plasma Anatomy 0.000 description 5
• 229910000027 potassium carbonate Inorganic materials 0.000 description 5
• LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 5
• RVJFZDZSVLMRGT-UHFFFAOYSA-N 7-formylnaphthalene-2-carbonitrile Chemical compound C1=CC(C#N)=CC2=CC(C=O)=CC=C21 RVJFZDZSVLMRGT-UHFFFAOYSA-N 0.000 description 4
• BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 4
• DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 4
• 238000005917 acylation reaction Methods 0.000 description 4
• 239000012267 brine Substances 0.000 description 4
• 239000000872 buffer Substances 0.000 description 4
• 239000004202 carbamide Substances 0.000 description 4
• VYNSZADTVZXEJF-UHFFFAOYSA-N ethanesulfonamide dihydrochloride Chemical compound Cl.Cl.C(C)S(=O)(=O)N VYNSZADTVZXEJF-UHFFFAOYSA-N 0.000 description 4
• AEOCXXJPGCBFJA-UHFFFAOYSA-N ethionamide Chemical compound CCC1=CC(C(N)=S)=CC=N1 AEOCXXJPGCBFJA-UHFFFAOYSA-N 0.000 description 4
• 239000003701 inert diluent Substances 0.000 description 4
• KQNPFQTWMSNSAP-UHFFFAOYSA-N isobutyric acid Chemical compound CC(C)C(O)=O KQNPFQTWMSNSAP-UHFFFAOYSA-N 0.000 description 4
• HNQIVZYLYMDVSB-NJFSPNSNSA-N methanesulfonamide Chemical compound [14CH3]S(N)(=O)=O HNQIVZYLYMDVSB-NJFSPNSNSA-N 0.000 description 4
• BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 4
• 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 4
• 125000001624 naphthyl group Chemical group 0.000 description 4
• 125000004433 nitrogen atom Chemical group N* 0.000 description 4
• 125000005936 piperidyl group Chemical group 0.000 description 4
• 229920006395 saturated elastomer Polymers 0.000 description 4
• HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 4
• 238000005063 solubilization Methods 0.000 description 4
• 238000001228 spectrum Methods 0.000 description 4
• JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 4
• 229940070710 valerate Drugs 0.000 description 4
• WGMHMVLZFAJNOT-UHFFFAOYSA-N 1-ethoxyethylideneazanium;chloride Chemical compound [Cl-].CCOC(C)=[NH2+] WGMHMVLZFAJNOT-UHFFFAOYSA-N 0.000 description 3
• QKNYBSVHEMOAJP-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;hydron;chloride Chemical compound Cl.OCC(N)(CO)CO QKNYBSVHEMOAJP-UHFFFAOYSA-N 0.000 description 3
• 125000004575 3-pyrrolidinyl group Chemical group [H]N1C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 3
• WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
• KHBQMWCZKVMBLN-UHFFFAOYSA-N Benzenesulfonamide Chemical compound NS(=O)(=O)C1=CC=CC=C1 KHBQMWCZKVMBLN-UHFFFAOYSA-N 0.000 description 3
• FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 3
• 108090000790 Enzymes Proteins 0.000 description 3
• 102000004190 Enzymes Human genes 0.000 description 3
• 108010049003 Fibrinogen Proteins 0.000 description 3
• 102000008946 Fibrinogen Human genes 0.000 description 3
• KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
• GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 3
• WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 3
• 241000699670 Mus sp. Species 0.000 description 3
• 238000005481 NMR spectroscopy Methods 0.000 description 3
• MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
• 239000002202 Polyethylene glycol Substances 0.000 description 3
• DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
• 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 3
• 230000002378 acidificating effect Effects 0.000 description 3
• 239000000654 additive Substances 0.000 description 3
• 235000019270 ammonium chloride Nutrition 0.000 description 3
• RWZYAGGXGHYGMB-UHFFFAOYSA-N anthranilic acid Chemical compound NC1=CC=CC=C1C(O)=O RWZYAGGXGHYGMB-UHFFFAOYSA-N 0.000 description 3
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