HRP20030160A2 - 1-thiadibenzoazulene derivatives and biological action thereof - Google Patents

1-thiadibenzoazulene derivatives and biological action thereof Download PDF

Info

Publication number: HRP20030160A2
Authority: HR; Croatia
Prior art keywords: oxa; formula; thia; alkyl; dibenzo
Prior art date: 2003-03-06

Application number

HR20030160A

Other languages

English (en)

Croatian (hr)

Inventor

Merep Mladen

Mesi Milan

Pe�i� Dijana

Benko Iva

Original Assignee

Pliva-Istra�iva�ki institut d.o.o.

Priority date (The priority date 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 date listed.)

2003-03-06

Filing date

2003-03-06

Publication date

2005-04-30

2003-03-06 Application filed by Pliva-Istra�iva�ki institut d.o.o. filed Critical Pliva-Istra�iva�ki institut d.o.o.

2003-03-06 Priority to HR20030160A priority Critical patent/HRP20030160A2/hr

2004-03-05 Priority to CA002517847A priority patent/CA2517847A1/en

2004-03-05 Priority to EP04717708A priority patent/EP1603921B1/de

2004-03-05 Priority to ARP040100693A priority patent/AR043484A1/es

2004-03-05 Priority to JP2006506243A priority patent/JP2006519829A/ja

2004-03-05 Priority to DE602004021568T priority patent/DE602004021568D1/de

2004-03-05 Priority to PCT/HR2004/000005 priority patent/WO2004078763A1/en

2004-03-05 Priority to CNA2004800085860A priority patent/CN1768064A/zh

2004-03-05 Priority to AT04717708T priority patent/ATE433983T1/de

2004-03-05 Priority to CL200400444A priority patent/CL2004000444A1/es

2005-04-30 Publication of HRP20030160A2 publication Critical patent/HRP20030160A2/hr

2005-09-06 Priority to US11/221,414 priority patent/US20060069149A1/en

Links

GXMSLNZIHPZWAI-UHFFFAOYSA-N 5-thiatetracyclo[12.4.0.02,6.08,13]octadeca-1(18),2,6,8,10,12,14,16-octaene Chemical class S1CC=C2C3=C(C4=C(C=C12)C=CC=C4)C=CC=C3 GXMSLNZIHPZWAI-UHFFFAOYSA-N 0.000 title claims description 7
230000031018 biological processes and functions Effects 0.000 title 1
150000001875 compounds Chemical class 0.000 claims description 78
238000000034 method Methods 0.000 claims description 46
-1 cyano-C1-C7-alkyl Chemical group 0.000 claims description 36
125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 23
238000002360 preparation method Methods 0.000 claims description 22
238000011282 treatment Methods 0.000 claims description 16
150000003839 salts Chemical class 0.000 claims description 14
125000006701 (C1-C7) alkyl group Chemical group 0.000 claims description 13
125000001424 substituent group Chemical group 0.000 claims description 12
LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 11
125000000623 heterocyclic group Chemical group 0.000 claims description 10
125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 10
125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 9
201000010099 disease Diseases 0.000 claims description 9
208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 9
125000001072 heteroaryl group Chemical group 0.000 claims description 8
239000000543 intermediate Substances 0.000 claims description 8
238000004519 manufacturing process Methods 0.000 claims description 8
125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 8
ODWWSOMISVACGQ-UHFFFAOYSA-N 10-(3-dimethylamino-propoxy)-8-oxa-1-thia-dibenzo[e,h]azulene-2-carboxylic acid Chemical compound C12=CC=CC=C2OC2=CC(OCCCN(C)C)=CC=C2C2=C1C=C(C(O)=O)S2 ODWWSOMISVACGQ-UHFFFAOYSA-N 0.000 claims description 7
230000001575 pathological effect Effects 0.000 claims description 7
102000004127 Cytokines Human genes 0.000 claims description 6
108090000695 Cytokines Proteins 0.000 claims description 6
125000003435 aroyl group Chemical group 0.000 claims description 6
238000006482 condensation reaction Methods 0.000 claims description 6
229940079593 drug Drugs 0.000 claims description 6
239000003814 drug Substances 0.000 claims description 6
150000002148 esters Chemical class 0.000 claims description 6
229910052736 halogen Inorganic materials 0.000 claims description 6
150000002367 halogens Chemical class 0.000 claims description 6
229910052739 hydrogen Inorganic materials 0.000 claims description 6
229910052757 nitrogen Inorganic materials 0.000 claims description 6
239000000825 pharmaceutical preparation Substances 0.000 claims description 6
230000008569 process Effects 0.000 claims description 6
125000003107 substituted aryl group Chemical group 0.000 claims description 6
206010061218 Inflammation Diseases 0.000 claims description 5
125000005842 heteroatom Chemical group 0.000 claims description 5
239000001257 hydrogen Substances 0.000 claims description 5
125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 5
230000004054 inflammatory process Effects 0.000 claims description 5
239000003112 inhibitor Substances 0.000 claims description 5
125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 5
125000006239 protecting group Chemical group 0.000 claims description 5
239000012453 solvate Substances 0.000 claims description 5
125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 claims description 5
125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 5
150000003573 thiols Chemical class 0.000 claims description 5
125000003277 amino group Chemical group 0.000 claims description 4
230000003110 anti-inflammatory effect Effects 0.000 claims description 4
125000004093 cyano group Chemical group *C#N 0.000 claims description 4
JIQHAUPAALONFJ-UHFFFAOYSA-N (10-benzyloxy-8-oxa-1-thia-dibenzo[e,h]azulene-2-yl)-methanol Chemical compound S1C(CO)=CC(C2=CC=CC=C2OC2=C3)=C1C2=CC=C3OCC1=CC=CC=C1 JIQHAUPAALONFJ-UHFFFAOYSA-N 0.000 claims description 3
TZUKWNGDEGAXJB-UHFFFAOYSA-N (11-benzyloxy-8-oxa-1-thia-dibenzo[e,h]azulene-2-yl)-methanol Chemical compound S1C(CO)=CC(C2=CC=CC=C2OC2=CC=3)=C1C2=CC=3OCC1=CC=CC=C1 TZUKWNGDEGAXJB-UHFFFAOYSA-N 0.000 claims description 3
ZXTYKTBHASCZME-UHFFFAOYSA-N [10-(3-dimethylamino-propoxy)-8-oxa-1-thia-dibenzo[e,h]azulene-2-yl]-methanol Chemical compound C12=CC=CC=C2OC2=CC(OCCCN(C)C)=CC=C2C2=C1C=C(CO)S2 ZXTYKTBHASCZME-UHFFFAOYSA-N 0.000 claims description 3
IOQJPQFABAPWJC-UHFFFAOYSA-N [11-(3-dimethylamino-propoxy)-8-oxa-1-thia-dibenzo[e,h]azulene-2-yl]-methanol Chemical compound C12=CC(OCCCN(C)C)=CC=C2OC2=CC=CC=C2C2=C1SC(CO)=C2 IOQJPQFABAPWJC-UHFFFAOYSA-N 0.000 claims description 3
125000005161 aryl oxy carbonyl group Chemical group 0.000 claims description 3
239000012634 fragment Substances 0.000 claims description 3
231100000252 nontoxic Toxicity 0.000 claims description 3
230000003000 nontoxic effect Effects 0.000 claims description 3
238000011321 prophylaxis Methods 0.000 claims description 3
XBIXFDBDXWMPDM-UHFFFAOYSA-N 10-(2-pyrrolidin-1-yl-ethoxy)-8-oxa-1-thia-dibenzo[e,h]azulene-2-carboxylic acid ethyl ester Chemical compound S1C(C(=O)OCC)=CC(C2=CC=CC=C2OC2=C3)=C1C2=CC=C3OCCN1CCCC1 XBIXFDBDXWMPDM-UHFFFAOYSA-N 0.000 claims description 2
RGTNMEAWDCKCTB-UHFFFAOYSA-N 10-(3-dimethylamino-propoxy)-8-oxa-1-thia-dibenzo[e,h]azulene-2-carboxylic acid ethyl ester Chemical compound C12=CC=C(OCCCN(C)C)C=C2OC2=CC=CC=C2C2=C1SC(C(=O)OCC)=C2 RGTNMEAWDCKCTB-UHFFFAOYSA-N 0.000 claims description 2
NGGSYUZDDPQVPV-UHFFFAOYSA-N 11-benzyloxy-8-oxa-1-thia-dibenzo[e,h]azulene-2-carboxylic acid ethyl ester Chemical compound S1C(C(=O)OCC)=CC(C2=CC=CC=C2OC2=CC=3)=C1C2=CC=3OCC1=CC=CC=C1 NGGSYUZDDPQVPV-UHFFFAOYSA-N 0.000 claims description 2
SOAFEUCSWNHDHI-UHFFFAOYSA-N [3-(10-benzyloxy-8-oxa-1-thia-dibenzo[e,h]azulene-2-ylmethoxy)-propyl]-dimethyl-amine Chemical compound S1C(COCCCN(C)C)=CC(C2=CC=CC=C2OC2=C3)=C1C2=CC=C3OCC1=CC=CC=C1 SOAFEUCSWNHDHI-UHFFFAOYSA-N 0.000 claims description 2
VKYMCNGORBHSRZ-UHFFFAOYSA-N [3-(11-benzyloxy-8-oxa-1-thia-dibenzo[e,h]azulene-2-ylmethoxy)-propyl]-dimethyl-amine Chemical compound S1C(COCCCN(C)C)=CC(C2=CC=CC=C2OC2=CC=3)=C1C2=CC=3OCC1=CC=CC=C1 VKYMCNGORBHSRZ-UHFFFAOYSA-N 0.000 claims description 2
238000009833 condensation Methods 0.000 claims description 2
230000005494 condensation Effects 0.000 claims description 2
XDQUTNOFGWXKHY-UHFFFAOYSA-N dimethyl-[3-(8-oxa-1-thia-dibenzo[e,h]azulene-10-yloxy)-propyl]-amine Chemical compound C12=CC=CC=C2OC2=CC(OCCCN(C)C)=CC=C2C2=C1C=CS2 XDQUTNOFGWXKHY-UHFFFAOYSA-N 0.000 claims description 2
NIFZQYSSCHSLDX-UHFFFAOYSA-N {3-[2-(3-dimethylamino-propoxymethyl)-8-oxa-1-thia-dibenzo[e,h]azulene-10-yloxy]-propyl}-dimethyl-amine Chemical compound C12=CC=C(OCCCN(C)C)C=C2OC2=CC=CC=C2C2=C1SC(COCCCN(C)C)=C2 NIFZQYSSCHSLDX-UHFFFAOYSA-N 0.000 claims description 2
BRTPPXJSAXMZTC-UHFFFAOYSA-N {3-[2-(3-dimethylamino-propoxymethyl)-8-oxa-1-thia-dibenzo[e,h]azulene-11-yloxy]-propyl}-dimethyl-amine Chemical compound C12=CC(OCCCN(C)C)=CC=C2OC2=CC=CC=C2C2=C1SC(COCCCN(C)C)=C2 BRTPPXJSAXMZTC-UHFFFAOYSA-N 0.000 claims description 2
125000004214 1-pyrrolidinyl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 claims 1
MBQYYUUTHHKIPM-UHFFFAOYSA-N 10-(2-dimethylamino-ethoxy)-8-oxa-1-thia-dibenzo[e,h]azulene-2-carboxylic acid ethyl ester Chemical compound C12=CC=C(OCCN(C)C)C=C2OC2=CC=CC=C2C2=C1SC(C(=O)OCC)=C2 MBQYYUUTHHKIPM-UHFFFAOYSA-N 0.000 claims 1
AFDSXYJLDZSRLQ-UHFFFAOYSA-N 10-benzyloxy-8-oxa-1-thia-dibenzo[e,h]azulene-2-carboxylic acid ethyl ester Chemical compound S1C(C(=O)OCC)=CC(C2=CC=CC=C2OC2=C3)=C1C2=CC=C3OCC1=CC=CC=C1 AFDSXYJLDZSRLQ-UHFFFAOYSA-N 0.000 claims 1
NDPNQZJEQYFRMX-UHFFFAOYSA-N 11-(3-dimethylamino-propoxy)-8-oxa-1-thia-dibenzo[e,h]azulene-2-carboxylic acid ethyl ester Chemical compound C12=CC(OCCCN(C)C)=CC=C2OC2=CC=CC=C2C2=C1SC(C(=O)OCC)=C2 NDPNQZJEQYFRMX-UHFFFAOYSA-N 0.000 claims 1
108060008682 Tumor Necrosis Factor Proteins 0.000 description 38
102000000852 Tumor Necrosis Factor-alpha Human genes 0.000 description 38
MZOFCQQQCNRIBI-VMXHOPILSA-N (3s)-4-[[(2s)-1-[[(2s)-1-[[(1s)-1-carboxy-2-hydroxyethyl]amino]-4-methyl-1-oxopentan-2-yl]amino]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-3-[[2-[[(2s)-2,6-diaminohexanoyl]amino]acetyl]amino]-4-oxobutanoic acid Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CC(O)=O)NC(=O)CNC(=O)[C@@H](N)CCCCN MZOFCQQQCNRIBI-VMXHOPILSA-N 0.000 description 36
HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 30
239000000047 product Substances 0.000 description 24
108010002352 Interleukin-1 Proteins 0.000 description 23
102000000589 Interleukin-1 Human genes 0.000 description 23
XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 18
238000005160 1H NMR spectroscopy Methods 0.000 description 17
230000028327 secretion Effects 0.000 description 17
239000002158 endotoxin Substances 0.000 description 16
125000004494 ethyl ester group Chemical group 0.000 description 16
239000011541 reaction mixture Substances 0.000 description 16
239000000243 solution Substances 0.000 description 16
ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 15
241001465754 Metazoa Species 0.000 description 14
HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 14
229920006008 lipopolysaccharide Polymers 0.000 description 14
ZAWUFVDTGBBVMW-UHFFFAOYSA-N 16-hydroxy-13-oxa-3-thiatetracyclo[12.4.0.02,6.07,12]octadeca-1(14),2(6),4,7,9,11,15,17-octaene-4-carboxylic acid Chemical compound C12=CC=C(O)C=C2OC2=CC=CC=C2C2=C1SC(C(=O)O)=C2 ZAWUFVDTGBBVMW-UHFFFAOYSA-N 0.000 description 13
210000004027 cell Anatomy 0.000 description 13
YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 12
125000003118 aryl group Chemical group 0.000 description 12
238000006243 chemical reaction Methods 0.000 description 12
238000012360 testing method Methods 0.000 description 12
MTJVQJRZIIKZJR-UHFFFAOYSA-N 10-methoxy-8-oxa-1-thia-dibenzo[e,h]azulene-2-carboxylic acid Chemical compound C12=CC=CC=C2OC2=CC(OC)=CC=C2C2=C1C=C(C(O)=O)S2 MTJVQJRZIIKZJR-UHFFFAOYSA-N 0.000 description 11
230000005764 inhibitory process Effects 0.000 description 11
206010039073 rheumatoid arthritis Diseases 0.000 description 11
XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 11
QMRQPPVYBQXNGZ-UHFFFAOYSA-N 10-hydroxy-8-oxa-1-thia-dibenzo[e,h]azulene-2-carboxylic acid ethyl ester Chemical compound C12=CC=C(O)C=C2OC2=CC=CC=C2C2=C1SC(C(=O)OCC)=C2 QMRQPPVYBQXNGZ-UHFFFAOYSA-N 0.000 description 10
LJQNMDZRCXJETK-UHFFFAOYSA-N 3-chloro-n,n-dimethylpropan-1-amine;hydron;chloride Chemical compound Cl.CN(C)CCCCl LJQNMDZRCXJETK-UHFFFAOYSA-N 0.000 description 10
230000002829 reductive effect Effects 0.000 description 10
QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
241000699670 Mus sp. Species 0.000 description 8
VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 8
238000004587 chromatography analysis Methods 0.000 description 8
238000001727 in vivo Methods 0.000 description 8
BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 8
239000000741 silica gel Substances 0.000 description 8
229910002027 silica gel Inorganic materials 0.000 description 8
PIYOXELXINZGLD-UHFFFAOYSA-N 17-hydroxy-13-oxa-3-thiatetracyclo[12.4.0.02,6.07,12]octadeca-1(14),2(6),4,7,9,11,15,17-octaene-4-carboxylic acid Chemical compound C12=CC(O)=CC=C2OC2=CC=CC=C2C2=C1SC(C(=O)O)=C2 PIYOXELXINZGLD-UHFFFAOYSA-N 0.000 description 7
239000007832 Na2SO4 Substances 0.000 description 7
PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 7
239000000654 additive Substances 0.000 description 7
238000000746 purification Methods 0.000 description 7
229910052938 sodium sulfate Inorganic materials 0.000 description 7
235000011152 sodium sulphate Nutrition 0.000 description 7
239000000126 substance Substances 0.000 description 7
230000006433 tumor necrosis factor production Effects 0.000 description 7
BHGGZXZKFFOEDE-UHFFFAOYSA-N 11-hydroxy-8-oxa-1-thia-dibenzo[e,h]azulene-2-carboxylic acid ethyl ester Chemical compound C12=CC(O)=CC=C2OC2=CC=CC=C2C2=C1SC(C(=O)OCC)=C2 BHGGZXZKFFOEDE-UHFFFAOYSA-N 0.000 description 6
GIHJWDIVTOEALR-UHFFFAOYSA-N 17-methoxy-13-oxa-3-thiatetracyclo[12.4.0.02,6.07,12]octadeca-1(14),2(6),4,7,9,11,15,17-octaene-4-carboxylic acid Chemical compound C12=CC(OC)=CC=C2OC2=CC=CC=C2C2=C1SC(C(O)=O)=C2 GIHJWDIVTOEALR-UHFFFAOYSA-N 0.000 description 6
VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
241000699666 Mus <mouse, genus> Species 0.000 description 6
YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 6
125000004122 cyclic group Chemical group 0.000 description 6
230000000694 effects Effects 0.000 description 6
RILRJVFNAJCCEM-UHFFFAOYSA-N 8-oxa-1-thia-dibenzo[e,h]azulene-10-ol Chemical compound C12=CC=CC=C2OC2=CC(O)=CC=C2C2=C1C=CS2 RILRJVFNAJCCEM-UHFFFAOYSA-N 0.000 description 5
238000002965 ELISA Methods 0.000 description 5
125000000217 alkyl group Chemical group 0.000 description 5
230000000202 analgesic effect Effects 0.000 description 5
LJQLBGIMNNMFFD-UHFFFAOYSA-N ethyl 16-methoxy-13-oxa-3-thiatetracyclo[12.4.0.02,6.07,12]octadeca-1(14),2(6),4,7,9,11,15,17-octaene-4-carboxylate Chemical compound C12=CC=C(OC)C=C2OC2=CC=CC=C2C2=C1SC(C(=O)OCC)=C2 LJQLBGIMNNMFFD-UHFFFAOYSA-N 0.000 description 5
239000012091 fetal bovine serum Substances 0.000 description 5
230000003647 oxidation Effects 0.000 description 5
238000007254 oxidation reaction Methods 0.000 description 5
238000006722 reduction reaction Methods 0.000 description 5
239000007858 starting material Substances 0.000 description 5
239000013589 supplement Substances 0.000 description 5
IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 4
KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
125000002252 acyl group Chemical group 0.000 description 4
125000003342 alkenyl group Chemical group 0.000 description 4
HTZCNXWZYVXIMZ-UHFFFAOYSA-M benzyl(triethyl)azanium;chloride Chemical compound [Cl-].CC[N+](CC)(CC)CC1=CC=CC=C1 HTZCNXWZYVXIMZ-UHFFFAOYSA-M 0.000 description 4
239000000460 chlorine Substances 0.000 description 4
229910052801 chlorine Inorganic materials 0.000 description 4
239000000706 filtrate Substances 0.000 description 4
125000005843 halogen group Chemical group 0.000 description 4
238000010438 heat treatment Methods 0.000 description 4
238000000338 in vitro Methods 0.000 description 4
208000027866 inflammatory disease Diseases 0.000 description 4
230000018276 interleukin-1 production Effects 0.000 description 4
229910052740 iodine Inorganic materials 0.000 description 4
239000007788 liquid Substances 0.000 description 4
229910000027 potassium carbonate Inorganic materials 0.000 description 4
230000009467 reduction Effects 0.000 description 4
239000007787 solid Substances 0.000 description 4
UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 4
JXEUJCGHWMFTPB-UHFFFAOYSA-N 10-methoxy-8-oxa-1-thia-dibenzo[e,h]azulene Chemical compound C12=CC=CC=C2OC2=CC(OC)=CC=C2C2=C1C=CS2 JXEUJCGHWMFTPB-UHFFFAOYSA-N 0.000 description 3
VRVQISUVAYKJOS-UHFFFAOYSA-N 11-chloro-8-oxa-1-thia-dibenzo[e,h]azulene-2-carboxylic acid Chemical compound C12=CC(Cl)=CC=C2OC2=CC=CC=C2C2=C1SC(C(=O)O)=C2 VRVQISUVAYKJOS-UHFFFAOYSA-N 0.000 description 3
RLWQHBBCPVECLI-UHFFFAOYSA-N 11-methoxy-8-oxa-1-thia-dibenzo[e,h]azulene-2-carboxylic acid ethyl ester Chemical compound C12=CC(OC)=CC=C2OC2=CC=CC=C2C2=C1SC(C(=O)OCC)=C2 RLWQHBBCPVECLI-UHFFFAOYSA-N 0.000 description 3
SYXQDHHGMKPQGZ-UHFFFAOYSA-N 17-methoxy-13-oxa-3-thiatetracyclo[12.4.0.02,6.07,12]octadeca-1(14),2(6),4,7,9,11,15,17-octaene Chemical compound C12=CC(OC)=CC=C2OC2=CC=CC=C2C2=C1SC=C2 SYXQDHHGMKPQGZ-UHFFFAOYSA-N 0.000 description 3
LQLJZSJKRYTKTP-UHFFFAOYSA-N 2-dimethylaminoethyl chloride hydrochloride Chemical compound Cl.CN(C)CCCl LQLJZSJKRYTKTP-UHFFFAOYSA-N 0.000 description 3
ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 3
WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 3
208000011231 Crohn disease Diseases 0.000 description 3
241000588724 Escherichia coli Species 0.000 description 3
108010008165 Etanercept Proteins 0.000 description 3
PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 3
241000282412 Homo Species 0.000 description 3
XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 3
KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
239000012980 RPMI-1640 medium Substances 0.000 description 3
206010040070 Septic Shock Diseases 0.000 description 3
125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 3
239000002253 acid Substances 0.000 description 3
230000009471 action Effects 0.000 description 3
230000000996 additive effect Effects 0.000 description 3
125000003545 alkoxy group Chemical group 0.000 description 3
125000003282 alkyl amino group Chemical group 0.000 description 3
125000000304 alkynyl group Chemical group 0.000 description 3
125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 3
230000004071 biological effect Effects 0.000 description 3
GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 3
229910052794 bromium Inorganic materials 0.000 description 3
125000001589 carboacyl group Chemical group 0.000 description 3
150000001721 carbon Chemical group 0.000 description 3
229910052799 carbon Inorganic materials 0.000 description 3
125000004432 carbon atom Chemical group C* 0.000 description 3
238000009903 catalytic hydrogenation reaction Methods 0.000 description 3
238000001704 evaporation Methods 0.000 description 3
230000008020 evaporation Effects 0.000 description 3
239000000284 extract Substances 0.000 description 3
229910052731 fluorine Inorganic materials 0.000 description 3
239000011737 fluorine Substances 0.000 description 3
125000000524 functional group Chemical group 0.000 description 3
150000004820 halides Chemical class 0.000 description 3
230000002757 inflammatory effect Effects 0.000 description 3
238000002347 injection Methods 0.000 description 3
239000007924 injection Substances 0.000 description 3
239000011630 iodine Substances 0.000 description 3
125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
239000013642 negative control Substances 0.000 description 3
210000003819 peripheral blood mononuclear cell Anatomy 0.000 description 3
210000003024 peritoneal macrophage Anatomy 0.000 description 3
239000013641 positive control Substances 0.000 description 3
108020003175 receptors Proteins 0.000 description 3
102000005962 receptors Human genes 0.000 description 3
239000002904 solvent Substances 0.000 description 3
QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid group Chemical class S(O)(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 3
LNAZSHAWQACDHT-XIYTZBAFSA-N (2r,3r,4s,5r,6s)-4,5-dimethoxy-2-(methoxymethyl)-3-[(2s,3r,4s,5r,6r)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxy-6-[(2r,3r,4s,5r,6r)-4,5,6-trimethoxy-2-(methoxymethyl)oxan-3-yl]oxyoxane Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](O[C@H]2[C@@H]([C@@H](OC)[C@H](OC)O[C@@H]2COC)OC)O[C@@H]1COC LNAZSHAWQACDHT-XIYTZBAFSA-N 0.000 description 2
125000004178 (C1-C4) alkyl group Chemical group 0.000 description 2
125000004768 (C1-C4) alkylsulfinyl group Chemical group 0.000 description 2
125000004769 (C1-C4) alkylsulfonyl group Chemical group 0.000 description 2
125000000229 (C1-C4)alkoxy group Chemical group 0.000 description 2
VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 2
JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 2
125000003006 2-dimethylaminoethyl group Chemical group [H]C([H])([H])N(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 2
IZHVBANLECCAGF-UHFFFAOYSA-N 2-hydroxy-3-(octadecanoyloxy)propyl octadecanoate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)COC(=O)CCCCCCCCCCCCCCCCC IZHVBANLECCAGF-UHFFFAOYSA-N 0.000 description 2
BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 2
108091003079 Bovine Serum Albumin Proteins 0.000 description 2
239000004215 Carbon black (E152) Substances 0.000 description 2
206010009900 Colitis ulcerative Diseases 0.000 description 2
239000007995 HEPES buffer Substances 0.000 description 2
MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 2
101710144554 Interleukin-1 receptor antagonist protein Proteins 0.000 description 2
102100026018 Interleukin-1 receptor antagonist protein Human genes 0.000 description 2
KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
229930182555 Penicillin Natural products 0.000 description 2
JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 2
NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
201000004681 Psoriasis Diseases 0.000 description 2
210000001744 T-lymphocyte Anatomy 0.000 description 2
DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
201000006704 Ulcerative Colitis Diseases 0.000 description 2
229960001138 acetylsalicylic acid Drugs 0.000 description 2
150000001298 alcohols Chemical group 0.000 description 2
125000004453 alkoxycarbonyl group Chemical group 0.000 description 2
125000005103 alkyl silyl group Chemical group 0.000 description 2
150000001408 amides Chemical class 0.000 description 2
239000006286 aqueous extract Substances 0.000 description 2
238000007080 aromatic substitution reaction Methods 0.000 description 2
230000002917 arthritic effect Effects 0.000 description 2
238000003556 assay Methods 0.000 description 2
208000006673 asthma Diseases 0.000 description 2
WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid group Chemical group C(C1=CC=CC=C1)(=O)O WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
KCXMKQUNVWSEMD-UHFFFAOYSA-N benzyl chloride Chemical compound ClCC1=CC=CC=C1 KCXMKQUNVWSEMD-UHFFFAOYSA-N 0.000 description 2
229940073608 benzyl chloride Drugs 0.000 description 2
125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 2
210000004369 blood Anatomy 0.000 description 2
239000008280 blood Substances 0.000 description 2
GZUXJHMPEANEGY-UHFFFAOYSA-N bromomethane Chemical compound BrC GZUXJHMPEANEGY-UHFFFAOYSA-N 0.000 description 2
239000011203 carbon fibre reinforced carbon Substances 0.000 description 2
239000003795 chemical substances by application Substances 0.000 description 2
NEHMKBQYUWJMIP-UHFFFAOYSA-N chloromethane Chemical compound ClC NEHMKBQYUWJMIP-UHFFFAOYSA-N 0.000 description 2
LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 2
229960000403 etanercept Drugs 0.000 description 2
125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 2
125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
125000006125 ethylsulfonyl group Chemical group 0.000 description 2
125000004705 ethylthio group Chemical group C(C)S* 0.000 description 2
238000002474 experimental method Methods 0.000 description 2
239000007903 gelatin capsule Substances 0.000 description 2
230000026030 halogenation Effects 0.000 description 2
238000005658 halogenation reaction Methods 0.000 description 2
229930195733 hydrocarbon Natural products 0.000 description 2
230000007062 hydrolysis Effects 0.000 description 2
238000006460 hydrolysis reaction Methods 0.000 description 2
125000002883 imidazolyl group Chemical group 0.000 description 2
230000004968 inflammatory condition Effects 0.000 description 2
229960000598 infliximab Drugs 0.000 description 2
230000002401 inhibitory effect Effects 0.000 description 2
125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
239000012280 lithium aluminium hydride Substances 0.000 description 2
HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
239000002609 medium Substances 0.000 description 2
125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 2
229920000609 methyl cellulose Polymers 0.000 description 2
125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 description 2
239000001923 methylcellulose Substances 0.000 description 2
235000010981 methylcellulose Nutrition 0.000 description 2
229960002900 methylcellulose Drugs 0.000 description 2
125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 description 2
125000006216 methylsulfinyl group Chemical group [H]C([H])([H])S(*)=O 0.000 description 2
125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 2
150000007522 mineralic acids Chemical class 0.000 description 2
239000000203 mixture Substances 0.000 description 2
239000001788 mono and diglycerides of fatty acids Substances 0.000 description 2
150000007524 organic acids Chemical class 0.000 description 2
201000008482 osteoarthritis Diseases 0.000 description 2
229910052760 oxygen Inorganic materials 0.000 description 2
229940049954 penicillin Drugs 0.000 description 2
210000003200 peritoneal cavity Anatomy 0.000 description 2
UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 2
239000002953 phosphate buffered saline Substances 0.000 description 2
239000000651 prodrug Substances 0.000 description 2
229940002612 prodrug Drugs 0.000 description 2
108090000623 proteins and genes Proteins 0.000 description 2
125000003373 pyrazinyl group Chemical group 0.000 description 2
229920006395 saturated elastomer Polymers 0.000 description 2
230000035945 sensitivity Effects 0.000 description 2
238000000926 separation method Methods 0.000 description 2
230000036303 septic shock Effects 0.000 description 2
238000003756 stirring Methods 0.000 description 2
229960005322 streptomycin Drugs 0.000 description 2
229910052717 sulfur Inorganic materials 0.000 description 2
239000006228 supernatant Substances 0.000 description 2
230000004083 survival effect Effects 0.000 description 2
238000003786 synthesis reaction Methods 0.000 description 2
239000006188 syrup Substances 0.000 description 2
235000020357 syrup Nutrition 0.000 description 2
125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
230000009466 transformation Effects 0.000 description 2
125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
229940046728 tumor necrosis factor alpha inhibitor Drugs 0.000 description 2
239000002452 tumor necrosis factor alpha inhibitor Substances 0.000 description 2
DGVVWUTYPXICAM-UHFFFAOYSA-N β‐Mercaptoethanol Chemical compound OCCS DGVVWUTYPXICAM-UHFFFAOYSA-N 0.000 description 2
FSNGFFWICFYWQC-UHFFFAOYSA-N 1-(2-chloroethyl)pyrrolidine;hydron;chloride Chemical compound Cl.ClCCN1CCCC1 FSNGFFWICFYWQC-UHFFFAOYSA-N 0.000 description 1
YIKHSCYIWAOTOP-UHFFFAOYSA-N 13-oxa-3-thiatetracyclo[12.4.0.02,6.07,12]octadeca-1(14),2(6),4,7,9,11,15,17-octaen-17-ol Chemical compound C12=CC(O)=CC=C2OC2=CC=CC=C2C2=C1SC=C2 YIKHSCYIWAOTOP-UHFFFAOYSA-N 0.000 description 1
NKTGZAKMRRHEKM-UHFFFAOYSA-N 3,5-diazatetracyclo[12.4.0.02,6.08,13]octadeca-1(18),2,4,6,8,10,12,14,16-nonaene Chemical class N1=CN=C2C3=C(C4=C(C=C12)C=CC=C4)C=CC=C3 NKTGZAKMRRHEKM-UHFFFAOYSA-N 0.000 description 1
BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 1
HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 1
208000030507 AIDS Diseases 0.000 description 1
QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical class CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 1
229920001817 Agar Polymers 0.000 description 1
GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
206010002556 Ankylosing Spondylitis Diseases 0.000 description 1
239000004342 Benzoyl peroxide Substances 0.000 description 1
OMPJBNCRMGITSC-UHFFFAOYSA-N Benzoylperoxide Chemical compound C=1C=CC=CC=1C(=O)OOC(=O)C1=CC=CC=C1 OMPJBNCRMGITSC-UHFFFAOYSA-N 0.000 description 1
CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
COVZYZSDYWQREU-UHFFFAOYSA-N Busulfan Chemical compound CS(=O)(=O)OCCCCOS(C)(=O)=O COVZYZSDYWQREU-UHFFFAOYSA-N 0.000 description 1
206010006895 Cachexia Diseases 0.000 description 1
206010007559 Cardiac failure congestive Diseases 0.000 description 1
208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 description 1
RZGJWVFLDKZTTI-UHFFFAOYSA-L Cl[Cr](=O)(=O)OC1=CC=CC=N1 Chemical compound Cl[Cr](=O)(=O)OC1=CC=CC=N1 RZGJWVFLDKZTTI-UHFFFAOYSA-L 0.000 description 1
102000029816 Collagenase Human genes 0.000 description 1
108060005980 Collagenase Proteins 0.000 description 1
RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
PMATZTZNYRCHOR-CGLBZJNRSA-N Cyclosporin A Chemical compound CC[C@@H]1NC(=O)[C@H]([C@H](O)[C@H](C)C\C=C\C)N(C)C(=O)[C@H](C(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)N(C)C(=O)CN(C)C1=O PMATZTZNYRCHOR-CGLBZJNRSA-N 0.000 description 1
108010036949 Cyclosporine Proteins 0.000 description 1
VVNCNSJFMMFHPL-VKHMYHEASA-N D-penicillamine Chemical compound CC(C)(S)[C@@H](N)C(O)=O VVNCNSJFMMFHPL-VKHMYHEASA-N 0.000 description 1
201000004624 Dermatitis Diseases 0.000 description 1
206010012438 Dermatitis atopic Diseases 0.000 description 1
206010012442 Dermatitis contact Diseases 0.000 description 1
VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 description 1
239000005977 Ethylene Substances 0.000 description 1
208000009386 Experimental Arthritis Diseases 0.000 description 1
BDAGIHXWWSANSR-UHFFFAOYSA-M Formate Chemical class [O-]C=O BDAGIHXWWSANSR-UHFFFAOYSA-M 0.000 description 1
238000005727 Friedel-Crafts reaction Methods 0.000 description 1
VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 1
108010010803 Gelatin Proteins 0.000 description 1
206010018364 Glomerulonephritis Diseases 0.000 description 1
244000068988 Glycine max Species 0.000 description 1
235000010469 Glycine max Nutrition 0.000 description 1
201000005569 Gout Diseases 0.000 description 1
206010019280 Heart failures Diseases 0.000 description 1
244000020551 Helianthus annuus Species 0.000 description 1
235000003222 Helianthus annuus Nutrition 0.000 description 1
101001076407 Homo sapiens Interleukin-1 receptor antagonist protein Proteins 0.000 description 1
101000599048 Homo sapiens Interleukin-6 receptor subunit alpha Proteins 0.000 description 1
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 1
206010022489 Insulin Resistance Diseases 0.000 description 1
102100037792 Interleukin-6 receptor subunit alpha Human genes 0.000 description 1
YQEZLKZALYSWHR-UHFFFAOYSA-N Ketamine Chemical compound C=1C=CC=C(Cl)C=1C1(NC)CCCCC1=O YQEZLKZALYSWHR-UHFFFAOYSA-N 0.000 description 1
FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 description 1
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 1
239000002841 Lewis acid Substances 0.000 description 1
241000124008 Mammalia Species 0.000 description 1
RHHSGLPWDHEVIR-UHFFFAOYSA-L O[Cr](O[Cr](OC1=CC=CC=N1)(=O)=O)(=O)=O Chemical compound O[Cr](O[Cr](OC1=CC=CC=N1)(=O)=O)(=O)=O RHHSGLPWDHEVIR-UHFFFAOYSA-L 0.000 description 1
240000007817 Olea europaea Species 0.000 description 1
229910020667 PBr3 Inorganic materials 0.000 description 1
208000037273 Pathologic Processes Diseases 0.000 description 1
206010036030 Polyarthritis Diseases 0.000 description 1
241000219061 Rheum Species 0.000 description 1
229910006124 SOCl2 Inorganic materials 0.000 description 1
206010039710 Scleroderma Diseases 0.000 description 1
206010040047 Sepsis Diseases 0.000 description 1
241000607720 Serratia Species 0.000 description 1
FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
201000002661 Spondylitis Diseases 0.000 description 1
CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
229930006000 Sucrose Natural products 0.000 description 1
QJJXYPPXXYFBGM-LFZNUXCKSA-N Tacrolimus Chemical compound C1C[C@@H](O)[C@H](OC)C[C@@H]1\C=C(/C)[C@@H]1[C@H](C)[C@@H](O)CC(=O)[C@H](CC=C)/C=C(C)/C[C@H](C)C[C@H](OC)[C@H]([C@H](C[C@H]2C)OC)O[C@@]2(O)C(=O)C(=O)N2CCCC[C@H]2C(=O)O1 QJJXYPPXXYFBGM-LFZNUXCKSA-N 0.000 description 1
241000906446 Theraps Species 0.000 description 1
206010044248 Toxic shock syndrome Diseases 0.000 description 1
231100000650 Toxic shock syndrome Toxicity 0.000 description 1
206010054094 Tumour necrosis Diseases 0.000 description 1
208000036142 Viral infection Diseases 0.000 description 1
229920000392 Zymosan Polymers 0.000 description 1
150000007513 acids Chemical class 0.000 description 1
230000004913 activation Effects 0.000 description 1
150000001266 acyl halides Chemical class 0.000 description 1
230000010933 acylation Effects 0.000 description 1
238000005917 acylation reaction Methods 0.000 description 1
239000008272 agar Substances 0.000 description 1
235000010419 agar Nutrition 0.000 description 1
125000003158 alcohol group Chemical group 0.000 description 1
125000003172 aldehyde group Chemical group 0.000 description 1
150000001335 aliphatic alkanes Chemical class 0.000 description 1
150000003973 alkyl amines Chemical class 0.000 description 1
150000001350 alkyl halides Chemical class 0.000 description 1
125000004644 alkyl sulfinyl group Chemical group 0.000 description 1
125000004414 alkyl thio group Chemical group 0.000 description 1
230000029936 alkylation Effects 0.000 description 1
238000005804 alkylation reaction Methods 0.000 description 1
HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 1
229910052782 aluminium Inorganic materials 0.000 description 1
XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
150000001412 amines Chemical group 0.000 description 1
150000008064 anhydrides Chemical group 0.000 description 1
238000010171 animal model Methods 0.000 description 1
239000005557 antagonist Substances 0.000 description 1
230000000259 anti-tumor effect Effects 0.000 description 1
238000013459 approach Methods 0.000 description 1
150000001491 aromatic compounds Chemical class 0.000 description 1
125000005098 aryl alkoxy carbonyl group Chemical group 0.000 description 1
125000005101 aryl methoxy carbonyl group Chemical group 0.000 description 1
125000004429 atom Chemical group 0.000 description 1
201000008937 atopic dermatitis Diseases 0.000 description 1
208000010668 atopic eczema Diseases 0.000 description 1
230000001363 autoimmune Effects 0.000 description 1
235000019400 benzoyl peroxide Nutrition 0.000 description 1
125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
CHQVQXZFZHACQQ-UHFFFAOYSA-M benzyl(triethyl)azanium;bromide Chemical compound [Br-].CC[N+](CC)(CC)CC1=CC=CC=C1 CHQVQXZFZHACQQ-UHFFFAOYSA-M 0.000 description 1
125000002619 bicyclic group Chemical group 0.000 description 1
239000011230 binding agent Substances 0.000 description 1
230000033228 biological regulation Effects 0.000 description 1
ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 description 1
230000031709 bromination Effects 0.000 description 1
238000005893 bromination reaction Methods 0.000 description 1
125000004369 butenyl group Chemical group C(=CCC)* 0.000 description 1
125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
125000000480 butynyl group Chemical group [*]C#CC([H])([H])C([H])([H])[H] 0.000 description 1
239000002775 capsule Substances 0.000 description 1
239000003054 catalyst Substances 0.000 description 1
230000003197 catalytic effect Effects 0.000 description 1
238000004113 cell culture Methods 0.000 description 1
230000009134 cell regulation Effects 0.000 description 1
238000005119 centrifugation Methods 0.000 description 1
239000003153 chemical reaction reagent Substances 0.000 description 1
239000003638 chemical reducing agent Substances 0.000 description 1
230000035605 chemotaxis Effects 0.000 description 1
238000005660 chlorination reaction Methods 0.000 description 1
ZCDOYSPFYFSLEW-UHFFFAOYSA-N chromate(2-) Chemical compound [O-][Cr]([O-])(=O)=O ZCDOYSPFYFSLEW-UHFFFAOYSA-N 0.000 description 1
230000001684 chronic effect Effects 0.000 description 1
208000037976 chronic inflammation Diseases 0.000 description 1
208000037893 chronic inflammatory disorder Diseases 0.000 description 1
229960001265 ciclosporin Drugs 0.000 description 1
229960002424 collagenase Drugs 0.000 description 1
208000010247 contact dermatitis Diseases 0.000 description 1
238000007796 conventional method Methods 0.000 description 1
229910052802 copper Inorganic materials 0.000 description 1
239000010949 copper Substances 0.000 description 1
125000000596 cyclohexenyl group Chemical group C1(=CCCCC1)* 0.000 description 1
125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
230000002950 deficient Effects 0.000 description 1
238000006193 diazotization reaction Methods 0.000 description 1
VILAVOFMIJHSJA-UHFFFAOYSA-N dicarbon monoxide Chemical group [C]=C=O VILAVOFMIJHSJA-UHFFFAOYSA-N 0.000 description 1
235000014113 dietary fatty acids Nutrition 0.000 description 1
125000001664 diethylamino group Chemical group [H]C([H])([H])C([H])([H])N(*)C([H])([H])C([H])([H])[H] 0.000 description 1
125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 description 1
238000001035 drying Methods 0.000 description 1
239000000839 emulsion Substances 0.000 description 1
229940073621 enbrel Drugs 0.000 description 1
125000004185 ester group Chemical group 0.000 description 1
150000002170 ethers Chemical class 0.000 description 1
125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 1
125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 1
208000030533 eye disease Diseases 0.000 description 1
239000000194 fatty acid Substances 0.000 description 1
229930195729 fatty acid Natural products 0.000 description 1
150000004665 fatty acids Chemical class 0.000 description 1
239000000945 filler Substances 0.000 description 1
125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 1
230000022244 formylation Effects 0.000 description 1
238000006170 formylation reaction Methods 0.000 description 1
108020001507 fusion proteins Proteins 0.000 description 1
102000037865 fusion proteins Human genes 0.000 description 1
239000008273 gelatin Substances 0.000 description 1
229920000159 gelatin Polymers 0.000 description 1
235000019322 gelatine Nutrition 0.000 description 1
235000011852 gelatine desserts Nutrition 0.000 description 1
239000011521 glass Substances 0.000 description 1
229940074045 glyceryl distearate Drugs 0.000 description 1
229940075507 glyceryl monostearate Drugs 0.000 description 1
150000002343 gold Chemical class 0.000 description 1
239000008187 granular material Substances 0.000 description 1
230000002140 halogenating effect Effects 0.000 description 1
210000003630 histaminocyte Anatomy 0.000 description 1
230000013632 homeostatic process Effects 0.000 description 1
150000004677 hydrates Chemical class 0.000 description 1
238000005984 hydrogenation reaction Methods 0.000 description 1
230000033444 hydroxylation Effects 0.000 description 1
238000005805 hydroxylation reaction Methods 0.000 description 1
230000007365 immunoregulation Effects 0.000 description 1
230000006872 improvement Effects 0.000 description 1
230000006698 induction Effects 0.000 description 1
239000004615 ingredient Substances 0.000 description 1
238000007918 intramuscular administration Methods 0.000 description 1
238000001990 intravenous administration Methods 0.000 description 1
229910052742 iron Inorganic materials 0.000 description 1
RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 description 1
230000002427 irreversible effect Effects 0.000 description 1
239000002085 irritant Substances 0.000 description 1
231100000021 irritant Toxicity 0.000 description 1
238000002955 isolation Methods 0.000 description 1
229960004592 isopropanol Drugs 0.000 description 1
239000008101 lactose Substances 0.000 description 1
VHOGYURTWQBHIL-UHFFFAOYSA-N leflunomide Chemical compound O1N=CC(C(=O)NC=2C=CC(=CC=2)C(F)(F)F)=C1C VHOGYURTWQBHIL-UHFFFAOYSA-N 0.000 description 1
229960000681 leflunomide Drugs 0.000 description 1
150000007517 lewis acids Chemical class 0.000 description 1
239000006194 liquid suspension Substances 0.000 description 1
DLEDOFVPSDKWEF-UHFFFAOYSA-N lithium butane Chemical compound [Li+].CCC[CH2-] DLEDOFVPSDKWEF-UHFFFAOYSA-N 0.000 description 1
206010025135 lupus erythematosus Diseases 0.000 description 1
235000019359 magnesium stearate Nutrition 0.000 description 1
230000007246 mechanism Effects 0.000 description 1
MYWUZJCMWCOHBA-VIFPVBQESA-N methamphetamine Chemical compound CN[C@@H](C)CC1=CC=CC=C1 MYWUZJCMWCOHBA-VIFPVBQESA-N 0.000 description 1
229960000485 methotrexate Drugs 0.000 description 1
125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 1
229940102396 methyl bromide Drugs 0.000 description 1
229940050176 methyl chloride Drugs 0.000 description 1
125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 1
ZAHQPTJLOCWVPG-UHFFFAOYSA-N mitoxantrone dihydrochloride Chemical compound Cl.Cl.O=C1C2=C(O)C=CC(O)=C2C(=O)C2=C1C(NCCNCCO)=CC=C2NCCNCCO ZAHQPTJLOCWVPG-UHFFFAOYSA-N 0.000 description 1
238000002156 mixing Methods 0.000 description 1
125000002950 monocyclic group Chemical group 0.000 description 1
125000002757 morpholinyl group Chemical group 0.000 description 1
201000006417 multiple sclerosis Diseases 0.000 description 1
MZRVEZGGRBJDDB-UHFFFAOYSA-N n-Butyllithium Substances [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 1
125000001624 naphthyl group Chemical group 0.000 description 1
210000000440 neutrophil Anatomy 0.000 description 1
125000002560 nitrile group Chemical group 0.000 description 1
150000002825 nitriles Chemical class 0.000 description 1
229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 description 1
238000010534 nucleophilic substitution reaction Methods 0.000 description 1
239000003921 oil Substances 0.000 description 1
235000005985 organic acids Nutrition 0.000 description 1
125000002971 oxazolyl group Chemical group 0.000 description 1
239000007800 oxidant agent Substances 0.000 description 1
231100000915 pathological change Toxicity 0.000 description 1
230000036285 pathological change Effects 0.000 description 1
230000009054 pathological process Effects 0.000 description 1
230000004963 pathophysiological condition Effects 0.000 description 1
230000001991 pathophysiological effect Effects 0.000 description 1
239000001814 pectin Substances 0.000 description 1
235000010987 pectin Nutrition 0.000 description 1
229920001277 pectin Polymers 0.000 description 1
229960001639 penicillamine Drugs 0.000 description 1
VLTRZXGMWDSKGL-UHFFFAOYSA-M perchlorate Chemical compound [O-]Cl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-M 0.000 description 1
150000002978 peroxides Chemical class 0.000 description 1
239000008194 pharmaceutical composition Substances 0.000 description 1
230000000144 pharmacologic effect Effects 0.000 description 1
239000003444 phase transfer catalyst Substances 0.000 description 1
UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 description 1
IPNPIHIZVLFAFP-UHFFFAOYSA-N phosphorus tribromide Chemical compound BrP(Br)Br IPNPIHIZVLFAFP-UHFFFAOYSA-N 0.000 description 1
125000004193 piperazinyl group Chemical group 0.000 description 1
125000003386 piperidinyl group Chemical group 0.000 description 1
239000000902 placebo Substances 0.000 description 1
229940068196 placebo Drugs 0.000 description 1
230000003389 potentiating effect Effects 0.000 description 1
239000000843 powder Substances 0.000 description 1
239000002244 precipitate Substances 0.000 description 1
238000012545 processing Methods 0.000 description 1
BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
125000001325 propanoyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
125000004368 propenyl group Chemical group C(=CC)* 0.000 description 1
125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
125000002568 propynyl group Chemical group [*]C#CC([H])([H])[H] 0.000 description 1
150000003180 prostaglandins Chemical class 0.000 description 1
102000004169 proteins and genes Human genes 0.000 description 1
208000005069 pulmonary fibrosis Diseases 0.000 description 1
125000003226 pyrazolyl group Chemical group 0.000 description 1
125000004076 pyridyl group Chemical group 0.000 description 1
125000000714 pyrimidinyl group Chemical group 0.000 description 1
125000000719 pyrrolidinyl group Chemical group 0.000 description 1
125000000168 pyrrolyl group Chemical group 0.000 description 1
150000003242 quaternary ammonium salts Chemical class 0.000 description 1
125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
230000005855 radiation Effects 0.000 description 1
238000001953 recrystallisation Methods 0.000 description 1
238000010992 reflux Methods 0.000 description 1
229940116176 remicade Drugs 0.000 description 1
125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
210000002966 serum Anatomy 0.000 description 1
230000035939 shock Effects 0.000 description 1
230000008054 signal transmission Effects 0.000 description 1
230000011664 signaling Effects 0.000 description 1
210000003491 skin Anatomy 0.000 description 1
239000011780 sodium chloride Substances 0.000 description 1
239000011877 solvent mixture Substances 0.000 description 1
230000000638 stimulation Effects 0.000 description 1
238000007920 subcutaneous administration Methods 0.000 description 1
125000005346 substituted cycloalkyl group Chemical group 0.000 description 1
238000006467 substitution reaction Methods 0.000 description 1
KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
239000005720 sucrose Substances 0.000 description 1
239000000725 suspension Substances 0.000 description 1
230000002195 synergetic effect Effects 0.000 description 1
229960001967 tacrolimus Drugs 0.000 description 1
239000000454 talc Substances 0.000 description 1
229910052623 talc Inorganic materials 0.000 description 1
235000012222 talc Nutrition 0.000 description 1
LXIKEPCNDFVJKC-QXMHVHEDSA-N tenidap Chemical compound C12=CC(Cl)=CC=C2N(C(=O)N)C(=O)\C1=C(/O)C1=CC=CS1 LXIKEPCNDFVJKC-QXMHVHEDSA-N 0.000 description 1
229960003676 tenidap Drugs 0.000 description 1
125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
125000003831 tetrazolyl group Chemical group 0.000 description 1
238000002560 therapeutic procedure Methods 0.000 description 1
125000000335 thiazolyl group Chemical group 0.000 description 1
125000001544 thienyl group Chemical group 0.000 description 1
229910052718 tin Inorganic materials 0.000 description 1
239000011135 tin Substances 0.000 description 1
VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
125000004306 triazinyl group Chemical group 0.000 description 1
WTVXIBRMWGUIMI-UHFFFAOYSA-N trifluoro($l^{1}-oxidanylsulfonyl)methane Chemical group [O]S(=O)(=O)C(F)(F)F WTVXIBRMWGUIMI-UHFFFAOYSA-N 0.000 description 1
125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
208000001072 type 2 diabetes mellitus Diseases 0.000 description 1
125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
230000009385 viral infection Effects 0.000 description 1
229910052725 zinc Inorganic materials 0.000 description 1
239000011701 zinc Substances 0.000 description 1

Classifications

- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D495/04—Ortho-condensed systems
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/06—Antiasthmatics
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/06—Antipsoriatics
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
- A61P31/18—Antivirals for RNA viruses for HIV

Landscapes

Health & Medical Sciences (AREA)
Organic Chemistry (AREA)
Chemical & Material Sciences (AREA)
Life Sciences & Earth Sciences (AREA)
Medicinal Chemistry (AREA)
Chemical Kinetics & Catalysis (AREA)
General Chemical & Material Sciences (AREA)
Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
Pharmacology & Pharmacy (AREA)
Animal Behavior & Ethology (AREA)
General Health & Medical Sciences (AREA)
Public Health (AREA)
Veterinary Medicine (AREA)
Engineering & Computer Science (AREA)
Bioinformatics & Cheminformatics (AREA)
Dermatology (AREA)
Virology (AREA)
Pulmonology (AREA)
Rheumatology (AREA)
Communicable Diseases (AREA)
Oncology (AREA)
Biomedical Technology (AREA)
Ophthalmology & Optometry (AREA)
Neurology (AREA)
Neurosurgery (AREA)
Pain & Pain Management (AREA)
AIDS & HIV (AREA)
Tropical Medicine & Parasitology (AREA)
Molecular Biology (AREA)
Immunology (AREA)
Orthopedic Medicine & Surgery (AREA)
Physical Education & Sports Medicine (AREA)
Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Medicines Containing Material From Animals Or Micro-Organisms (AREA)
Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)

HR20030160A 2003-03-06 2003-03-06 1-thiadibenzoazulene derivatives and biological action thereof HRP20030160A2 (en)

Priority Applications (11)

Application Number	Priority Date	Filing Date	Title
HR20030160A HRP20030160A2 (en)	2003-03-06	2003-03-06	1-thiadibenzoazulene derivatives and biological action thereof
DE602004021568T DE602004021568D1 (de)	2003-03-06	2004-03-05	Thiadibenzoazulenderivate zur behandlung von entzündlichen erkrankungen
EP04717708A EP1603921B1 (de)	2003-03-06	2004-03-05	Thiadibenzoazulenderivate zur behandlung von entzündlichen erkrankungen
ARP040100693A AR043484A1 (es)	2003-03-06	2004-03-05	Derivados de 1-tiadibenzozuleno y sus acciones biologicas
JP2006506243A JP2006519829A (ja)	2003-03-06	2004-03-05	１−チアジベンゾアズレン誘導体及びその生物作用
CA002517847A CA2517847A1 (en)	2003-03-06	2004-03-05	Thiadibenzoazulene derivatives for the treatment of inflammatory diseases
PCT/HR2004/000005 WO2004078763A1 (en)	2003-03-06	2004-03-05	Thiadibenzoazulene derivatives for the treatment of inflammatory diseases
CNA2004800085860A CN1768064A (zh)	2003-03-06	2004-03-05	用于炎性疾病治疗的硫杂二苯并薁衍生物
AT04717708T ATE433983T1 (de)	2003-03-06	2004-03-05	Thiadibenzoazulenderivate zur behandlung von entzündlichen erkrankungen
CL200400444A CL2004000444A1 (es)	2003-03-06	2004-03-05	Compuestos derivados de 1-tiadibenzozuleno sustituidos; procedimiento de preparacion; composicion farmaceutica; y uso del compuesto en el tratamiento de artritis reumatoide, espondilitis reumatoide, osteoartritis, eczemas, psoriasis y asma.
US11/221,414 US20060069149A1 (en)	2003-03-06	2005-09-06	Thiadibenzoazulene derivatives for the treatment of inflammatory diseases

Applications Claiming Priority (1)

Application Number	Priority Date	Filing Date	Title
HR20030160A HRP20030160A2 (en)	2003-03-06	2003-03-06	1-thiadibenzoazulene derivatives and biological action thereof

Publications (1)

Publication Number	Publication Date
HRP20030160A2 true HRP20030160A2 (en)	2005-04-30

Family

ID=32947942

Family Applications (1)

Application Number	Title	Priority Date	Filing Date
HR20030160A HRP20030160A2 (en)	2003-03-06	2003-03-06	1-thiadibenzoazulene derivatives and biological action thereof

Country Status (11)

Country	Link
US (1)	US20060069149A1 (de)
EP (1)	EP1603921B1 (de)
JP (1)	JP2006519829A (de)
CN (1)	CN1768064A (de)
AR (1)	AR043484A1 (de)
AT (1)	ATE433983T1 (de)
CA (1)	CA2517847A1 (de)
CL (1)	CL2004000444A1 (de)
DE (1)	DE602004021568D1 (de)
HR (1)	HRP20030160A2 (de)
WO (1)	WO2004078763A1 (de)

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number	Priority date	Publication date	Assignee	Title
HRP20020304B1 (en) *	2002-04-10	2008-04-30	GlaxoSmithKline istra�iva�ki centar Zagreb d.o.o.	1-oxa-3-aza-dibenzoazulenes as inhibitors of tumor necrosis factor production and intermediates for the production thereof
US20080096830A1 (en) *	2005-01-13	2008-04-24	Mladen Mercep	Anti-Inflammatory Macrolide Conjugates
WO2006109190A1 (en) *	2005-02-02	2006-10-19	Glaxosmithkline Istrazivacki Centar Zagreb D.O.O.	Tetracyclic monoamine reuptake inhibitors for treatment of cns diseases and disorders

Family Cites Families (20)

* Cited by examiner, † Cited by third party
Publication number	Priority date	Publication date	Assignee	Title
CH532038A (de) *	1970-05-25	1972-12-31	Ciba Geigy Ag	Verfahren zur Herstellung von neuen Cycloheptenderivaten
US3859439A (en) *	1970-05-26	1975-01-07	Ciba Geigy Corp	2,3-dihydro-5 -trifluoromethyl-1h-dibenzo(2,3:6,7) thiepino (4,5-c) pyrroles as cns-depressants
US3711489A (en) *	1971-03-31	1973-01-16	Pfizer	Certain 8,9-dihydro(3,4,7,8)cycloocta(1,2-d)imidazoles
US4112110A (en) *	1974-02-22	1978-09-05	Ciba-Geigy Corporation	Oxygenated azatetracyclic compounds
US3894032A (en) *	1974-04-10	1975-07-08	Merck & Co Inc	10,11-Furo derivatives of cyproheptadine
US3974285A (en) *	1974-04-10	1976-08-10	Merck & Co., Inc.	10,11-Furo-derivatives of cyproheptadine
US4271179A (en) *	1976-05-24	1981-06-02	Akzona Incorporated	1,2,3,3a,8,12b-Hexahydro-dibenzo[1,2;5,6]cyclohepta[3,4-C]pyrroles and pharmaceutical use thereof
NL7605526A (nl) *	1976-05-24	1977-11-28	Akzo Nv	Nieuwe tetracyclische derivaten.
US4198421A (en) *	1978-11-30	1980-04-15	E. I. Du Pont De Nemours And Company	Antiinflammatory 2-substituted-dibenzo[2,3:6,7]oxepino[4,5-d]imidazoles
US4267184A (en) *	1979-02-08	1981-05-12	E. I. Du Pont De Nemours And Company	Antiinflammatory 4,5-diaryl-2-(substituted-thio)pyrroles and their corresponding sulfoxides and sulfones
US4267190A (en) *	1980-04-18	1981-05-12	E. I. Du Pont De Nemours And Company	Antiinflammatory 4,5-diaryl-α,α-bis(polyfluoromethyl)-1H-pyrrole-2-methanethiols
US5840749A (en) *	1989-08-25	1998-11-24	Hoechst Marion Roussel, Inc.	N-hydroxy-dibenz b,e!oxepinalkylamines, N-hydroxy-dibenz b,e!oxepinalkanoic acid amides and related heterocyclic analogues
EE03612B1 (et) *	1996-04-12	2002-02-15	Janssen Pharmaceutica N.V.	Asendatud tetratsüklilised tetrahüdrofuraanderivaadid
UA52778C2 (uk) *	1997-10-10	2003-01-15	Янссен Фармацевтика Н.В.	Галогенозаміщені тетрациклічні похідні тетрагідрофурану, спосіб їх отримання та композиція на їх основі
US6471961B1 (en) *	1999-02-24	2002-10-29	Edward L. Tobinick	Interleukin antagonists for the treatment of neurological, retinal and muscular disorders
US6982089B2 (en) *	1999-02-24	2006-01-03	Tact Ip, Llc	Cytokine antagonists for neurological and neuropsychiatric disorders
HRP20000310A2 (en) *	2000-05-17	2002-02-28	Pliva Farmaceutska Ind Dioniko	New dibenzoazulene compounds as tumor necrosis factor inhibitors
HRP20020303B8 (en) *	2002-04-10	2009-03-31	GlaxoSmithKline istra�iva�ki centar Zagreb d.o.o.	Benzonaphthoazulenes as inhibitors of tumour necrosis factor production and intermediates for the preparation thereof
HRP20020440B1 (en) *	2002-05-21	2008-02-29	GlaxoSmithKline istra�iva�ki centar Zagreb d.o.o.	1-aza-dibenzoazulenes as inhibitors of tumor necrosis factor production and intermediates for the preparation thereof
HRP20020441A2 (en) *	2002-05-21	2003-12-31	Pliva D D	1-oxa-dibenzoazulen as inhibitor of production of tumor necrosis factors and intermediate for preparation thereof

2003
- 2003-03-06 HR HR20030160A patent/HRP20030160A2/hr not_active Application Discontinuation
2004
- 2004-03-05 CL CL200400444A patent/CL2004000444A1/es unknown
- 2004-03-05 WO PCT/HR2004/000005 patent/WO2004078763A1/en not_active Ceased
- 2004-03-05 EP EP04717708A patent/EP1603921B1/de not_active Expired - Lifetime
- 2004-03-05 AR ARP040100693A patent/AR043484A1/es not_active Application Discontinuation
- 2004-03-05 AT AT04717708T patent/ATE433983T1/de not_active IP Right Cessation
- 2004-03-05 CA CA002517847A patent/CA2517847A1/en not_active Abandoned
- 2004-03-05 DE DE602004021568T patent/DE602004021568D1/de not_active Expired - Fee Related
- 2004-03-05 CN CNA2004800085860A patent/CN1768064A/zh active Pending
- 2004-03-05 JP JP2006506243A patent/JP2006519829A/ja active Pending
2005
- 2005-09-06 US US11/221,414 patent/US20060069149A1/en not_active Abandoned

Also Published As

Publication number	Publication date
CN1768064A (zh)	2006-05-03
CL2004000444A1 (es)	2005-04-15
DE602004021568D1 (de)	2009-07-30
AR043484A1 (es)	2005-08-03
JP2006519829A (ja)	2006-08-31
ATE433983T1 (de)	2009-07-15
WO2004078763A1 (en)	2004-09-16
EP1603921B1 (de)	2009-06-17
US20060069149A1 (en)	2006-03-30
CA2517847A1 (en)	2004-09-16
EP1603921A1 (de)	2005-12-14

Legal Events

Date	Code	Title	Description
2005-04-30	A1OB	Publication of a patent application
2005-10-31	ARAI	Request for the grant of a patent on the basis of the submitted results of a substantive examination of a patent application
2007-01-05	PNAN	Change of the applicant name, address/residence	Owner name: GLAXOSMITHKLINE ISTRAZIVACKI CENTAR ZAGREB D.O.O.,
2008-12-30	ODRP	Renewal fee for the maintenance of a patent	Payment date: 20081230 Year of fee payment: 7
2012-02-24	OBST	Application withdrawn

Publication	Publication Date	Title
RS50893B (sr)	2010-08-31	Nova dibenzoazulen jedinjenja kao inhibitori faktora nekroze tumora
EP1506202B1 (de)	2007-08-08	1-azadibenzoazulene als inhibitoren der produktion von tumornekrosefaktor und zwischenprodukte für deren herstellung
HRP20020453A2 (en)	2003-12-31	1,3-diaza-dibenzoazulen as inhibitor of production of tumor necrosis factors and intermediate for preparation thereof
DE60302344T2 (de)	2006-07-27	1- oder 3-thia-benzonaphthoazulene als inhibitoren der produktion von tumornekrosefaktor und zwischenprodukte für deren herstellung
HRP20020441A2 (en)	2003-12-31	1-oxa-dibenzoazulen as inhibitor of production of tumor necrosis factors and intermediate for preparation thereof
DE60304048T2 (de)	2006-10-19	2-thia-dibenzoazulene als inhibitoren der produktion von tumornekrosefaktor und zwischenprodukte für deren herstellung
HRP20020451A2 (en)	2003-12-31	1-tia-3-aza-dibenzoazulen as inhibitor of production of tumor necrosis factors and intermediates for preparation thereof
HRP20030160A2 (en)	2005-04-30	1-thiadibenzoazulene derivatives and biological action thereof
HRP20020452A2 (en)	2004-02-29	1,2-diaza-dibenzoazulen as inhibitor of production of tumor necrosis factors and intermediates for preparation thereof
DE60304047T2 (de)	2006-11-09	1-oxa-3-aza-dibenzoazulene als inhibitoren der produktion von tumornekrosefaktor und zwischenprodukte für deren herstellung
HK1081950B (en)	2007-11-23	1-oxa-dibenzoazulenes as inhibitors of thmour necrosis factor production and intermediates for the preparation thereof
ZA200408060B (en)	2006-08-30	1-oxa-3-aza-deibenzoazulenes as inhibitors of tumour necrosis factor production and intermediates for the production thereof