SK12742000A3 - Inhibítory fosfolipázových enzýmov, farmaceutický prostriedok s ich obsahom a ich použitie - Google Patents

Inhibítory fosfolipázových enzýmov, farmaceutický prostriedok s ich obsahom a ich použitie Download PDF

Info

Publication number: SK12742000A3
Authority: SK; Slovakia
Prior art keywords: alkyl; methyl; phenyl; pharmaceutically acceptable; acceptable salt
Prior art date: 1998-02-25

Application number

SK1274-2000A

Other languages

English (en)

Slovak (sk)

Inventor

Jasbir S. Seehra

Neelu Kaila

John C. Mckew

Frank Lovering

Jean E. Bemis

Yibin Xiang

Original Assignee

Genetics Institute, Inc.

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.)

1998-02-25

Filing date

1999-02-24

Publication date

2001-05-10

1999-02-24 Application filed by Genetics Institute, Inc. filed Critical Genetics Institute, Inc.

2001-05-10 Publication of SK12742000A3 publication Critical patent/SK12742000A3/sk

Links

108010064785 Phospholipases Proteins 0.000 title claims abstract description 132
102000015439 Phospholipases Human genes 0.000 title claims abstract description 132
239000003112 inhibitor Substances 0.000 title claims description 15
239000008194 pharmaceutical composition Substances 0.000 claims abstract description 23
230000000694 effects Effects 0.000 claims abstract description 21
-1 -O-phenyl Chemical group 0.000 claims description 180
125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 148
ZIIUUSVHCHPIQD-UHFFFAOYSA-N 2,4,6-trimethyl-N-[3-(trifluoromethyl)phenyl]benzenesulfonamide Chemical compound CC1=CC(C)=CC(C)=C1S(=O)(=O)NC1=CC=CC(C(F)(F)F)=C1 ZIIUUSVHCHPIQD-UHFFFAOYSA-N 0.000 claims description 113
150000003839 salts Chemical class 0.000 claims description 111
229910052736 halogen Inorganic materials 0.000 claims description 110
239000002532 enzyme inhibitor Substances 0.000 claims description 109
150000002367 halogens Chemical class 0.000 claims description 109
WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 106
SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 claims description 86
125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 82
125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 80
125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 78
239000002253 acid Substances 0.000 claims description 71
125000000217 alkyl group Chemical group 0.000 claims description 69
125000001424 substituent group Chemical group 0.000 claims description 64
239000005711 Benzoic acid Substances 0.000 claims description 60
235000010233 benzoic acid Nutrition 0.000 claims description 54
125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 50
229910052739 hydrogen Inorganic materials 0.000 claims description 49
PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 claims description 44
RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 claims description 44
229910052760 oxygen Inorganic materials 0.000 claims description 39
229910052799 carbon Inorganic materials 0.000 claims description 38
229910052717 sulfur Inorganic materials 0.000 claims description 37
RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 33
229910052757 nitrogen Inorganic materials 0.000 claims description 32
125000004076 pyridyl group Chemical group 0.000 claims description 32
125000003545 alkoxy group Chemical group 0.000 claims description 30
125000002541 furyl group Chemical group 0.000 claims description 26
125000000168 pyrrolyl group Chemical group 0.000 claims description 26
125000001544 thienyl group Chemical group 0.000 claims description 26
125000001041 indolyl group Chemical group 0.000 claims description 25
150000003536 tetrazoles Chemical class 0.000 claims description 24
125000005979 2-naphthyloxy group Chemical group 0.000 claims description 20
QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 20
125000000623 heterocyclic group Chemical group 0.000 claims description 20
125000005842 heteroatom Chemical group 0.000 claims description 19
125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 claims description 17
VLRGXXKFHVJQOL-UHFFFAOYSA-N 3-chloropentane-2,4-dione Chemical compound CC(=O)C(Cl)C(C)=O VLRGXXKFHVJQOL-UHFFFAOYSA-N 0.000 claims description 14
125000000896 monocarboxylic acid group Chemical group 0.000 claims description 13
125000000027 (C1-C10) alkoxy group Chemical group 0.000 claims description 12
YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 12
RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 12
YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 11
241000124008 Mammalia Species 0.000 claims description 11
150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 11
125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 11
UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 10
UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 claims description 10
JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 10
239000001257 hydrogen Substances 0.000 claims description 10
125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 9
125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 9
125000006638 cyclopentyl carbonyl group Chemical group 0.000 claims description 9
125000002757 morpholinyl group Chemical group 0.000 claims description 9
125000001624 naphthyl group Chemical group 0.000 claims description 9
239000000126 substance Substances 0.000 claims description 9
NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 8
KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 claims description 8
SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 claims description 8
YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 claims description 8
125000001188 haloalkyl group Chemical group 0.000 claims description 8
125000003387 indolinyl group Chemical group N1(CCC2=CC=CC=C12)* 0.000 claims description 8
230000028709 inflammatory response Effects 0.000 claims description 8
230000002401 inhibitory effect Effects 0.000 claims description 8
125000000714 pyrimidinyl group Chemical group 0.000 claims description 8
125000005493 quinolyl group Chemical group 0.000 claims description 8
125000005073 adamantyl group Chemical group C12(CC3CC(CC(C1)C3)C2)* 0.000 claims description 7
125000002619 bicyclic group Chemical group 0.000 claims description 7
239000003937 drug carrier Substances 0.000 claims description 7
KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical compound N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 claims description 6
GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims description 6
125000000753 cycloalkyl group Chemical group 0.000 claims description 6
125000006518 morpholino carbonyl group Chemical group [H]C1([H])OC([H])([H])C([H])([H])N(C(*)=O)C1([H])[H] 0.000 claims description 5
125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 5
UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 5
125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 5
WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 claims description 4
CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 claims description 4
RFRXIWQYSOIBDI-UHFFFAOYSA-N benzarone Chemical compound CCC=1OC2=CC=CC=C2C=1C(=O)C1=CC=C(O)C=C1 RFRXIWQYSOIBDI-UHFFFAOYSA-N 0.000 claims description 4
229930192474 thiophene Natural products 0.000 claims description 4
YJTCXUDVHWLYPB-UHFFFAOYSA-N 1-[1-[[4-(1,3-benzothiazole-2-carbonyl)phenyl]methyl]-5-benzylsulfanyl-2-(naphthalen-2-ylsulfanylmethyl)indol-3-yl]ethanone Chemical compound C1=C2C(C(=O)C)=C(CSC=3C=C4C=CC=CC4=CC=3)N(CC=3C=CC(=CC=3)C(=O)C=3SC4=CC=CC=C4N=3)C2=CC=C1SCC1=CC=CC=C1 YJTCXUDVHWLYPB-UHFFFAOYSA-N 0.000 claims description 3
OEXARBJNOQARFV-UHFFFAOYSA-N 2-[4-[[3-(naphthalene-1-carbonyl)-5-phenylmethoxyindol-1-yl]methyl]phenyl]acetic acid Chemical compound C1=CC(CC(=O)O)=CC=C1CN1C2=CC=C(OCC=3C=CC=CC=3)C=C2C(C(=O)C=2C3=CC=CC=C3C=CC=2)=C1 OEXARBJNOQARFV-UHFFFAOYSA-N 0.000 claims description 3
FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Natural products CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 claims description 3
125000006309 butyl amino group Chemical group 0.000 claims description 3
125000004122 cyclic group Chemical group 0.000 claims description 3
XRLDSWLMHUQECH-UHFFFAOYSA-N cyclopentanecarboxamide Chemical compound NC(=O)C1CCCC1 XRLDSWLMHUQECH-UHFFFAOYSA-N 0.000 claims description 3
SODNQSQGAIFUJN-UHFFFAOYSA-N 2-[3-(2-methylpropanoyl)-2-(naphthalen-2-ylsulfanylmethyl)-5-phenylmethoxyindol-1-yl]acetic acid Chemical compound C1=C2C(C(=O)C(C)C)=C(CSC=3C=C4C=CC=CC4=CC=3)N(CC(O)=O)C2=CC=C1OCC1=CC=CC=C1 SODNQSQGAIFUJN-UHFFFAOYSA-N 0.000 claims description 2
BAEMDODKDIQWKC-UHFFFAOYSA-N 2-[3-[[3-acetyl-2-(naphthalen-2-ylsulfanylmethyl)-5-phenylmethoxyindol-1-yl]methyl]benzoyl]-1,3-benzothiazole-6-carboxylic acid Chemical compound C1=C2C(C(=O)C)=C(CSC=3C=C4C=CC=CC4=CC=3)N(CC=3C=C(C=CC=3)C(=O)C=3SC4=CC(=CC=C4N=3)C(O)=O)C2=CC=C1OCC1=CC=CC=C1 BAEMDODKDIQWKC-UHFFFAOYSA-N 0.000 claims description 2
AEMVESKVBNFDCE-UHFFFAOYSA-N 2-[4-[[3-(naphthalene-2-carbonyl)-5-phenylmethoxyindol-1-yl]methyl]phenyl]acetic acid Chemical compound C1=CC(CC(=O)O)=CC=C1CN1C2=CC=C(OCC=3C=CC=CC=3)C=C2C(C(=O)C=2C=C3C=CC=CC3=CC=2)=C1 AEMVESKVBNFDCE-UHFFFAOYSA-N 0.000 claims description 2
RPIABDIOCBNDTD-UHFFFAOYSA-N 4-[[3-chloro-5-(cyclopentanecarbonylamino)-2-(2-phenylethylsulfanylmethyl)indol-1-yl]methyl]benzoic acid Chemical compound C1=CC(C(=O)O)=CC=C1CN1C2=CC=C(NC(=O)C3CCCC3)C=C2C(Cl)=C1CSCCC1=CC=CC=C1 RPIABDIOCBNDTD-UHFFFAOYSA-N 0.000 claims description 2
ISKVLCIRFKUOML-UHFFFAOYSA-N 4-[[3-chloro-5-(cyclopentanecarbonylamino)-2-(naphthalen-2-ylsulfanylmethyl)indol-1-yl]methyl]-n-(trifluoromethylsulfonyl)benzamide Chemical compound C1=CC(C(=O)NS(=O)(=O)C(F)(F)F)=CC=C1CN1C2=CC=C(NC(=O)C3CCCC3)C=C2C(Cl)=C1CSC1=CC=C(C=CC=C2)C2=C1 ISKVLCIRFKUOML-UHFFFAOYSA-N 0.000 claims description 2
AQVDIHXVAOTXPO-UHFFFAOYSA-N 5-[3-benzoyl-2-(naphthalen-2-yloxymethyl)-5-phenylmethoxyindol-1-yl]pentanoic acid Chemical compound C12=CC(OCC=3C=CC=CC=3)=CC=C2N(CCCCC(=O)O)C(COC=2C=C3C=CC=CC3=CC=2)=C1C(=O)C1=CC=CC=C1 AQVDIHXVAOTXPO-UHFFFAOYSA-N 0.000 claims description 2
125000002490 anilino group Chemical group [H]N(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 2
125000004429 atom Chemical group 0.000 claims description 2
125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
125000005843 halogen group Chemical group 0.000 claims description 2
125000005647 linker group Chemical group 0.000 claims description 2
WARLBQLHVRYWHC-UHFFFAOYSA-N n-[3-(morpholine-4-carbonyl)-2-(naphthalen-2-yloxymethyl)-1-[4-oxo-4-(trifluoromethylsulfonylamino)butyl]indol-5-yl]cyclopentanecarboxamide Chemical compound C12=CC(NC(=O)C3CCCC3)=CC=C2N(CCCC(=O)NS(=O)(=O)C(F)(F)F)C(COC=2C=C3C=CC=CC3=CC=2)=C1C(=O)N1CCOCC1 WARLBQLHVRYWHC-UHFFFAOYSA-N 0.000 claims description 2
125000003261 o-tolyl group Chemical group [H]C1=C([H])C(*)=C(C([H])=C1[H])C([H])([H])[H] 0.000 claims description 2
229940125532 enzyme inhibitor Drugs 0.000 claims 93
150000001413 amino acids Chemical class 0.000 claims 5
239000000546 pharmaceutical excipient Substances 0.000 claims 5
ATUOYWHBWRKTHZ-UHFFFAOYSA-N Propane Chemical compound CCC ATUOYWHBWRKTHZ-UHFFFAOYSA-N 0.000 claims 4
125000004080 3-carboxypropanoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C(O[H])=O 0.000 claims 2
ALYNCZNDIQEVRV-UHFFFAOYSA-N 4-aminobenzoic acid Chemical compound NC1=CC=C(C(O)=O)C=C1 ALYNCZNDIQEVRV-UHFFFAOYSA-N 0.000 claims 2
125000000738 acetamido group Chemical group [H]C([H])([H])C(=O)N([H])[*] 0.000 claims 2
229960004050 aminobenzoic acid Drugs 0.000 claims 2
125000004063 butyryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims 2
ZWLPBLYKEWSWPD-UHFFFAOYSA-N o-toluic acid Chemical compound CC1=CC=CC=C1C(O)=O ZWLPBLYKEWSWPD-UHFFFAOYSA-N 0.000 claims 2
239000001294 propane Substances 0.000 claims 2
125000003396 thiol group Chemical group [H]S* 0.000 claims 2
PLJCHEFJWIQVNJ-UHFFFAOYSA-N 2-[3-acetyl-2-(naphthalen-2-ylsulfanylmethyl)-5-phenylmethoxyindol-1-yl]acetic acid Chemical compound C1=C2C(C(=O)C)=C(CSC=3C=C4C=CC=CC4=CC=3)N(CC(O)=O)C2=CC=C1OCC1=CC=CC=C1 PLJCHEFJWIQVNJ-UHFFFAOYSA-N 0.000 claims 1
CRUDIMLKIYWDJS-UHFFFAOYSA-N 3-[4-[5-(cyclopentanecarbonylamino)-2-(naphthalen-2-yloxymethyl)-3-(pyrrolidine-1-carbonyl)indol-1-yl]butanoylamino]-n-(trifluoromethylsulfonyl)benzamide Chemical compound FC(F)(F)S(=O)(=O)NC(=O)C1=CC=CC(NC(=O)CCCN2C3=CC=C(NC(=O)C4CCCC4)C=C3C(C(=O)N3CCCC3)=C2COC=2C=C3C=CC=CC3=CC=2)=C1 CRUDIMLKIYWDJS-UHFFFAOYSA-N 0.000 claims 1
125000006180 3-methyl benzyl group Chemical group [H]C1=C([H])C(=C([H])C(=C1[H])C([H])([H])[H])C([H])([H])* 0.000 claims 1
QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims 1
GPLPUBZZORCROH-UHFFFAOYSA-N C(C1=CC=CC=C1)OC=1C=C2C(=C(N(C2=CC1)CC1=C(C(=O)O)C=CC=C1)CSC1=CC2=CC=CC=C2C=C1)C(C(C)C)=O Chemical compound C(C1=CC=CC=C1)OC=1C=C2C(=C(N(C2=CC1)CC1=C(C(=O)O)C=CC=C1)CSC1=CC2=CC=CC=C2C=C1)C(C(C)C)=O GPLPUBZZORCROH-UHFFFAOYSA-N 0.000 claims 1
CZCLVPCHGTYJJC-UHFFFAOYSA-N ClC1=C(N(C2=CC=C(C=C12)NC(=O)C1COCC1)CC1=C(C(=O)O)C=CC=C1)CSC1=CC2=CC=CC=C2C=C1 Chemical compound ClC1=C(N(C2=CC=C(C=C12)NC(=O)C1COCC1)CC1=C(C(=O)O)C=CC=C1)CSC1=CC2=CC=CC=C2C=C1 CZCLVPCHGTYJJC-UHFFFAOYSA-N 0.000 claims 1
AFIXYKBNZYOHSX-UHFFFAOYSA-N NC=1C=C2C(=C(N(C2=CC1)CC1=C(C(=O)O)C=CC=C1)CSC1=CC2=CC=CC=C2C=C1)Cl Chemical compound NC=1C=C2C(=C(N(C2=CC1)CC1=C(C(=O)O)C=CC=C1)CSC1=CC2=CC=CC=C2C=C1)Cl AFIXYKBNZYOHSX-UHFFFAOYSA-N 0.000 claims 1
125000000440 benzylamino group Chemical group [H]N(*)C([H])([H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims 1
125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 claims 1
125000001887 cyclopentyloxy group Chemical group C1(CCCC1)O* 0.000 claims 1
125000001664 diethylamino group Chemical group [H]C([H])([H])C([H])([H])N(*)C([H])([H])C([H])([H])[H] 0.000 claims 1
125000000814 indol-3-yl group Chemical group [H]C1=C([H])C([H])=C2N([H])C([H])=C([*])C2=C1[H] 0.000 claims 1
KMAKOBLIOCQGJP-UHFFFAOYSA-N indole-3carboxylic acid Natural products C1=CC=C2C(C(=O)O)=CNC2=C1 KMAKOBLIOCQGJP-UHFFFAOYSA-N 0.000 claims 1
MQIWNGNYIAGSCS-UHFFFAOYSA-N n-(benzenesulfonyl)-4-[[3-chloro-5-(cyclopentanecarbonylamino)-2-(naphthalen-2-ylsulfanylmethyl)indol-1-yl]methyl]benzamide Chemical compound C12=CC=C(NC(=O)C3CCCC3)C=C2C(Cl)=C(CSC=2C=C3C=CC=CC3=CC=2)N1CC(C=C1)=CC=C1C(=O)NS(=O)(=O)C1=CC=CC=C1 MQIWNGNYIAGSCS-UHFFFAOYSA-N 0.000 claims 1
125000001736 nosyl group Chemical group S(=O)(=O)(C1=CC=C([N+](=O)[O-])C=C1)* 0.000 claims 1
125000001325 propanoyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 claims 1
150000001875 compounds Chemical class 0.000 abstract description 100
239000000203 mixture Substances 0.000 abstract description 65
238000000034 method Methods 0.000 abstract description 61
238000011282 treatment Methods 0.000 abstract description 50
102100037611 Lysophospholipase Human genes 0.000 abstract description 2
108020002496 Lysophospholipase Proteins 0.000 abstract 1
XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 341
WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 136
VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 131
235000019439 ethyl acetate Nutrition 0.000 description 125
ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 91
OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 87
YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 81
239000011541 reaction mixture Substances 0.000 description 79
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239000000243 solution Substances 0.000 description 61
239000000047 product Substances 0.000 description 59
LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 43
HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 42
238000004587 chromatography analysis Methods 0.000 description 37
150000002148 esters Chemical class 0.000 description 34
238000006243 chemical reaction Methods 0.000 description 32
WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 31
239000012044 organic layer Substances 0.000 description 31
150000001412 amines Chemical class 0.000 description 30
RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 29
WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 24
150000001408 amides Chemical class 0.000 description 24
239000010410 layer Substances 0.000 description 23
238000001665 trituration Methods 0.000 description 23
VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 22
IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 22
238000011097 chromatography purification Methods 0.000 description 22
239000002904 solvent Substances 0.000 description 22
ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 21
229910000104 sodium hydride Inorganic materials 0.000 description 21
VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 20
239000012267 brine Substances 0.000 description 19
HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 19
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QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 description 1
230000001991 pathophysiological effect Effects 0.000 description 1
239000000312 peanut oil Substances 0.000 description 1
239000008188 pellet Substances 0.000 description 1
IPWFJLQDVFKJDU-UHFFFAOYSA-N pentanamide Chemical compound CCCCC(N)=O IPWFJLQDVFKJDU-UHFFFAOYSA-N 0.000 description 1
150000002989 phenols Chemical class 0.000 description 1
125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 description 1
NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
239000010452 phosphate Substances 0.000 description 1
RLOWWWKZYUNIDI-UHFFFAOYSA-N phosphinic chloride Chemical compound ClP=O RLOWWWKZYUNIDI-UHFFFAOYSA-N 0.000 description 1
LFSXCDWNBUNEEM-UHFFFAOYSA-N phthalazine Chemical compound C1=NN=CC2=CC=CC=C21 LFSXCDWNBUNEEM-UHFFFAOYSA-N 0.000 description 1
239000002504 physiological saline solution Substances 0.000 description 1
229920001223 polyethylene glycol Polymers 0.000 description 1
235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
229920000053 polysorbate 80 Polymers 0.000 description 1
IUBQJLUDMLPAGT-UHFFFAOYSA-N potassium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([K])[Si](C)(C)C IUBQJLUDMLPAGT-UHFFFAOYSA-N 0.000 description 1
229910000027 potassium carbonate Inorganic materials 0.000 description 1
239000002243 precursor Substances 0.000 description 1
239000003755 preservative agent Substances 0.000 description 1
239000012460 protein solution Substances 0.000 description 1
USPWKWBDZOARPV-UHFFFAOYSA-N pyrazolidine Chemical compound C1CNNC1 USPWKWBDZOARPV-UHFFFAOYSA-N 0.000 description 1
DNXIASIHZYFFRO-UHFFFAOYSA-N pyrazoline Chemical compound C1CN=NC1 DNXIASIHZYFFRO-UHFFFAOYSA-N 0.000 description 1
PBMFSQRYOILNGV-UHFFFAOYSA-N pyridazine Chemical compound C1=CC=NN=C1 PBMFSQRYOILNGV-UHFFFAOYSA-N 0.000 description 1
GRJJQCWNZGRKAU-UHFFFAOYSA-N pyridin-1-ium;fluoride Chemical compound F.C1=CC=NC=C1 GRJJQCWNZGRKAU-UHFFFAOYSA-N 0.000 description 1
238000010791 quenching Methods 0.000 description 1
239000001397 quillaja saponaria molina bark Substances 0.000 description 1
JWVCLYRUEFBMGU-UHFFFAOYSA-N quinazoline Chemical compound N1=CN=CC2=CC=CC=C21 JWVCLYRUEFBMGU-UHFFFAOYSA-N 0.000 description 1
125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
238000009790 rate-determining step (RDS) Methods 0.000 description 1
238000006268 reductive amination reaction Methods 0.000 description 1
206010039073 rheumatoid arthritis Diseases 0.000 description 1
125000006413 ring segment Chemical group 0.000 description 1
238000007127 saponification reaction Methods 0.000 description 1
229930182490 saponin Natural products 0.000 description 1
150000007949 saponins Chemical class 0.000 description 1
150000003335 secondary amines Chemical class 0.000 description 1
230000003248 secreting effect Effects 0.000 description 1
239000012679 serum free medium Substances 0.000 description 1
239000008159 sesame oil Substances 0.000 description 1
235000011803 sesame oil Nutrition 0.000 description 1
125000003808 silyl group Chemical group [H][Si]([H])([H])[*] 0.000 description 1
239000003998 snake venom Substances 0.000 description 1
239000011734 sodium Substances 0.000 description 1
239000008354 sodium chloride injection Substances 0.000 description 1
229940048181 sodium sulfide nonahydrate Drugs 0.000 description 1
VGTPCRGMBIAPIM-UHFFFAOYSA-M sodium thiocyanate Chemical compound [Na+].[S-]C#N VGTPCRGMBIAPIM-UHFFFAOYSA-M 0.000 description 1
WMDLZMCDBSJMTM-UHFFFAOYSA-M sodium;sulfanide;nonahydrate Chemical compound O.O.O.O.O.O.O.O.O.[Na+].[SH-] WMDLZMCDBSJMTM-UHFFFAOYSA-M 0.000 description 1
239000003549 soybean oil Substances 0.000 description 1
235000012424 soybean oil Nutrition 0.000 description 1
210000000952 spleen Anatomy 0.000 description 1
238000013222 sprague-dawley male rat Methods 0.000 description 1
238000010561 standard procedure Methods 0.000 description 1
239000007858 starting material Substances 0.000 description 1
230000000638 stimulation Effects 0.000 description 1
238000006467 substitution reaction Methods 0.000 description 1
239000011593 sulfur Substances 0.000 description 1
230000002195 synergetic effect Effects 0.000 description 1
210000001179 synovial fluid Anatomy 0.000 description 1
QEOUGFSILBVRCP-UHFFFAOYSA-N tert-butyl-dimethyl-[(5-phenylmethoxy-1h-indol-2-yl)methoxy]silane Chemical compound C=1C=C2NC(CO[Si](C)(C)C(C)(C)C)=CC2=CC=1OCC1=CC=CC=C1 QEOUGFSILBVRCP-UHFFFAOYSA-N 0.000 description 1
125000001981 tert-butyldimethylsilyl group Chemical group [H]C([H])([H])[Si]([H])(C([H])([H])[H])[*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
150000003511 tertiary amides Chemical class 0.000 description 1
229940124597 therapeutic agent Drugs 0.000 description 1
238000002560 therapeutic procedure Methods 0.000 description 1
150000003568 thioethers Chemical class 0.000 description 1
210000001519 tissue Anatomy 0.000 description 1
125000003774 valeryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
235000013311 vegetables Nutrition 0.000 description 1
238000003260 vortexing Methods 0.000 description 1
238000005406 washing Methods 0.000 description 1
MWLSOWXNZPKENC-SSDOTTSWSA-N zileuton Chemical compound C1=CC=C2SC([C@H](N(O)C(N)=O)C)=CC2=C1 MWLSOWXNZPKENC-SSDOTTSWSA-N 0.000 description 1
229960005332 zileuton Drugs 0.000 description 1

Classifications

- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
- 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
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
- C07D209/12—Radicals substituted by oxygen atoms
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
- C07D209/42—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings

Landscapes

Chemical & Material Sciences (AREA)
Organic Chemistry (AREA)
Health & Medical Sciences (AREA)
Life Sciences & Earth Sciences (AREA)
Public Health (AREA)
General Chemical & Material Sciences (AREA)
Medicinal Chemistry (AREA)
Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
Chemical Kinetics & Catalysis (AREA)
Pharmacology & Pharmacy (AREA)
Veterinary Medicine (AREA)
Animal Behavior & Ethology (AREA)
General Health & Medical Sciences (AREA)
Bioinformatics & Cheminformatics (AREA)
Engineering & Computer Science (AREA)
Pain & Pain Management (AREA)
Rheumatology (AREA)
Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Indole Compounds (AREA)
Plural Heterocyclic Compounds (AREA)

SK1274-2000A 1998-02-25 1999-02-24 Inhibítory fosfolipázových enzýmov, farmaceutický prostriedok s ich obsahom a ich použitie SK12742000A3 (sk)

Applications Claiming Priority (2)

Application Number	Priority Date	Filing Date	Title
US3006298A	1998-02-25	1998-02-25
PCT/US1999/003899 WO1999043651A2 (en)	1998-02-25	1999-02-24	Inhibitors of phospholipase enzymes

Publications (1)

Publication Number	Publication Date
SK12742000A3 true SK12742000A3 (sk)	2001-05-10

Family

ID=21852314

Family Applications (1)

Application Number	Title	Priority Date	Filing Date
SK1274-2000A SK12742000A3 (sk)	1998-02-25	1999-02-24	Inhibítory fosfolipázových enzýmov, farmaceutický prostriedok s ich obsahom a ich použitie

Country Status (19)

Country	Link
EP (1)	EP1056719A2 (hu)
JP (1)	JP2002504539A (hu)
KR (1)	KR20010041343A (hu)
CN (1)	CN1299347A (hu)
AU (1)	AU2782699A (hu)
BG (1)	BG104780A (hu)
BR (1)	BR9908280A (hu)
CA (1)	CA2322161A1 (hu)
EA (1)	EA200000868A1 (hu)
EE (1)	EE200000486A (hu)
HR (1)	HRP20000552A2 (hu)
HU (1)	HUP0100757A3 (hu)
ID (1)	ID27280A (hu)
IL (1)	IL137718A0 (hu)
NO (1)	NO20004220L (hu)
PL (1)	PL342995A1 (hu)
SK (1)	SK12742000A3 (hu)
TR (1)	TR200002446T2 (hu)
WO (1)	WO1999043651A2 (hu)

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IL109311A0 (en) *	1993-04-16	1994-07-31	Lilly Co Eli	1H-indole-3-acetamide sPla2 inhibitors
DE4338770A1 (de) *	1993-11-12	1995-05-18	Matthias Dr Lehr	Indol-2-alkansäuren und ihre Derivate als Hemmstoffe der Phospholipase A¶2¶
AU3767997A (en) *	1996-08-01	1998-02-25	Merckle Gmbh	Acylpyrroldicarboxylic acids and acylindoldicarboxylic acids and their derivatives and inhibitors of the cytosolic phospholipase a2
AU717430B2 (en) *	1996-08-26	2000-03-23	Genetics Institute, Llc	Inhibitors of phospholipase enzymes

1999
- 1999-02-24 SK SK1274-2000A patent/SK12742000A3/sk unknown
- 1999-02-24 EA EA200000868A patent/EA200000868A1/ru unknown
- 1999-02-24 JP JP2000533409A patent/JP2002504539A/ja not_active Withdrawn
- 1999-02-24 CN CN99805385A patent/CN1299347A/zh active Pending
- 1999-02-24 AU AU27826/99A patent/AU2782699A/en not_active Abandoned
- 1999-02-24 PL PL99342995A patent/PL342995A1/xx unknown
- 1999-02-24 EE EEP200000486A patent/EE200000486A/xx unknown
- 1999-02-24 EP EP99908379A patent/EP1056719A2/en not_active Withdrawn
- 1999-02-24 CA CA002322161A patent/CA2322161A1/en not_active Abandoned
- 1999-02-24 WO PCT/US1999/003899 patent/WO1999043651A2/en not_active Ceased
- 1999-02-24 IL IL13771899A patent/IL137718A0/xx unknown
- 1999-02-24 ID IDW20001594A patent/ID27280A/id unknown
- 1999-02-24 TR TR2000/02446T patent/TR200002446T2/xx unknown
- 1999-02-24 HU HU0100757A patent/HUP0100757A3/hu unknown
- 1999-02-24 HR HR20000552A patent/HRP20000552A2/hr not_active Application Discontinuation
- 1999-02-24 KR KR1020007009456A patent/KR20010041343A/ko not_active Withdrawn
- 1999-02-24 BR BR9908280-2A patent/BR9908280A/pt not_active IP Right Cessation
2000
- 2000-08-23 NO NO20004220A patent/NO20004220L/no unknown
- 2000-09-19 BG BG104780A patent/BG104780A/xx unknown

Also Published As

Publication number	Publication date
AU2782699A (en)	1999-09-15
NO20004220D0 (no)	2000-08-23
EE200000486A (et)	2002-02-15
HUP0100757A1 (hu)	2001-08-28
BR9908280A (pt)	2000-10-31
WO1999043651A3 (en)	1999-12-16
BG104780A (en)	2001-10-31
HRP20000552A2 (en)	2001-04-30
TR200002446T2 (tr)	2000-12-21
CN1299347A (zh)	2001-06-13
IL137718A0 (en)	2001-10-31
JP2002504539A (ja)	2002-02-12
HUP0100757A3 (en)	2001-11-28
CA2322161A1 (en)	1999-09-02
ID27280A (id)	2001-03-22
KR20010041343A (ko)	2001-05-15
NO20004220L (no)	2000-10-05
EA200000868A1 (ru)	2001-04-23
PL342995A1 (en)	2001-07-16
WO1999043651A2 (en)	1999-09-02
EP1056719A2 (en)	2000-12-06

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US6828344B1 (en)	2004-12-07	Inhibitors of phospholipase enzymes
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JP4657605B2 (ja)	2011-03-23	細胞質内ホスホリパーゼａ２の阻害剤
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MXPA00008292A (en)	2002-07-25	Inhibitors of phospholipase enzymes
CZ20003117A3 (cs)	2001-01-17	Inhibitory fosfolipázy
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