CA2583986A1 - Method of preventing and treating airway remodeling and pulmonary inflammation using a2b adenosine receptor antagonists - Google Patents

Info

Publication number

CA2583986A1

CA2583986A1 CA002583986A CA2583986A CA2583986A1 CA 2583986 A1 CA2583986 A1 CA 2583986A1 CA 002583986 A CA002583986 A CA 002583986A CA 2583986 A CA2583986 A CA 2583986A CA 2583986 A1 CA2583986 A1 CA 2583986A1

Authority

CA

Canada

Prior art keywords

optionally substituted

propyl

dione

methyl

pyrazol

Prior art date

2004-10-15

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

• 238000000034 method Methods 0.000 title claims abstract description 129
• 208000036065 Airway Remodeling Diseases 0.000 title claims abstract description 30
• 101150078577 Adora2b gene Proteins 0.000 title claims abstract description 29
• 206010035664 Pneumonia Diseases 0.000 title claims description 27
• 229940121359 adenosine receptor antagonist Drugs 0.000 title abstract description 20
• 239000000296 purinergic P1 receptor antagonist Substances 0.000 title abstract description 20
• 238000011282 treatment Methods 0.000 claims abstract description 37
• 208000006673 asthma Diseases 0.000 claims abstract description 20
• 208000005069 pulmonary fibrosis Diseases 0.000 claims abstract description 12
• 230000002265 prevention Effects 0.000 claims abstract description 9
• 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 claims abstract 2
• 150000001875 compounds Chemical class 0.000 claims description 236
• -1 5-(2-methoxyphenyl)-(1,2,4-oxadiazol-3-yl) Chemical group 0.000 claims description 93
• 125000000217 alkyl group Chemical group 0.000 claims description 65
• 125000001072 heteroaryl group Chemical group 0.000 claims description 48
• 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 43
• 125000003545 alkoxy group Chemical group 0.000 claims description 35
• 229910052739 hydrogen Inorganic materials 0.000 claims description 33
• 239000001257 hydrogen Substances 0.000 claims description 32
• 125000000753 cycloalkyl group Chemical group 0.000 claims description 29
• 125000002947 alkylene group Chemical group 0.000 claims description 26
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 26
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 26
• 125000004432 carbon atom Chemical group C* 0.000 claims description 24
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 23
• 150000002431 hydrogen Chemical class 0.000 claims description 22
• 125000000623 heterocyclic group Chemical group 0.000 claims description 21
• 125000000547 substituted alkyl group Chemical group 0.000 claims description 15
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 14
• 201000010099 disease Diseases 0.000 claims description 13
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 12
• 241000124008 Mammalia Species 0.000 claims description 11
• 125000005346 substituted cycloalkyl group Chemical group 0.000 claims description 10
• 125000005017 substituted alkenyl group Chemical group 0.000 claims description 9
• 229940044551 receptor antagonist Drugs 0.000 claims description 8
• 239000002464 receptor antagonist Substances 0.000 claims description 8
• 229910052799 carbon Inorganic materials 0.000 claims description 7
• 125000004076 pyridyl group Chemical group 0.000 claims description 7
• 125000003107 substituted aryl group Chemical group 0.000 claims description 7
• KOYXXLLNCXWUNF-UHFFFAOYSA-N 3-ethyl-1-propyl-8-[1-[[3-(trifluoromethyl)phenyl]methyl]pyrazol-4-yl]-7h-purine-2,6-dione Chemical compound N1C=2C(=O)N(CCC)C(=O)N(CC)C=2N=C1C(=C1)C=NN1CC1=CC=CC(C(F)(F)F)=C1 KOYXXLLNCXWUNF-UHFFFAOYSA-N 0.000 claims description 6
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 6
• 125000004426 substituted alkynyl group Chemical group 0.000 claims description 6
• 125000000732 arylene group Chemical group 0.000 claims description 5
• RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 5
• 150000004866 oxadiazoles Chemical class 0.000 claims description 5
• 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 4
• 125000004180 3-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(F)=C1[H] 0.000 claims description 4
• 125000005549 heteroarylene group Chemical group 0.000 claims description 4
• 125000005842 heteroatom Chemical group 0.000 claims description 4
• 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 4
• 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 4
• 125000000843 phenylene group Chemical group C1(=C(C=CC=C1)*)* 0.000 claims description 4
• FOPDIVBIDYTGMD-UHFFFAOYSA-N 1-(cyclopropylmethyl)-3-ethyl-8-[1-[[6-(trifluoromethyl)pyridin-3-yl]methyl]pyrazol-4-yl]-7h-purine-2,6-dione Chemical compound O=C1N(CC)C=2N=C(C3=CN(CC=4C=NC(=CC=4)C(F)(F)F)N=C3)NC=2C(=O)N1CC1CC1 FOPDIVBIDYTGMD-UHFFFAOYSA-N 0.000 claims description 3
• UWWGEIHSFZWTAF-UHFFFAOYSA-N 3-ethyl-1-(2-methylpropyl)-8-[1-[[6-(trifluoromethyl)pyridin-3-yl]methyl]pyrazol-4-yl]-7h-purine-2,6-dione Chemical compound N1C=2C(=O)N(CC(C)C)C(=O)N(CC)C=2N=C1C(=C1)C=NN1CC1=CC=C(C(F)(F)F)N=C1 UWWGEIHSFZWTAF-UHFFFAOYSA-N 0.000 claims description 3
• KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical group N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 claims description 3
• JNJWKLSCJORTLT-UHFFFAOYSA-N 8-[4-[[5-(2-methoxyphenyl)-1,2,4-oxadiazol-3-yl]methoxy]phenyl]-1,3-dipropyl-7h-purine-2,6-dione Chemical compound N1C=2C(=O)N(CCC)C(=O)N(CCC)C=2N=C1C(C=C1)=CC=C1OCC(N=1)=NOC=1C1=CC=CC=C1OC JNJWKLSCJORTLT-UHFFFAOYSA-N 0.000 claims description 3
• 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 3
• FJOWCRNUYDSBQY-UHFFFAOYSA-N 1,3-dipropyl-8-(1h-pyrazol-4-yl)-7h-purine-2,6-dione Chemical compound N1C=2C(=O)N(CCC)C(=O)N(CCC)C=2N=C1C=1C=NNC=1 FJOWCRNUYDSBQY-UHFFFAOYSA-N 0.000 claims description 2
• RAFXNBDJRQNLBT-UHFFFAOYSA-N 1,3-dipropyl-8-[1-(pyridin-2-ylmethyl)pyrazol-4-yl]-7h-purine-2,6-dione Chemical compound N1C=2C(=O)N(CCC)C(=O)N(CCC)C=2N=C1C(=C1)C=NN1CC1=CC=CC=N1 RAFXNBDJRQNLBT-UHFFFAOYSA-N 0.000 claims description 2
• VKTXMHRAIBKAOF-UHFFFAOYSA-N 1,3-dipropyl-8-[1-[2-[3-(trifluoromethyl)phenyl]ethyl]pyrazol-4-yl]-7h-purine-2,6-dione Chemical compound N1C=2C(=O)N(CCC)C(=O)N(CCC)C=2N=C1C(=C1)C=NN1CCC1=CC=CC(C(F)(F)F)=C1 VKTXMHRAIBKAOF-UHFFFAOYSA-N 0.000 claims description 2
• NNBVIKCVEVSEMX-UHFFFAOYSA-N 1,3-dipropyl-8-[1-[[3-(2h-tetrazol-5-yl)phenyl]methyl]pyrazol-4-yl]-7h-purine-2,6-dione Chemical compound N1C=2C(=O)N(CCC)C(=O)N(CCC)C=2N=C1C(=C1)C=NN1CC(C=1)=CC=CC=1C1=NN=NN1 NNBVIKCVEVSEMX-UHFFFAOYSA-N 0.000 claims description 2
• YTNFLFXQFWBCKN-UHFFFAOYSA-N 1,3-dipropyl-8-[1-[[5-[4-(trifluoromethyl)phenyl]-1,2-oxazol-3-yl]methyl]pyrazol-4-yl]-7h-purine-2,6-dione Chemical compound N1C=2C(=O)N(CCC)C(=O)N(CCC)C=2N=C1C(=C1)C=NN1CC(=NO1)C=C1C1=CC=C(C(F)(F)F)C=C1 YTNFLFXQFWBCKN-UHFFFAOYSA-N 0.000 claims description 2
• JBGRNTKBOQPADE-UHFFFAOYSA-N 1-butyl-8-[1-[(3-fluorophenyl)methyl]pyrazol-4-yl]-3,7-dihydropurine-2,6-dione Chemical compound N1C=2C(=O)N(CCCC)C(=O)NC=2N=C1C(=C1)C=NN1CC1=CC=CC(F)=C1 JBGRNTKBOQPADE-UHFFFAOYSA-N 0.000 claims description 2
• QSEYHOMIGYEFFY-UHFFFAOYSA-N 1-butyl-8-[1-[[5-(4-chlorophenyl)-1,2,4-oxadiazol-3-yl]methyl]pyrazol-4-yl]-3,7-dihydropurine-2,6-dione Chemical compound N1C=2C(=O)N(CCCC)C(=O)NC=2N=C1C(=C1)C=NN1CC(N=1)=NOC=1C1=CC=C(Cl)C=C1 QSEYHOMIGYEFFY-UHFFFAOYSA-N 0.000 claims description 2
• SEKFWEUZFWPIIW-UHFFFAOYSA-N 1-propyl-8-[1-[[3-(trifluoromethyl)phenyl]methyl]pyrazol-4-yl]-3,7-dihydropurine-2,6-dione Chemical compound N1C=2C(=O)N(CCC)C(=O)NC=2N=C1C(=C1)C=NN1CC1=CC=CC(C(F)(F)F)=C1 SEKFWEUZFWPIIW-UHFFFAOYSA-N 0.000 claims description 2
• UDNGNWOKQLQPJV-UHFFFAOYSA-N 2-[4-[6-oxo-1-(2-oxopropyl)-3-propyl-2,7-dihydropurin-8-yl]-1H-pyrazol-5-yl]-2-phenylacetic acid Chemical compound O=C(CN1CN(C=2N=C(NC=2C1=O)C=1C(=NNC=1)C(C(=O)O)C1=CC=CC=C1)CCC)C UDNGNWOKQLQPJV-UHFFFAOYSA-N 0.000 claims description 2
• AZIMJLTVUFLESS-UHFFFAOYSA-N 3-[[4-(2,6-dioxo-1,3-dipropyl-7h-purin-8-yl)-1h-pyrazol-5-yl]methyl]benzoic acid Chemical compound N1C=2C(=O)N(CCC)C(=O)N(CCC)C=2N=C1C1=CNN=C1CC1=CC=CC(C(O)=O)=C1 AZIMJLTVUFLESS-UHFFFAOYSA-N 0.000 claims description 2
• FSZJGDMXEQVTPM-UHFFFAOYSA-N 3-butan-2-yl-1-methyl-8-(1h-pyrazol-4-yl)-7h-purine-2,6-dione Chemical compound N1C=2C(=O)N(C)C(=O)N(C(C)CC)C=2N=C1C=1C=NNC=1 FSZJGDMXEQVTPM-UHFFFAOYSA-N 0.000 claims description 2
• RGSFBJFXDRCAQB-UHFFFAOYSA-N 3-ethyl-1-propyl-8-[1-(pyridin-2-ylmethyl)pyrazol-4-yl]-7h-purine-2,6-dione Chemical compound N1C=2C(=O)N(CCC)C(=O)N(CC)C=2N=C1C(=C1)C=NN1CC1=CC=CC=N1 RGSFBJFXDRCAQB-UHFFFAOYSA-N 0.000 claims description 2
• TXEFUDYEMBGBMN-UHFFFAOYSA-N 3-ethyl-1-propyl-8-[1-[[6-(trifluoromethyl)pyridin-3-yl]methyl]pyrazol-4-yl]-7h-purine-2,6-dione Chemical compound N1C=2C(=O)N(CCC)C(=O)N(CC)C=2N=C1C(=C1)C=NN1CC1=CC=C(C(F)(F)F)N=C1 TXEFUDYEMBGBMN-UHFFFAOYSA-N 0.000 claims description 2
• VKONPLGZIZPWGJ-UHFFFAOYSA-N 4-[[4-(2,6-dioxo-1,3-dipropyl-7h-purin-8-yl)pyrazol-1-yl]methyl]benzoic acid Chemical compound N1C=2C(=O)N(CCC)C(=O)N(CCC)C=2N=C1C(=C1)C=NN1CC1=CC=C(C(O)=O)C=C1 VKONPLGZIZPWGJ-UHFFFAOYSA-N 0.000 claims description 2
• BKVOEOMEFAFQJL-UHFFFAOYSA-N 6-[[4-(2,6-dioxo-1,3-dipropyl-7h-purin-8-yl)-1h-pyrazol-5-yl]methyl]pyridine-2-carboxylic acid Chemical compound N1C=2C(=O)N(CCC)C(=O)N(CCC)C=2N=C1C1=CNN=C1CC1=CC=CC(C(O)=O)=N1 BKVOEOMEFAFQJL-UHFFFAOYSA-N 0.000 claims description 2
• KAYVCWBEIZTVCN-UHFFFAOYSA-N 8-(1-benzylpyrazol-4-yl)-1-propyl-3,7-dihydropurine-2,6-dione Chemical compound N1C=2C(=O)N(CCC)C(=O)NC=2N=C1C(=C1)C=NN1CC1=CC=CC=C1 KAYVCWBEIZTVCN-UHFFFAOYSA-N 0.000 claims description 2
• INMYJCHAOZGGBA-UHFFFAOYSA-N 8-[1-(2-phenylethyl)pyrazol-4-yl]-1-propyl-3,7-dihydropurine-2,6-dione Chemical compound N1C=2C(=O)N(CCC)C(=O)NC=2N=C1C(=C1)C=NN1CCC1=CC=CC=C1 INMYJCHAOZGGBA-UHFFFAOYSA-N 0.000 claims description 2
• HLTWCJCIPYYETO-UHFFFAOYSA-N 8-[1-[[3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl]methyl]pyrazol-4-yl]-1,3-dipropyl-7h-purine-2,6-dione Chemical compound N1C=2C(=O)N(CCC)C(=O)N(CCC)C=2N=C1C(=C1)C=NN1CC(ON=1)=NC=1C1=CC=C(Cl)C=C1 HLTWCJCIPYYETO-UHFFFAOYSA-N 0.000 claims description 2
• HEHWDTREEVPBPD-UHFFFAOYSA-N 8-[1-[[3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl]methyl]pyrazol-4-yl]-3-ethyl-1-propyl-7h-purine-2,6-dione Chemical compound N1C=2C(=O)N(CCC)C(=O)N(CC)C=2N=C1C(=C1)C=NN1CC(ON=1)=NC=1C1=CC=C(Cl)C=C1 HEHWDTREEVPBPD-UHFFFAOYSA-N 0.000 claims description 2
• HWHLLTUJISZFDN-UHFFFAOYSA-N 8-[1-[[5-(4-chlorophenyl)-1,2,4-oxadiazol-3-yl]methyl]pyrazol-4-yl]-1-propyl-3,7-dihydropurine-2,6-dione Chemical compound N1C=2C(=O)N(CCC)C(=O)NC=2N=C1C(=C1)C=NN1CC(N=1)=NOC=1C1=CC=C(Cl)C=C1 HWHLLTUJISZFDN-UHFFFAOYSA-N 0.000 claims description 2
• PSHSAHVUUAGSSH-UHFFFAOYSA-N 8-[1-[[5-(4-chlorophenyl)-1,2-oxazol-3-yl]methyl]pyrazol-4-yl]-3-ethyl-1-propyl-7h-purine-2,6-dione Chemical compound N1C=2C(=O)N(CCC)C(=O)N(CC)C=2N=C1C(=C1)C=NN1CC(=NO1)C=C1C1=CC=C(Cl)C=C1 PSHSAHVUUAGSSH-UHFFFAOYSA-N 0.000 claims description 2
• AHJHSANRNGKAFS-UHFFFAOYSA-N 8-[4-[[5-(3-methoxyphenyl)-1,2,4-oxadiazol-3-yl]methoxy]phenyl]-1,3-dipropyl-7h-purine-2,6-dione Chemical compound N1C=2C(=O)N(CCC)C(=O)N(CCC)C=2N=C1C(C=C1)=CC=C1OCC(N=1)=NOC=1C1=CC=CC(OC)=C1 AHJHSANRNGKAFS-UHFFFAOYSA-N 0.000 claims description 2
• LHMYROXNDKDUQN-UHFFFAOYSA-N 8-[4-[[5-(4-fluorophenyl)-1,2,4-oxadiazol-3-yl]methoxy]phenyl]-1,3-dipropyl-7h-purine-2,6-dione Chemical compound N1C=2C(=O)N(CCC)C(=O)N(CCC)C=2N=C1C(C=C1)=CC=C1OCC(N=1)=NOC=1C1=CC=C(F)C=C1 LHMYROXNDKDUQN-UHFFFAOYSA-N 0.000 claims description 2
• VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical group C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 claims description 2
• 239000005977 Ethylene Chemical group 0.000 claims description 2
• 238000007912 intraperitoneal administration Methods 0.000 claims description 2
• 125000005415 substituted alkoxy group Chemical group 0.000 claims description 2
• 230000009885 systemic effect Effects 0.000 claims description 2
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims 7
• 125000004186 cyclopropylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C1([H])[H] 0.000 claims 2
• 125000000842 isoxazolyl group Chemical group 0.000 claims 2
• 238000006467 substitution reaction Methods 0.000 claims 2
• 150000002460 imidazoles Chemical class 0.000 claims 1
• 238000007918 intramuscular administration Methods 0.000 claims 1
• 238000001990 intravenous administration Methods 0.000 claims 1
• 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims 1
• 125000001715 oxadiazolyl group Chemical group 0.000 claims 1
• 239000000018 receptor agonist Substances 0.000 claims 1
• 229940044601 receptor agonist Drugs 0.000 claims 1
• 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims 1
• 239000008194 pharmaceutical composition Substances 0.000 abstract description 8
• 208000019693 Lung disease Diseases 0.000 abstract description 5
• 206010014561 Emphysema Diseases 0.000 abstract description 3
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 96
• 241000699670 Mus sp. Species 0.000 description 86
• 238000002360 preparation method Methods 0.000 description 84
• 238000006243 chemical reaction Methods 0.000 description 83
• 239000000203 mixture Substances 0.000 description 58
• 210000004072 lung Anatomy 0.000 description 54
• 102000055025 Adenosine deaminases Human genes 0.000 description 47
• 101710169336 5'-deoxyadenosine deaminase Proteins 0.000 description 46
• 125000001424 substituent group Chemical group 0.000 description 45
• 125000003118 aryl group Chemical group 0.000 description 42
• 239000000047 product Substances 0.000 description 41
• 239000003981 vehicle Substances 0.000 description 37
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 35
• OIRDTQYFTABQOQ-KQYNXXCUSA-N adenosine Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O OIRDTQYFTABQOQ-KQYNXXCUSA-N 0.000 description 34
• IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 32
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 32
• 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 32
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 30
• 239000002904 solvent Substances 0.000 description 30
• 230000002829 reductive effect Effects 0.000 description 28
• 229940123053 Adenosine A2b receptor antagonist Drugs 0.000 description 26
• 229910052736 halogen Inorganic materials 0.000 description 23
• 150000002367 halogens Chemical class 0.000 description 23
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 22
• 125000004181 carboxyalkyl group Chemical group 0.000 description 22
• 210000004027 cell Anatomy 0.000 description 22
• 125000004093 cyano group Chemical group *C#N 0.000 description 22
• 125000004356 hydroxy functional group Chemical group O* 0.000 description 22
• 239000000243 solution Substances 0.000 description 22
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 21
• 125000003342 alkenyl group Chemical group 0.000 description 19
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• IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 17
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• BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 16
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• 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 15
• NAWXUBYGYWOOIX-SFHVURJKSA-N (2s)-2-[[4-[2-(2,4-diaminoquinazolin-6-yl)ethyl]benzoyl]amino]-4-methylidenepentanedioic acid Chemical compound C1=CC2=NC(N)=NC(N)=C2C=C1CCC1=CC=C(C(=O)N[C@@H](CC(=C)C(O)=O)C(O)=O)C=C1 NAWXUBYGYWOOIX-SFHVURJKSA-N 0.000 description 13
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• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 13
• 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 13
• 238000000692 Student's t-test Methods 0.000 description 12
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• 239000005557 antagonist Substances 0.000 description 12
• 239000003795 chemical substances by application Substances 0.000 description 12
• 239000002244 precipitate Substances 0.000 description 12
• 150000003839 salts Chemical class 0.000 description 12
• LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 12
• 229920001436 collagen Polymers 0.000 description 11
• 239000003814 drug Substances 0.000 description 11
• 238000001914 filtration Methods 0.000 description 11
• 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 11
• 239000011734 sodium Substances 0.000 description 11
• FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 11
• 241001465754 Metazoa Species 0.000 description 10
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• 125000004414 alkyl thio group Chemical group 0.000 description 10
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• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
• 125000002252 acyl group Chemical group 0.000 description 9
• 125000004442 acylamino group Chemical group 0.000 description 9
• 125000004423 acyloxy group Chemical group 0.000 description 9
• 238000004458 analytical method Methods 0.000 description 9
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