UA79277C2 - 2-thia-dibenzoazulenes as inhibitors of tumors necrosis factor production, process for the preparation and use thereof - Google Patents

2-thia-dibenzoazulenes as inhibitors of tumors necrosis factor production, process for the preparation and use thereof Download PDF

Info

Publication number: UA79277C2
Authority: UA; Ukraine
Prior art keywords: alkyl; group; amino; compounds; formula
Prior art date: 2002-04-10

Application number

UA20041008547A

Other languages

English (en)

Ukrainian (uk)

Inventor

Mladen Mercep

Milan Mesic

Dijana Pesic

Ivana Ozimec

Original Assignee

Pliva Istrazivacki Inst 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.)

2002-04-10

Filing date

2003-09-04

Publication date

2007-06-11

2003-09-04 Application filed by Pliva Istrazivacki Inst D O O filed Critical Pliva Istrazivacki Inst D O O

2007-06-11 Publication of UA79277C2 publication Critical patent/UA79277C2/uk

Links

238000000034 method Methods 0.000 title claims abstract description 30
238000004519 manufacturing process Methods 0.000 title claims abstract description 19
239000003112 inhibitor Substances 0.000 title claims description 8
238000002360 preparation method Methods 0.000 title abstract description 9
ZOJHYZMNGGBPBV-UHFFFAOYSA-N 4-thiatetracyclo[12.4.0.02,6.08,13]octadeca-1(18),2,6,8,10,12,14,16-octaene Chemical class C1SC=C2C3=C(C4=C(C=C12)C=CC=C4)C=CC=C3 ZOJHYZMNGGBPBV-UHFFFAOYSA-N 0.000 title abstract description 6
206010028980 Neoplasm Diseases 0.000 title 1
230000017074 necrotic cell death Effects 0.000 title 1
150000001875 compounds Chemical class 0.000 claims abstract description 105
150000003839 salts Chemical class 0.000 claims abstract description 17
230000003110 anti-inflammatory effect Effects 0.000 claims abstract description 6
239000012453 solvate Substances 0.000 claims abstract description 6
-1 nitro, hydroxy Chemical group 0.000 claims description 41
125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 33
238000006243 chemical reaction Methods 0.000 claims description 29
125000003118 aryl group Chemical group 0.000 claims description 25
229910052739 hydrogen Inorganic materials 0.000 claims description 21
125000001424 substituent group Chemical group 0.000 claims description 20
239000001257 hydrogen Substances 0.000 claims description 18
125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 17
229910052799 carbon Inorganic materials 0.000 claims description 16
125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 claims description 16
125000004093 cyano group Chemical group *C#N 0.000 claims description 15
150000002431 hydrogen Chemical class 0.000 claims description 15
125000000217 alkyl group Chemical group 0.000 claims description 14
125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 14
150000001298 alcohols Chemical class 0.000 claims description 13
125000001072 heteroaryl group Chemical group 0.000 claims description 13
125000003342 alkenyl group Chemical group 0.000 claims description 12
125000003282 alkyl amino group Chemical group 0.000 claims description 12
229910052736 halogen Inorganic materials 0.000 claims description 12
150000002367 halogens Chemical class 0.000 claims description 12
125000000623 heterocyclic group Chemical group 0.000 claims description 12
125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 12
CUFNKYGDVFVPHO-UHFFFAOYSA-N azulene Chemical compound C1=CC=CC2=CC=CC2=C1 CUFNKYGDVFVPHO-UHFFFAOYSA-N 0.000 claims description 11
125000004432 carbon atom Chemical group C* 0.000 claims description 11
IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 10
ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical group [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 10
125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 10
125000000304 alkynyl group Chemical group 0.000 claims description 10
239000000460 chlorine Chemical group 0.000 claims description 10
229910052801 chlorine Inorganic materials 0.000 claims description 10
125000005843 halogen group Chemical group 0.000 claims description 10
125000005842 heteroatom Chemical group 0.000 claims description 10
229910052731 fluorine Inorganic materials 0.000 claims description 9
239000011737 fluorine Substances 0.000 claims description 9
125000003545 alkoxy group Chemical group 0.000 claims description 8
125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 8
125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 8
201000010099 disease Diseases 0.000 claims description 8
208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 8
229910052757 nitrogen Inorganic materials 0.000 claims description 8
229910052760 oxygen Inorganic materials 0.000 claims description 8
125000003435 aroyl group Chemical group 0.000 claims description 7
150000001721 carbon Chemical group 0.000 claims description 7
125000002950 monocyclic group Chemical group 0.000 claims description 7
230000001575 pathological effect Effects 0.000 claims description 7
125000006239 protecting group Chemical group 0.000 claims description 7
102000004127 Cytokines Human genes 0.000 claims description 6
108090000695 Cytokines Proteins 0.000 claims description 6
125000004644 alkyl sulfinyl group Chemical group 0.000 claims description 6
125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 6
125000005161 aryl oxy carbonyl group Chemical group 0.000 claims description 6
229940079593 drug Drugs 0.000 claims description 6
125000001588 azulen-1-yl group Chemical group [H]C1=C([H])C2=C([H])C([H])=C([H])C([H])=C([H])C2=C1* 0.000 claims description 5
125000002619 bicyclic group Chemical group 0.000 claims description 5
OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Substances OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 5
FGOJCPKOOGIRPA-UHFFFAOYSA-N 1-o-tert-butyl 4-o-ethyl 5-oxoazepane-1,4-dicarboxylate Chemical compound CCOC(=O)C1CCN(C(=O)OC(C)(C)C)CCC1=O FGOJCPKOOGIRPA-UHFFFAOYSA-N 0.000 claims description 4
PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 4
206010061218 Inflammation Diseases 0.000 claims description 4
NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 4
QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 4
230000004054 inflammatory process Effects 0.000 claims description 4
239000001301 oxygen Substances 0.000 claims description 4
238000007363 ring formation reaction Methods 0.000 claims description 4
229920006395 saturated elastomer Polymers 0.000 claims description 4
229910052717 sulfur Inorganic materials 0.000 claims description 4
239000011593 sulfur Substances 0.000 claims description 4
125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 4
125000004214 1-pyrrolidinyl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 3
UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 3
125000005098 aryl alkoxy carbonyl group Chemical group 0.000 claims description 3
BHEPBYXIRTUNPN-UHFFFAOYSA-N hydridophosphorus(.) (triplet) Chemical compound [PH] BHEPBYXIRTUNPN-UHFFFAOYSA-N 0.000 claims description 3
125000002962 imidazol-1-yl group Chemical group [*]N1C([H])=NC([H])=C1[H] 0.000 claims description 3
125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 claims description 3
125000004433 nitrogen atom Chemical group N* 0.000 claims description 3
125000004194 piperazin-1-yl group Chemical group [H]N1C([H])([H])C([H])([H])N(*)C([H])([H])C1([H])[H] 0.000 claims description 3
125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 3
230000002265 prevention Effects 0.000 claims description 3
125000000547 substituted alkyl group Chemical group 0.000 claims description 3
235000010357 aspartame Nutrition 0.000 claims description 2
CZRXLQPVJOJLML-UHFFFAOYSA-N azulene-1-carbaldehyde Chemical compound C1=CC=CC=C2C(C=O)=CC=C21 CZRXLQPVJOJLML-UHFFFAOYSA-N 0.000 claims description 2
125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 claims description 2
231100000252 nontoxic Toxicity 0.000 claims description 2
230000003000 nontoxic effect Effects 0.000 claims description 2
125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 2
125000003396 thiol group Chemical class [H]S* 0.000 claims 14
125000002887 hydroxy group Chemical group [H]O* 0.000 claims 7
125000001153 fluoro group Chemical group F* 0.000 claims 5
XTFIVUDBNACUBN-UHFFFAOYSA-N 1,3,5-trinitro-1,3,5-triazinane Chemical group [O-][N+](=O)N1CN([N+]([O-])=O)CN([N+]([O-])=O)C1 XTFIVUDBNACUBN-UHFFFAOYSA-N 0.000 claims 4
OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims 4
FRYVITLFHRLVKD-UHFFFAOYSA-N azulene-1,3-dicarboxylic acid Chemical compound C1=CC=CC=C2C(C(=O)O)=CC(C(O)=O)=C21 FRYVITLFHRLVKD-UHFFFAOYSA-N 0.000 claims 2
125000001841 imino group Chemical group [H]N=* 0.000 claims 2
125000004738 (C1-C6) alkyl sulfinyl group Chemical group 0.000 claims 1
125000003161 (C1-C6) alkylene group Chemical group 0.000 claims 1
229910018540 Si C Inorganic materials 0.000 claims 1
125000004429 atom Chemical group 0.000 claims 1
ROSDSFDQCJNGOL-UHFFFAOYSA-N protonated dimethyl amine Natural products CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 claims 1
229910010271 silicon carbide Inorganic materials 0.000 claims 1
238000012876 topography Methods 0.000 claims 1
230000005764 inhibitory process Effects 0.000 abstract description 12
230000000202 analgesic effect Effects 0.000 abstract description 6
239000000543 intermediate Substances 0.000 abstract description 4
102000000589 Interleukin-1 Human genes 0.000 abstract description 3
108010002352 Interleukin-1 Proteins 0.000 abstract description 3
206010054094 Tumour necrosis Diseases 0.000 abstract description 2
108060008682 Tumor Necrosis Factor Proteins 0.000 description 26
102000003390 tumor necrosis factor Human genes 0.000 description 26
RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 20
YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 18
239000000243 solution Substances 0.000 description 18
LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 16
239000000047 product Substances 0.000 description 16
230000028327 secretion Effects 0.000 description 16
YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 15
HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
238000012360 testing method Methods 0.000 description 14
239000000203 mixture Substances 0.000 description 13
QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 12
210000004027 cell Anatomy 0.000 description 12
241001465754 Metazoa Species 0.000 description 11
239000011541 reaction mixture Substances 0.000 description 11
206010039073 rheumatoid arthritis Diseases 0.000 description 11
241000699670 Mus sp. Species 0.000 description 10
125000002252 acyl group Chemical group 0.000 description 10
HTZCNXWZYVXIMZ-UHFFFAOYSA-M benzyl(triethyl)azanium;chloride Chemical compound [Cl-].CC[N+](CC)(CC)CC1=CC=CC=C1 HTZCNXWZYVXIMZ-UHFFFAOYSA-M 0.000 description 10
239000000126 substance Substances 0.000 description 10
238000004440 column chromatography Methods 0.000 description 9
241000699666 Mus <mouse, genus> Species 0.000 description 8
150000002148 esters Chemical class 0.000 description 8
XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
229910001868 water Inorganic materials 0.000 description 7
208000007101 Muscle Cramp Diseases 0.000 description 6
208000005392 Spasm Diseases 0.000 description 6
DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 6
125000004122 cyclic group Chemical group 0.000 description 6
239000002904 solvent Substances 0.000 description 6
125000004414 alkyl thio group Chemical group 0.000 description 5
239000013078 crystal Substances 0.000 description 5
239000003814 drug Substances 0.000 description 5
230000000694 effects Effects 0.000 description 5
230000002757 inflammatory effect Effects 0.000 description 5
238000006722 reduction reaction Methods 0.000 description 5
239000007858 starting material Substances 0.000 description 5
238000003756 stirring Methods 0.000 description 5
150000003573 thiols Chemical class 0.000 description 5
LQLJZSJKRYTKTP-UHFFFAOYSA-N 2-dimethylaminoethyl chloride hydrochloride Chemical compound Cl.CN(C)CCCl LQLJZSJKRYTKTP-UHFFFAOYSA-N 0.000 description 4
IHPRVZKJZGXTBQ-UHFFFAOYSA-N 3-chloropropan-1-amine;hydron;chloride Chemical compound Cl.NCCCCl IHPRVZKJZGXTBQ-UHFFFAOYSA-N 0.000 description 4
QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 4
KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
239000002253 acid Substances 0.000 description 4
125000004185 ester group Chemical group 0.000 description 4
229910052740 iodine Inorganic materials 0.000 description 4
239000007788 liquid Substances 0.000 description 4
230000003647 oxidation Effects 0.000 description 4
238000007254 oxidation reaction Methods 0.000 description 4
210000003819 peripheral blood mononuclear cell Anatomy 0.000 description 4
238000000746 purification Methods 0.000 description 4
108020003175 receptors Proteins 0.000 description 4
238000010992 reflux Methods 0.000 description 4
230000008054 signal transmission 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
LJQNMDZRCXJETK-UHFFFAOYSA-N 3-chloro-n,n-dimethylpropan-1-amine;hydron;chloride Chemical compound Cl.CN(C)CCCCl LJQNMDZRCXJETK-UHFFFAOYSA-N 0.000 description 3
UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
208000011231 Crohn disease Diseases 0.000 description 3
235000010469 Glycine max Nutrition 0.000 description 3
ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 3
125000005103 alkyl silyl group Chemical group 0.000 description 3
125000002947 alkylene group Chemical group 0.000 description 3
150000001412 amines Chemical class 0.000 description 3
125000005101 aryl methoxy carbonyl 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
125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 3
230000004071 biological effect Effects 0.000 description 3
239000000969 carrier Substances 0.000 description 3
239000002158 endotoxin Substances 0.000 description 3
125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
238000002474 experimental method Methods 0.000 description 3
125000000524 functional group Chemical group 0.000 description 3
230000007062 hydrolysis Effects 0.000 description 3
238000006460 hydrolysis reaction Methods 0.000 description 3
125000004356 hydroxy functional group Chemical group O* 0.000 description 3
230000002401 inhibitory effect Effects 0.000 description 3
238000002347 injection Methods 0.000 description 3
239000007924 injection Substances 0.000 description 3
229910052751 metal Inorganic materials 0.000 description 3
239000002184 metal Substances 0.000 description 3
VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
239000013642 negative control Substances 0.000 description 3
238000010534 nucleophilic substitution reaction Methods 0.000 description 3
210000003024 peritoneal macrophage Anatomy 0.000 description 3
239000008194 pharmaceutical composition Substances 0.000 description 3
UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 3
239000013641 positive control Substances 0.000 description 3
230000009467 reduction Effects 0.000 description 3
QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid group Chemical class S(O)(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 3
125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 3
150000007970 thio esters Chemical class 0.000 description 3
125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 3
VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 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
ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-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
239000004342 Benzoyl peroxide Substances 0.000 description 2
OMPJBNCRMGITSC-UHFFFAOYSA-N Benzoylperoxide Chemical compound C=1C=CC=CC=1C(=O)OOC(=O)C1=CC=CC=C1 OMPJBNCRMGITSC-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
RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 2
108010008165 Etanercept Proteins 0.000 description 2
MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 2
XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 2
KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
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 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
201000004681 Psoriasis Diseases 0.000 description 2
206010040070 Septic Shock Diseases 0.000 description 2
210000001744 T-lymphocyte Anatomy 0.000 description 2
201000006704 Ulcerative Colitis Diseases 0.000 description 2
210000000683 abdominal cavity Anatomy 0.000 description 2
229960001138 acetylsalicylic acid Drugs 0.000 description 2
125000003172 aldehyde group Chemical group 0.000 description 2
150000001350 alkyl halides Chemical class 0.000 description 2
150000001408 amides Chemical class 0.000 description 2
229910021529 ammonia Inorganic materials 0.000 description 2
239000005557 antagonist Substances 0.000 description 2
238000007080 aromatic substitution reaction Methods 0.000 description 2
230000002917 arthritic effect Effects 0.000 description 2
208000006673 asthma Diseases 0.000 description 2
239000012298 atmosphere Substances 0.000 description 2
235000019400 benzoyl peroxide Nutrition 0.000 description 2
230000015572 biosynthetic process Effects 0.000 description 2
GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
229910052794 bromium Inorganic materials 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
239000003054 catalyst Substances 0.000 description 2
238000009903 catalytic hydrogenation reaction Methods 0.000 description 2
238000004113 cell culture Methods 0.000 description 2
239000003153 chemical reaction reagent Substances 0.000 description 2
NEHMKBQYUWJMIP-UHFFFAOYSA-N chloromethane Chemical compound ClC NEHMKBQYUWJMIP-UHFFFAOYSA-N 0.000 description 2
229940125773 compound 10 Drugs 0.000 description 2
238000006482 condensation reaction Methods 0.000 description 2
229910052802 copper Inorganic materials 0.000 description 2
239000010949 copper Substances 0.000 description 2
238000006114 decarboxylation reaction Methods 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
125000006125 ethylsulfonyl group Chemical group 0.000 description 2
125000004705 ethylthio group Chemical group C(C)S* 0.000 description 2
239000012091 fetal bovine serum Substances 0.000 description 2
239000000706 filtrate Substances 0.000 description 2
239000007903 gelatin capsule Substances 0.000 description 2
125000001188 haloalkyl group Chemical group 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
125000002883 imidazolyl group Chemical group 0.000 description 2
229960000598 infliximab Drugs 0.000 description 2
239000011630 iodine Substances 0.000 description 2
238000002955 isolation Methods 0.000 description 2
125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 description 2
229920006008 lipopolysaccharide Polymers 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
125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 2
229920000609 methyl cellulose Polymers 0.000 description 2
125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
239000001923 methylcellulose Substances 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
239000001788 mono and diglycerides of fatty acids Substances 0.000 description 2
239000003921 oil Substances 0.000 description 2
235000019198 oils Nutrition 0.000 description 2
150000007524 organic acids Chemical class 0.000 description 2
201000008482 osteoarthritis Diseases 0.000 description 2
230000001590 oxidative effect Effects 0.000 description 2
230000004963 pathophysiological condition Effects 0.000 description 2
229940049954 penicillin Drugs 0.000 description 2
125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
239000008363 phosphate buffer Substances 0.000 description 2
WGYKZJWCGVVSQN-UHFFFAOYSA-N propylamine Chemical compound CCCN WGYKZJWCGVVSQN-UHFFFAOYSA-N 0.000 description 2
108090000623 proteins and genes Proteins 0.000 description 2
125000003373 pyrazinyl group Chemical group 0.000 description 2
230000002829 reductive effect Effects 0.000 description 2
230000035945 sensitivity Effects 0.000 description 2
230000035939 shock Effects 0.000 description 2
229960005322 streptomycin Drugs 0.000 description 2
125000003107 substituted aryl group Chemical group 0.000 description 2
239000006228 supernatant Substances 0.000 description 2
230000004083 survival effect Effects 0.000 description 2
235000020357 syrup Nutrition 0.000 description 2
239000006188 syrup Substances 0.000 description 2
150000003568 thioethers Chemical class 0.000 description 2
238000004448 titration Methods 0.000 description 2
230000009466 transformation Effects 0.000 description 2
DGVVWUTYPXICAM-UHFFFAOYSA-N β‐Mercaptoethanol Chemical compound OCCS DGVVWUTYPXICAM-UHFFFAOYSA-N 0.000 description 2
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
GXMSLNZIHPZWAI-UHFFFAOYSA-N 5-thiatetracyclo[12.4.0.02,6.08,13]octadeca-1(18),2,6,8,10,12,14,16-octaene Chemical group S1CC=C2C3=C(C4=C(C=C12)C=CC=C4)C=CC=C3 GXMSLNZIHPZWAI-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
CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 1
229920001817 Agar Polymers 0.000 description 1
206010002556 Ankylosing Spondylitis Diseases 0.000 description 1
MVVPIAAVGAWJNQ-DOFZRALJSA-N Arachidonoyl dopamine Chemical compound CCCCC\C=C/C\C=C/C\C=C/C\C=C/CCCC(=O)NCCC1=CC=C(O)C(O)=C1 MVVPIAAVGAWJNQ-DOFZRALJSA-N 0.000 description 1
WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 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
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
QPLDLSVMHZLSFG-UHFFFAOYSA-N Copper oxide Chemical compound [Cu]=O QPLDLSVMHZLSFG-UHFFFAOYSA-N 0.000 description 1
239000005751 Copper oxide Substances 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
201000004624 Dermatitis Diseases 0.000 description 1
206010012438 Dermatitis atopic Diseases 0.000 description 1
206010012442 Dermatitis contact Diseases 0.000 description 1
RWSOTUBLDIXVET-UHFFFAOYSA-N Dihydrogen sulfide Chemical compound S RWSOTUBLDIXVET-UHFFFAOYSA-N 0.000 description 1
108090000790 Enzymes Proteins 0.000 description 1
102000004190 Enzymes Human genes 0.000 description 1
241000052339 Epidares Species 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
238000005727 Friedel-Crafts reaction Methods 0.000 description 1
206010017964 Gastrointestinal infection Diseases 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
201000005569 Gout Diseases 0.000 description 1
208000010496 Heart Arrest Diseases 0.000 description 1
206010022489 Insulin Resistance Diseases 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
206010028347 Muscle twitching Diseases 0.000 description 1
GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
206010061876 Obstruction Diseases 0.000 description 1
208000037273 Pathologic Processes Diseases 0.000 description 1
206010036030 Polyarthritis Diseases 0.000 description 1
244000117054 Rungia klossii Species 0.000 description 1
235000002492 Rungia klossii Nutrition 0.000 description 1
206010039710 Scleroderma Diseases 0.000 description 1
206010040047 Sepsis Diseases 0.000 description 1
VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
201000002661 Spondylitis Diseases 0.000 description 1
229930006000 Sucrose Natural products 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
235000019486 Sunflower oil Nutrition 0.000 description 1
206010044248 Toxic shock syndrome Diseases 0.000 description 1
231100000650 Toxic shock syndrome Toxicity 0.000 description 1
241000256856 Vespidae Species 0.000 description 1
229920000392 Zymosan Polymers 0.000 description 1
230000002378 acidificating effect Effects 0.000 description 1
150000007513 acids Chemical class 0.000 description 1
230000009471 action Effects 0.000 description 1
230000004913 activation Effects 0.000 description 1
239000004480 active ingredient Substances 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
125000004423 acyloxy group Chemical group 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
150000001335 aliphatic alkanes Chemical class 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
125000003277 amino group Chemical group 0.000 description 1
125000004103 aminoalkyl group Chemical group 0.000 description 1
150000008064 anhydrides Chemical class 0.000 description 1
238000010171 animal model Methods 0.000 description 1
230000000259 anti-tumor effect Effects 0.000 description 1
238000013459 approach Methods 0.000 description 1
239000007864 aqueous solution Substances 0.000 description 1
125000003710 aryl alkyl group Chemical group 0.000 description 1
238000003556 assay Methods 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
235000013405 beer Nutrition 0.000 description 1
WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid group Chemical group C(C1=CC=CC=C1)(=O)O WPYMKLBDIGXBTP-UHFFFAOYSA-N 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
230000033228 biological regulation Effects 0.000 description 1
210000004369 blood Anatomy 0.000 description 1
239000008280 blood Substances 0.000 description 1
238000004159 blood analysis Methods 0.000 description 1
238000009835 boiling Methods 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
150000007942 carboxylates Chemical class 0.000 description 1
230000003197 catalytic effect Effects 0.000 description 1
230000009134 cell regulation Effects 0.000 description 1
238000005119 centrifugation Methods 0.000 description 1
239000003795 chemical substances by application Substances 0.000 description 1
230000035605 chemotaxis Effects 0.000 description 1
238000005660 chlorination reaction Methods 0.000 description 1
125000004218 chloromethyl group Chemical group [H]C([H])(Cl)* 0.000 description 1
ZCDOYSPFYFSLEW-UHFFFAOYSA-N chromate(2-) Chemical compound [O-][Cr]([O-])(=O)=O ZCDOYSPFYFSLEW-UHFFFAOYSA-N 0.000 description 1
238000004587 chromatography analysis Methods 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
238000003776 cleavage reaction Methods 0.000 description 1
239000003245 coal Substances 0.000 description 1
229960002424 collagenase Drugs 0.000 description 1
238000009833 condensation Methods 0.000 description 1
230000005494 condensation Effects 0.000 description 1
238000012790 confirmation Methods 0.000 description 1
208000010247 contact dermatitis Diseases 0.000 description 1
230000036461 convulsion Effects 0.000 description 1
238000001816 cooling Methods 0.000 description 1
229910000431 copper oxide Inorganic materials 0.000 description 1
239000012043 crude product 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
229930182912 cyclosporin Natural products 0.000 description 1
230000003111 delayed effect Effects 0.000 description 1
238000006193 diazotization reaction Methods 0.000 description 1
125000004772 dichloromethyl group Chemical group [H]C(Cl)(Cl)* 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
239000003937 drug carrier Substances 0.000 description 1
238000001035 drying Methods 0.000 description 1
230000008030 elimination Effects 0.000 description 1
238000003379 elimination reaction Methods 0.000 description 1
239000000839 emulsion Substances 0.000 description 1
229940088598 enzyme Drugs 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
239000000284 extract Substances 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
238000009472 formulation Methods 0.000 description 1
125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 1
108020001507 fusion proteins Proteins 0.000 description 1
102000037865 fusion proteins Human genes 0.000 description 1
238000002290 gas chromatography-mass spectrometry Methods 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
239000008187 granular material Substances 0.000 description 1
150000004820 halides Chemical class 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
239000008240 homogeneous mixture Substances 0.000 description 1
229910000037 hydrogen sulfide Inorganic materials 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
239000003547 immunosorbent Substances 0.000 description 1
230000001771 impaired effect Effects 0.000 description 1
230000006872 improvement Effects 0.000 description 1
230000006698 induction Effects 0.000 description 1
230000004968 inflammatory condition Effects 0.000 description 1
208000027866 inflammatory disease Diseases 0.000 description 1
239000004615 ingredient Substances 0.000 description 1
230000003993 interaction Effects 0.000 description 1
230000016507 interphase Effects 0.000 description 1
230000003834 intracellular effect Effects 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
239000008101 lactose Substances 0.000 description 1
ACKFDYCQCBEDNU-UHFFFAOYSA-J lead(2+);tetraacetate Chemical compound [Pb+2].CC([O-])=O.CC([O-])=O.CC([O-])=O.CC([O-])=O ACKFDYCQCBEDNU-UHFFFAOYSA-J 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
239000012280 lithium aluminium hydride Substances 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
229910052987 metal hydride Inorganic materials 0.000 description 1
150000004681 metal hydrides Chemical class 0.000 description 1
150000002739 metals Chemical class 0.000 description 1
229960000485 methotrexate Drugs 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
150000007522 mineralic acids Chemical class 0.000 description 1
238000002156 mixing Methods 0.000 description 1
230000004048 modification Effects 0.000 description 1
238000012986 modification Methods 0.000 description 1
125000002757 morpholinyl group Chemical group 0.000 description 1
201000006417 multiple sclerosis Diseases 0.000 description 1
125000001624 naphthyl group Chemical group 0.000 description 1
210000000440 neutrophil Anatomy 0.000 description 1
229910017604 nitric acid Inorganic materials 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
239000004006 olive oil Substances 0.000 description 1
235000008390 olive oil Nutrition 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
125000005489 p-toluenesulfonic acid group Chemical class 0.000 description 1
229910052763 palladium Inorganic materials 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
239000001814 pectin Substances 0.000 description 1
229920001277 pectin Polymers 0.000 description 1
235000010987 pectin Nutrition 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
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
LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
CUQOHAYJWVTKDE-UHFFFAOYSA-N potassium;butan-1-olate Chemical compound [K+].CCCC[O-] CUQOHAYJWVTKDE-UHFFFAOYSA-N 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
238000000197 pyrolysis Methods 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
230000007017 scission Effects 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
230000036303 septic shock Effects 0.000 description 1
210000002966 serum Anatomy 0.000 description 1
239000000741 silica gel Substances 0.000 description 1
229910002027 silica gel Inorganic materials 0.000 description 1
210000003491 skin Anatomy 0.000 description 1
ODZPKZBBUMBTMG-UHFFFAOYSA-N sodium amide Chemical compound [NH2-].[Na+] ODZPKZBBUMBTMG-UHFFFAOYSA-N 0.000 description 1
229910000033 sodium borohydride Inorganic materials 0.000 description 1
239000012279 sodium borohydride Substances 0.000 description 1
239000003549 soybean oil Substances 0.000 description 1
235000012424 soybean oil Nutrition 0.000 description 1
230000004936 stimulating effect Effects 0.000 description 1
230000000638 stimulation Effects 0.000 description 1
238000007920 subcutaneous administration Methods 0.000 description 1
125000005017 substituted alkenyl group Chemical group 0.000 description 1
238000006467 substitution reaction Methods 0.000 description 1
239000005720 sucrose Substances 0.000 description 1
239000002600 sunflower oil Substances 0.000 description 1
239000000725 suspension Substances 0.000 description 1
230000002195 synergetic effect Effects 0.000 description 1
238000003786 synthesis reaction Methods 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
125000000335 thiazolyl group Chemical group 0.000 description 1
125000001544 thienyl group Chemical group 0.000 description 1
238000004809 thin layer chromatography Methods 0.000 description 1
125000004306 triazinyl group Chemical group 0.000 description 1
DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 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
230000003612 virological effect Effects 0.000 description 1

Classifications

- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
- C07D333/78—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems condensed with rings other than six-membered or with ring systems containing such rings
- C07D333/80—Seven-membered rings
- 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
- A61P25/04—Centrally acting analgesics, e.g. opioids
- 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
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- 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
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Landscapes

Chemical & Material Sciences (AREA)
Organic Chemistry (AREA)
Health & Medical Sciences (AREA)
General Health & Medical Sciences (AREA)
Veterinary Medicine (AREA)
General Chemical & Material Sciences (AREA)
Medicinal Chemistry (AREA)
Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
Chemical Kinetics & Catalysis (AREA)
Pharmacology & Pharmacy (AREA)
Life Sciences & Earth Sciences (AREA)
Animal Behavior & Ethology (AREA)
Public Health (AREA)
Engineering & Computer Science (AREA)
Bioinformatics & Cheminformatics (AREA)
Pain & Pain Management (AREA)
Neurosurgery (AREA)
Biomedical Technology (AREA)
Neurology (AREA)
Rheumatology (AREA)
Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Thiazole And Isothizaole Compounds (AREA)
Medicines Containing Plant Substances (AREA)
Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Steroid Compounds (AREA)

UA20041008547A 2002-04-10 2003-09-04 2-thia-dibenzoazulenes as inhibitors of tumors necrosis factor production, process for the preparation and use thereof UA79277C2 (en)

Applications Claiming Priority (2)

Application Number	Priority Date	Filing Date	Title
HR20020305A HRP20020305A8 (en)	2002-04-10	2002-04-10	2-thia-dibenzoazulenes as inhibitors of tumour necrosis factor production and intermediates for the preparation thereof
PCT/HR2003/000016 WO2003084962A1 (en)	2002-04-10	2003-04-09	2-thia-dibenzoazulenes as inhibitors of tumour necrosis factor production and intermediates for the preparation thereof

Publications (1)

Publication Number	Publication Date
UA79277C2 true UA79277C2 (en)	2007-06-11

Family

ID=28686903

Family Applications (1)

Application Number	Title	Priority Date	Filing Date
UA20041008547A UA79277C2 (en)	2002-04-10	2003-09-04	2-thia-dibenzoazulenes as inhibitors of tumors necrosis factor production, process for the preparation and use thereof

Country Status (26)

Country	Link
US (1)	US7435834B2 (ru)
EP (1)	EP1509530B1 (ru)
JP (1)	JP2005526828A (ru)
CN (1)	CN1649875A (ru)
AT (1)	ATE320433T1 (ru)
AU (1)	AU2003259963A1 (ru)
BR (1)	BR0309094A (ru)
CA (1)	CA2481514A1 (ru)
CY (1)	CY1105036T1 (ru)
DE (1)	DE60304048T2 (ru)
DK (1)	DK1509530T3 (ru)
ES (1)	ES2260637T3 (ru)
HR (1)	HRP20020305A8 (ru)
IL (1)	IL164396A0 (ru)
IS (1)	IS7474A (ru)
MX (1)	MXPA04009943A (ru)
NO (1)	NO20044506L (ru)
NZ (1)	NZ535620A (ru)
PL (1)	PL372748A1 (ru)
PT (1)	PT1509530E (ru)
RU (1)	RU2334749C2 (ru)
SI (1)	SI1509530T1 (ru)
UA (1)	UA79277C2 (ru)
WO (1)	WO2003084962A1 (ru)
YU (1)	YU88304A (ru)
ZA (1)	ZA200408063B (ru)

Families Citing this family (6)

* 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
HRP20020305A8 (en)	2002-04-10	2009-03-31	GlaxoSmithKline istra�iva�ki centar Zagreb d.o.o.	2-thia-dibenzoazulenes as inhibitors of tumour necrosis factor production and intermediates for the preparation thereof
HRP20020452A2 (en) *	2002-05-23	2004-02-29	Pliva D D	1,2-diaza-dibenzoazulen as inhibitor of production of tumor necrosis factors and intermediates for preparation thereof
HRP20030885A2 (en) *	2003-11-03	2005-08-31	Pliva-Istra�iva�ki institut d.o.o.	USE OF 2-THIA-DIBENZO[e,h]AZULENES FOR THE MANUFACTURE OF PHARMACEUTICAL FORMULATIONS FOR THE TREATMENT AND PREVENTION OF CENTRAL NERVOUS SYYTEM DISEASES AND DISORDERS
HRP20030956A2 (en) *	2003-11-21	2005-08-31	Pliva-Istra�iva�ki institut d.o.o.	USE OF 1,2-DIAZA-DIBENZO[e,h]AZULENES FOR THE MANU
EP1968583A4 (en) *	2005-12-20	2010-09-15	Harvard College	COMPOUNDS, TESTS AND METHODS OF TREATMENT

Family Cites Families (16)

* Cited by examiner, † Cited by third party
Publication number	Priority date	Publication date	Assignee	Title
US3711489A (en) *	1971-03-31	1973-01-16	Pfizer	Certain 8,9-dihydro(3,4,7,8)cycloocta(1,2-d)imidazoles
CA967573A (en)	1972-12-22	1975-05-13	Joseph G. Lombardino	Tetracyclic anti-inflammatory agents
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
FR2504140A1 (fr)	1981-04-16	1982-10-22	Centre Nat Rech Scient	Nouveaux derives tetracycliques de la dibenzazepine, leur procede de preparation et les compositions pharmaceutiques en renfermant
EP0125484A1 (de)	1983-04-12	1984-11-21	Ciba-Geigy Ag	Polycyclische Carbonsäureverbindungen, Verfahren zu ihrer Herstellung und Präparate enthaltend solche Carbonsäureverbindungen, sowie deren Verwendung
IE62754B1 (en)	1988-08-26	1995-02-22	Akzo Nv	Tetracyclic antidepressants
IT1227527B (it)	1988-12-05	1991-04-12	Ciatti Maurizio	Spazzolino da denti a setole rotanti
US5552399A (en)	1994-11-02	1996-09-03	Janssen Pharmaceutica N.V.	Substituted tetracyclic azepine derivatives
PL183618B1 (pl)	1994-11-02	2002-06-28	Janssen Pharmaceutica Nv	Nowy związek, pochodna podstawionej tetracyklicznej oksazepiny lub tiazepiny, kompozycja farmaceutyczna i sposób wytwarzania pochodnej podstawionej tetracyklicznej oksazepiny lub tiazepiny
KR100389298B1 (ko)	1996-04-12	2003-10-30	얀센 파마슈티카 엔.브이.	치환된테트라사이클릭테트라하이드로퓨란유도체
UA52778C2 (ru)	1997-10-10	2003-01-15	Янссен Фармацевтика Н.В.	Галогенозамещенные тетрациклические производные тетрагидрофурана, способ их получения и композиции на их основе
HRP20000310A2 (en)	2000-05-17	2002-02-28	Pliva Farmaceutska Ind Dioniko	New dibenzoazulene compounds as tumor necrosis factor inhibitors
HRP20020305A8 (en)	2002-04-10	2009-03-31	GlaxoSmithKline istra�iva�ki centar Zagreb d.o.o.	2-thia-dibenzoazulenes as inhibitors of tumour necrosis factor production and intermediates for the preparation thereof
HRP20030957A2 (en)	2003-11-21	2005-08-31	Pliva-Istra�iva�ki institut d.o.o.	USE OF 1-THIA-3-AZA-DIBENZO[e,h]AZULENES FOR THE MANUFACTURE OF PHARMACEUTICAL FORMULATIONS FOR THE TREATMENT AND PREVENTION OF CENTRAL NERVOUS SYSTEM DISEASES AND DISORDERS
HRP20040104A2 (en)	2004-01-30	2005-10-31	Pliva-Istra�iva�ki institut d.o.o.	Use of benzonaphthoazulenes for the manufacture of pharmaceutical formulations for the treatment and prevention of central nervous system diseases and disorders

2002
- 2002-04-10 HR HR20020305A patent/HRP20020305A8/xx not_active Application Discontinuation
2003
- 2003-04-09 EP EP03745849A patent/EP1509530B1/en not_active Expired - Lifetime
- 2003-04-09 JP JP2003582159A patent/JP2005526828A/ja active Pending
- 2003-04-09 DE DE60304048T patent/DE60304048T2/de not_active Expired - Fee Related
- 2003-04-09 CA CA002481514A patent/CA2481514A1/en not_active Abandoned
- 2003-04-09 BR BR0309094-9A patent/BR0309094A/pt not_active IP Right Cessation
- 2003-04-09 AU AU2003259963A patent/AU2003259963A1/en not_active Abandoned
- 2003-04-09 CN CNA038094932A patent/CN1649875A/zh active Pending
- 2003-04-09 ES ES03745849T patent/ES2260637T3/es not_active Expired - Lifetime
- 2003-04-09 YU YU88304A patent/YU88304A/sh unknown
- 2003-04-09 SI SI200330275T patent/SI1509530T1/sl unknown
- 2003-04-09 IL IL16439603A patent/IL164396A0/xx unknown
- 2003-04-09 PL PL03372748A patent/PL372748A1/xx not_active Application Discontinuation
- 2003-04-09 DK DK03745849T patent/DK1509530T3/da active
- 2003-04-09 PT PT03745849T patent/PT1509530E/pt unknown
- 2003-04-09 RU RU2004132868/04A patent/RU2334749C2/ru not_active IP Right Cessation
- 2003-04-09 WO PCT/HR2003/000016 patent/WO2003084962A1/en active IP Right Grant
- 2003-04-09 AT AT03745849T patent/ATE320433T1/de not_active IP Right Cessation
- 2003-04-09 NZ NZ535620A patent/NZ535620A/xx unknown
- 2003-04-09 MX MXPA04009943A patent/MXPA04009943A/es active IP Right Grant
- 2003-04-09 US US10/510,866 patent/US7435834B2/en not_active Expired - Fee Related
- 2003-09-04 UA UA20041008547A patent/UA79277C2/uk unknown
2004
- 2004-09-27 IS IS7474A patent/IS7474A/is unknown
- 2004-10-06 ZA ZA200408063A patent/ZA200408063B/en unknown
- 2004-10-21 NO NO20044506A patent/NO20044506L/no not_active Application Discontinuation
2006
- 2006-05-18 CY CY20061100649T patent/CY1105036T1/el unknown

Also Published As

Publication number	Publication date
DE60304048D1 (de)	2006-05-11
PT1509530E (pt)	2006-07-31
SI1509530T1 (sl)	2006-08-31
ATE320433T1 (de)	2006-04-15
US20050182126A1 (en)	2005-08-18
HRP20020305A8 (en)	2009-03-31
NZ535620A (en)	2006-03-31
WO2003084962A1 (en)	2003-10-16
ES2260637T3 (es)	2006-11-01
DE60304048T2 (de)	2006-10-19
CY1105036T1 (el)	2010-03-03
MXPA04009943A (es)	2005-09-30
CA2481514A1 (en)	2003-10-16
US7435834B2 (en)	2008-10-14
YU88304A (sh)	2006-08-17
RU2004132868A (ru)	2005-06-10
IS7474A (is)	2004-09-27
BR0309094A (pt)	2005-02-09
RU2334749C2 (ru)	2008-09-27
IL164396A0 (en)	2005-12-18
NO20044506L (no)	2004-11-09
JP2005526828A (ja)	2005-09-08
PL372748A1 (en)	2005-08-08
EP1509530A1 (en)	2005-03-02
EP1509530B1 (en)	2006-03-15
DK1509530T3 (da)	2006-07-17
HRP20020305A2 (en)	2003-10-31
AU2003259963A1 (en)	2003-10-20
CN1649875A (zh)	2005-08-03
ZA200408063B (en)	2006-07-26

Publication	Publication Date	Title
UA79277C2 (en)	2007-06-11	2-thia-dibenzoazulenes as inhibitors of tumors necrosis factor production, process for the preparation and use thereof
US7312203B2 (en)	2007-12-25	1-aza-dibenzoazulenes as inhibitors of tumour necrosis factor production and intermediates for the preparation thereof
US7166583B2 (en)	2007-01-23	1,3-diaza-dibenzoazulenes as inhibitors of tumour necrosis factor production and intermediates for the preparation thereof
US7262302B2 (en)	2007-08-28	1-thia-3-aza-dibenzoazulenes as inhibitors of tumour necrosis factor production and intermediates for the preparation thereof
UA78297C2 (en)	2007-03-15	1- or 3-thiabenzonaphlhoazulene as inhibitors of tumour necrosis factor production and intermediates for synthesis thereof
US20060069149A1 (en)	2006-03-30	Thiadibenzoazulene derivatives for the treatment of inflammatory diseases
US20050148577A1 (en)	2005-07-07	1-oxa-dibenzoazulenes as inhibitors of tumor necrosis factor production and intermediates for the preparation thereof
US7232815B2 (en)	2007-06-19	1-oxa-3-aza-dibenzoazulenes as inhibitors of tumor necrosis factor production and intermediates for the production thereof
US7550498B2 (en)	2009-06-23	1,2-Diaza-dibenzoazulenes as inhibitors of tumour necrosis factor production and intermediates for the preparation thereof
US20050131056A1 (en)	2005-06-16	2- thia-dibenzoazulenes as inhibitors of tumor necrosis factor production and intermediates for the preparation thereof
US20050130956A1 (en)	2005-06-16	1-oxa 3-aza-dibenzoazulenes as inhibitors of tumor necrosis factor production and intermediates for the production thereof
KR20050016336A (ko)	2005-02-21	종양괴사인자 생성 억제제로서의 2-티아-디벤조아줄렌 및그의 제조를 위한 중간체
KR20050020774A (ko)	2005-03-04	종양괴사인자 생성의 억제제로서의1-옥사-3-아자-디벤조아줄렌 및 그의 제조를 위한 중간체
ZA200408060B (en)	2006-08-30	1-oxa-3-aza-deibenzoazulenes as inhibitors of tumour necrosis factor production and intermediates for the production thereof