IE46825B1 - Pyrrole derivatives - Google Patents
Pyrrole derivativesInfo
- Publication number
- IE46825B1 IE46825B1 IE942/78A IE94278A IE46825B1 IE 46825 B1 IE46825 B1 IE 46825B1 IE 942/78 A IE942/78 A IE 942/78A IE 94278 A IE94278 A IE 94278A IE 46825 B1 IE46825 B1 IE 46825B1
- Authority
- IE
- Ireland
- Prior art keywords
- group
- compound
- methyl
- formula
- choh
- Prior art date
Links
- 150000003233 pyrroles Chemical class 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 134
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 36
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 27
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 20
- 229940002612 prodrug Drugs 0.000 claims abstract description 12
- 239000000651 prodrug Substances 0.000 claims abstract description 12
- 239000000460 chlorine Substances 0.000 claims abstract description 8
- 125000001544 thienyl group Chemical group 0.000 claims abstract description 5
- GRVDJDISBSALJP-UHFFFAOYSA-N methyloxidanyl Chemical group [O]C GRVDJDISBSALJP-UHFFFAOYSA-N 0.000 claims abstract description 4
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims abstract description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims abstract description 3
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims abstract description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims abstract description 3
- 229910052794 bromium Inorganic materials 0.000 claims abstract description 3
- 229910052801 chlorine Inorganic materials 0.000 claims abstract description 3
- 239000011737 fluorine Substances 0.000 claims abstract description 3
- 229910052731 fluorine Inorganic materials 0.000 claims abstract description 3
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims abstract description 3
- 239000000203 mixture Substances 0.000 claims description 33
- 238000000034 method Methods 0.000 claims description 30
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 claims description 22
- 238000005917 acylation reaction Methods 0.000 claims description 15
- BTANRVKWQNVYAZ-UHFFFAOYSA-N butan-2-ol Chemical compound CCC(C)O BTANRVKWQNVYAZ-UHFFFAOYSA-N 0.000 claims description 14
- -1 mono-substituted phenyl group Chemical group 0.000 claims description 14
- 230000010933 acylation Effects 0.000 claims description 13
- 239000002904 solvent Substances 0.000 claims description 12
- 238000006243 chemical reaction Methods 0.000 claims description 11
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 10
- 239000003795 chemical substances by application Substances 0.000 claims description 9
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 9
- 239000001273 butane Substances 0.000 claims description 8
- 125000004432 carbon atom Chemical group C* 0.000 claims description 8
- OFBQJSOFQDEBGM-UHFFFAOYSA-N n-pentane Natural products CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 claims description 8
- 238000002360 preparation method Methods 0.000 claims description 8
- 125000000217 alkyl group Chemical group 0.000 claims description 7
- IJDNQMDRQITEOD-UHFFFAOYSA-N n-butane Chemical compound CCCC IJDNQMDRQITEOD-UHFFFAOYSA-N 0.000 claims description 7
- 239000002841 Lewis acid Substances 0.000 claims description 6
- 150000007517 lewis acids Chemical class 0.000 claims description 6
- 230000000269 nucleophilic effect Effects 0.000 claims description 6
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 5
- 150000003512 tertiary amines Chemical class 0.000 claims description 5
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims description 4
- 125000003118 aryl group Chemical group 0.000 claims description 4
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 4
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 4
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 4
- 239000008194 pharmaceutical composition Substances 0.000 claims description 3
- 125000003944 tolyl group Chemical group 0.000 claims description 3
- 125000004201 2,4-dichlorophenyl group Chemical group [H]C1=C([H])C(*)=C(Cl)C([H])=C1Cl 0.000 claims description 2
- 125000000022 2-aminoethyl group Chemical group [H]C([*])([H])C([H])([H])N([H])[H] 0.000 claims description 2
- 125000004204 2-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C(OC([H])([H])[H])C([H])=C1[H] 0.000 claims description 2
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 claims description 2
- 125000003762 3,4-dimethoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C(OC([H])([H])[H])C([H])=C1* 0.000 claims description 2
- 125000001541 3-thienyl group Chemical group S1C([H])=C([*])C([H])=C1[H] 0.000 claims description 2
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 2
- OMPJBNCRMGITSC-UHFFFAOYSA-N Benzoylperoxide Chemical group C=1C=CC=CC=1C(=O)OOC(=O)C1=CC=CC=C1 OMPJBNCRMGITSC-UHFFFAOYSA-N 0.000 claims description 2
- 125000000738 acetamido group Chemical group [H]C([H])([H])C(=O)N([H])[*] 0.000 claims description 2
- 125000003282 alkyl amino group Chemical group 0.000 claims description 2
- 229960003328 benzoyl peroxide Drugs 0.000 claims description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 2
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 2
- 238000009833 condensation Methods 0.000 claims description 2
- 230000005494 condensation Effects 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 2
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims description 2
- 230000002757 inflammatory effect Effects 0.000 claims description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 2
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 claims description 2
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 claims description 2
- 125000000286 phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
- 125000004188 dichlorophenyl group Chemical group 0.000 claims 3
- 125000000068 chlorophenyl group Chemical group 0.000 claims 2
- 125000001207 fluorophenyl group Chemical group 0.000 claims 2
- 125000000590 4-methylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 claims 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims 1
- 150000001412 amines Chemical class 0.000 claims 1
- 239000001257 hydrogen Substances 0.000 claims 1
- 229910052739 hydrogen Inorganic materials 0.000 claims 1
- 239000003960 organic solvent Substances 0.000 claims 1
- 230000003110 anti-inflammatory effect Effects 0.000 abstract description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 18
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 11
- 238000012360 testing method Methods 0.000 description 11
- JYGXADMDTFJGBT-VWUMJDOOSA-N hydrocortisone Chemical compound O=C1CC[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 JYGXADMDTFJGBT-VWUMJDOOSA-N 0.000 description 10
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 9
- UPSPUYADGBWSHF-UHFFFAOYSA-N tolmetin Chemical compound C1=CC(C)=CC=C1C(=O)C1=CC=C(CC(O)=O)N1C UPSPUYADGBWSHF-UHFFFAOYSA-N 0.000 description 9
- 229960001017 tolmetin Drugs 0.000 description 9
- 230000000063 preceeding effect Effects 0.000 description 7
- 239000013543 active substance Substances 0.000 description 6
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- GMRLQAKEZKMSSK-UHFFFAOYSA-N 4-[1-methyl-5-(4-methylbenzoyl)pyrrol-2-yl]butan-2-one Chemical compound CN1C(CCC(=O)C)=CC=C1C(=O)C1=CC=C(C)C=C1 GMRLQAKEZKMSSK-UHFFFAOYSA-N 0.000 description 5
- 241001465754 Metazoa Species 0.000 description 5
- 229960000890 hydrocortisone Drugs 0.000 description 5
- 239000012044 organic layer Substances 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- 238000001953 recrystallisation Methods 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- CLGHZGLGXDZHFX-UHFFFAOYSA-N 4-(1-methylpyrrol-2-yl)butan-2-one Chemical compound CC(=O)CCC1=CC=CN1C CLGHZGLGXDZHFX-UHFFFAOYSA-N 0.000 description 4
- HTBUSLQJPBLMOT-UHFFFAOYSA-N 4-[5-(4-chlorobenzoyl)-1-methylpyrrol-2-yl]butan-2-one Chemical compound CN1C(CCC(=O)C)=CC=C1C(=O)C1=CC=C(Cl)C=C1 HTBUSLQJPBLMOT-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 4
- 150000002085 enols Chemical class 0.000 description 4
- 239000007903 gelatin capsule Substances 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 3
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 3
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 3
- CYTYCFOTNPOANT-UHFFFAOYSA-N Perchloroethylene Chemical group ClC(Cl)=C(Cl)Cl CYTYCFOTNPOANT-UHFFFAOYSA-N 0.000 description 3
- 241000700159 Rattus Species 0.000 description 3
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 3
- 239000004141 Sodium laurylsulphate Substances 0.000 description 3
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 3
- 230000001760 anti-analgesic effect Effects 0.000 description 3
- 239000003054 catalyst Substances 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 238000001704 evaporation Methods 0.000 description 3
- 230000002496 gastric effect Effects 0.000 description 3
- 239000012442 inert solvent Substances 0.000 description 3
- 239000008101 lactose Substances 0.000 description 3
- 239000000314 lubricant Substances 0.000 description 3
- 235000019359 magnesium stearate Nutrition 0.000 description 3
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 3
- 239000008108 microcrystalline cellulose Substances 0.000 description 3
- 229940016286 microcrystalline cellulose Drugs 0.000 description 3
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 3
- 229950011008 tetrachloroethylene Drugs 0.000 description 3
- 125000005809 3,4,5-trimethoxyphenyl group Chemical group [H]C1=C(OC([H])([H])[H])C(OC([H])([H])[H])=C(OC([H])([H])[H])C([H])=C1* 0.000 description 2
- NQUVCRCCRXRJCK-UHFFFAOYSA-N 4-methylbenzoyl chloride Chemical compound CC1=CC=C(C(Cl)=O)C=C1 NQUVCRCCRXRJCK-UHFFFAOYSA-N 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- 101150041968 CDC13 gene Proteins 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 150000008064 anhydrides Chemical class 0.000 description 2
- 239000000730 antalgic agent Substances 0.000 description 2
- 206010003246 arthritis Diseases 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 239000007884 disintegrant Substances 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 230000003628 erosive effect Effects 0.000 description 2
- 238000006266 etherification reaction Methods 0.000 description 2
- 230000008020 evaporation Effects 0.000 description 2
- 239000000945 filler Substances 0.000 description 2
- CGIGDMFJXJATDK-UHFFFAOYSA-N indomethacin Chemical compound CC1=C(CC(O)=O)C2=CC(OC)=CC=C2N1C(=O)C1=CC=C(Cl)C=C1 CGIGDMFJXJATDK-UHFFFAOYSA-N 0.000 description 2
- 239000011872 intimate mixture Substances 0.000 description 2
- 231100000225 lethality Toxicity 0.000 description 2
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Chemical compound C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 2
- SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 description 2
- LQNUZADURLCDLV-UHFFFAOYSA-N nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC=C1 LQNUZADURLCDLV-UHFFFAOYSA-N 0.000 description 2
- 230000003287 optical effect Effects 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 229910000033 sodium borohydride Inorganic materials 0.000 description 2
- 239000012279 sodium borohydride Substances 0.000 description 2
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 2
- 210000001541 thymus gland Anatomy 0.000 description 2
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 description 1
- QNRATNLHPGXHMA-XZHTYLCXSA-N (r)-(6-ethoxyquinolin-4-yl)-[(2s,4s,5r)-5-ethyl-1-azabicyclo[2.2.2]octan-2-yl]methanol;hydrochloride Chemical compound Cl.C([C@H]([C@H](C1)CC)C2)CN1[C@@H]2[C@H](O)C1=CC=NC2=CC=C(OCC)C=C21 QNRATNLHPGXHMA-XZHTYLCXSA-N 0.000 description 1
- RLQZIECDMISZHS-UHFFFAOYSA-N 2-phenylcyclohexa-2,5-diene-1,4-dione Chemical compound O=C1C=CC(=O)C(C=2C=CC=CC=2)=C1 RLQZIECDMISZHS-UHFFFAOYSA-N 0.000 description 1
- RKIDDEGICSMIJA-UHFFFAOYSA-N 4-chlorobenzoyl chloride Chemical compound ClC(=O)C1=CC=C(Cl)C=C1 RKIDDEGICSMIJA-UHFFFAOYSA-N 0.000 description 1
- 101100277337 Arabidopsis thaliana DDM1 gene Proteins 0.000 description 1
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- 108700018454 CDC15 Proteins 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 229920000742 Cotton Polymers 0.000 description 1
- 239000004150 EU approved colour Substances 0.000 description 1
- 241000283086 Equidae Species 0.000 description 1
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- 238000005863 Friedel-Crafts acylation reaction Methods 0.000 description 1
- 206010018691 Granuloma Diseases 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- CMWTZPSULFXXJA-UHFFFAOYSA-N Naproxen Natural products C1=C(C(C)C(O)=O)C=CC2=CC(OC)=CC=C21 CMWTZPSULFXXJA-UHFFFAOYSA-N 0.000 description 1
- 206010030113 Oedema Diseases 0.000 description 1
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 1
- 208000025747 Rheumatic disease Diseases 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 241000906446 Theraps Species 0.000 description 1
- FVPFPFJKIYJTJC-UHFFFAOYSA-N [1-methyl-5-[2-(2-methyl-1,3-dioxolan-2-yl)ethyl]pyrrol-2-yl]-(4-methylphenyl)methanone Chemical compound C1=CC(C)=CC=C1C(=O)C(N1C)=CC=C1CCC1(C)OCCO1 FVPFPFJKIYJTJC-UHFFFAOYSA-N 0.000 description 1
- OUUOKVNTSZPFDX-UHFFFAOYSA-N [5-(3-hydroxybutyl)-1-methylpyrrol-2-yl]-(4-methylphenyl)methanone Chemical compound CN1C(CCC(O)C)=CC=C1C(=O)C1=CC=C(C)C=C1 OUUOKVNTSZPFDX-UHFFFAOYSA-N 0.000 description 1
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 1
- 239000012346 acetyl chloride Substances 0.000 description 1
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- 239000004480 active ingredient Substances 0.000 description 1
- 150000001266 acyl halides Chemical class 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
- 239000000010 aprotic solvent Substances 0.000 description 1
- 239000011260 aqueous acid Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 150000008365 aromatic ketones Chemical class 0.000 description 1
- 230000002917 arthritic effect Effects 0.000 description 1
- 150000001540 azides Chemical class 0.000 description 1
- RWCCWEUUXYIKHB-UHFFFAOYSA-N benzophenone Chemical compound C=1C=CC=CC=1C(=O)C1=CC=CC=C1 RWCCWEUUXYIKHB-UHFFFAOYSA-N 0.000 description 1
- 239000012965 benzophenone Substances 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 235000010418 carrageenan Nutrition 0.000 description 1
- 229920001525 carrageenan Polymers 0.000 description 1
- 101150081467 cdc15 gene Proteins 0.000 description 1
- 101150113676 chr1 gene Proteins 0.000 description 1
- 239000000356 contaminant Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 125000005594 diketone group Chemical group 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
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- 239000000706 filtrate Substances 0.000 description 1
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- 239000000796 flavoring agent Substances 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 150000004678 hydrides Chemical class 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 229960000905 indomethacin Drugs 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 239000002085 irritant Substances 0.000 description 1
- 231100000021 irritant Toxicity 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- DKYWVDODHFEZIM-UHFFFAOYSA-N ketoprofen Chemical group OC(=O)C(C)C1=CC=CC(C(=O)C=2C=CC=CC=2)=C1 DKYWVDODHFEZIM-UHFFFAOYSA-N 0.000 description 1
- 229960000991 ketoprofen Drugs 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 239000011968 lewis acid catalyst Substances 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 229960002009 naproxen Drugs 0.000 description 1
- CMWTZPSULFXXJA-VIFPVBQESA-N naproxen Chemical compound C1=C([C@H](C)C(O)=O)C=CC2=CC(OC)=CC=C21 CMWTZPSULFXXJA-VIFPVBQESA-N 0.000 description 1
- 229940006093 opthalmologic coloring agent diagnostic Drugs 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 125000001037 p-tolyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 230000000552 rheumatic effect Effects 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229940080313 sodium starch Drugs 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 238000011287 therapeutic dose Methods 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 235000019786 weight gain Nutrition 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D207/32—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D207/33—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms with substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D207/333—Radicals substituted by oxygen or sulfur atoms
-
- 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]
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Pain & Pain Management (AREA)
- Rheumatology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Pyrrole Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
The compounds of the formula: and pro-drugs therefor wherin R1 is a hydrogen atom or a methyl group; Ar is a phenyl group or is a phenyl group substituted by one or two moieties selected from fluorine, chlorine, bromine, methyl, methoxyl or trifluoromethyl or is a thienyl group; and X is a CO or CHOH group have antiinflammatory activity.
Description
The present invention relates to pyrrole derivatives, to ; ί a process for their preparation and to compositions containing I them.
Tolmetin, a clihically used anti-inflammatory and analgesic 5 agent of the formula (I): (I) has been reported in J. Pharmacol. Exptl. Therap. 1973, 185. 127-138 to possess anti-inflammatory activity. Tolmetin and related compounds have also been described in British Patent Specification No: 1195628. It has been found that tolmetin causes gastric irritancy in test animals at doses not greatly exceeding the therapeutic dose. A group of anti-inflammatory and analgesic compounds has now been found which have reduced propensity to cause gastric irritancy. These compounds may be thus used in pharmaceutical compositions for the treatment of 1-$ * inflammatory or painful conditions such as rheumatism, arthritis or the like.
The present invention provides the compounds of the formula (II): Ar-CO CHtLjCHg-X-CH^ (II) ch3 - 2 46825 Wherein R^ is a hydrogen atom or methyl group; Ar is a phenyl group or a phenyl group substituted by one or two groups selected from fluorine, chlorine, bromine, methyl, methoxyl or trifluoromethyl or is a thienyl group; X is a CO or CHOH group; and pro-drugs thereof.
Suitably Ar is a phenyl or substituted phenyl group.
More suitably Ar is a phenyl or mono-substituted phenyl group.
Particularly apt groups Ar include the phenyl, methylphenyl, fluoromethyl chlorophenyl dichlorophenyl and the methoxyphenyl group.
A favoured group Ar is the phenyl group. A further favoured group Ar is the 4-methylphenyl. Another favoured group Ar is the 4-chlorophenyl group. Yet a further favoured group Ar is the 4-fluorophenyl group. Yet another favoured group Ar is the 4-methoxyphenyl group.
Other suitable values for Ar include di-halogenated phenyl such as di-chlorophenyl, for example 2,4-dichlorophenyl.
Suitably Ar is a thienyl group. A favoured group Ar is the 2-thienyl group. A further favoured group Ar is the 3-thienyl group.
Suitably R^ in the preceeding compounds represents a hydrogen atom.
Suitably R^ in the preceeding compounds represents a methyl group.
Suitably X in the preceeding compounds is a CO group.
Suitably X in the preceeding compounds is a CHOH group. - 5 4G82S When used herein the term 'pro-drug' means a compound metabolised in-vivo to or via a compound of the formula (II).
The pro-drugs will be compounds containing deriva5 tives of the group X, for example those wherein the CHR^CHg-X-CH^ side chain hereinafter referred to as 'Q' is the .subrformulae (a) - (d): R1 (a) V. (b) (c) (d) wherein R^ is a hydrogen atom or a methyl group; Rg is a group CO.Rg wherein Rg is the residue of a pharmaceutically acceptable carboxylic acid of up to 9 carbon atoms of the formula RgCOOH; Rg is a C1-4 alkyl group or a CO.Rg group; R4 is a methyl, ethyl or propyl group and R^ is a methyl, ethyl or propyl group or Rg is joined to R^ so that they together represent a CHgCHg or CHgCHgCHg group. -446 825 A favoured side chain Q in the preceeding compounds is the Ci^.CI^.CO.CH^ group.
Another favoured side chain Q in the preceeding compounds is the ΟΗ^ΟΗ,,.ΟΗΟΗ.ΟΗ^ group.
Further favoured gide chains Q are those of the formula CH2.CH2.CH(0.C0.Rg)CH^ wherein Rg is as defined in relation to sub-formula (a).
Apt values forRg include phenyl, alkyl of 1-4 carbon atoms, and alkyl of 1-4 carbon atoms substituted by phenyl, or one of the aforementioned groups substituted by a hydroxyl, acetoxyl, methoxyl, acetamido, optionally salted amino or alkylamino or optionally salted carboxyl group.
Favoured values for r g include the methyl, ethyl, n-propyl, iso-propyl, t-butyl, phenyl, benzyl, phenylethyl, acetoxymethyl, methoxymethyl, hydroxymethyl optionally salted aminoethyl, α-acetoxyphenyl, 4-methoxyphenyl, 3,4-dimethoxyphenyl and 3,4, 5-trimethoxyphenyl groups.
Particularly suitable values for R g include the methyl, ethyl, benzyl, 2-methoxyphenyl, phenyl and 3,4,5-trimethoxyphenyl group.
A preferred group Rg is the methyl group.
From the foregoing it will be realised a further favoured 2- position side chain is the CHg.CI^.CHiO.CO.CH^CH^ group.
One group of favoured side chains Q is that of the formula CH2CH2X1CH3 where X1 is a CO, CHOH or CHOCOR? group where R? is an alkyl group of 1-4 carbon atoms. Most suitably Ry is a methyl group. - 5 46825 These compounds of the formula (II) wherein R1 is a methyl group may he in the form of an isolated optical isomer or may be presented as a mixture of isomers, for example the R, S ox* RS form.
These compounds of the formula (II) wherein X is a CHOH or CHORg group may be in the form of an isolated optical isomer or may be presented as a mixture of isomers, for example as the R, S or RS form.
Certain particularly effective compounds of this invention 10 include those of the formula (IV): CH.
(IV) wherein R^ is a hydrogen atom or methyl group and X is a CO, CHOH ., or CH.OCOCH^ group. ·. - In the compounds of formula (IV) Rq is suitably a hydrogen atom. In the compounds of the formula (IV) R^ is suitably a methyl group.
In the compounds of the formula (IV) X is suitably a CO group. In the compounds of the formula (IV) X is suitably a CHOH group. In the compounds of the formula (IV) X is suitably a CHOCOCH^ group. - 6 46825 Certain other particularly effective invention include those of the formula (V) compounds of this CH5 wherein R^ is a hydrogen atom or a methyl group and X is a CO, CHOH or CH.O.CO.CH^ group, In the compounds of the formula (V) R^ is suitably a hydrogen atom. In the compounds of the formula (V) R^ is suitably a methyl group.
Suitably in the compounds of the formula (V) X is a CO group. Suitably in the compounds of the formula (V) X is a CHOH group. Suitably in the compounds of the formula (V) X is a CHOCOCH^ group.
Certain further particularly effective compounds of this invention include those of the formula (VI): wherein R^ is a hydrogen atom or a methyl group and X is a CO, CHOH or CHOCOCH^ group.
In the compounds of the formula (VI) R^ is suitably a hydrogen atom. In the compounds of the formula (VI) is suitably a methyl group.
' In the compounds of the formula (VI) X is suitably a t CO group. In the compounds of the formula (VI) X is suitably a CHOH group. In the compounds of the formula (VI), X is suitably a CHOCOCH^ group.
Particularly suitable compounds of this invention include: 4-(1 -m ethyl-5-p-toluoyl-2-pyrryl)butan-2-one; 2-a cetoxy-4- (1 -methyl-5-p-toluoyl (-2- pyrpyl) butane; 4-(1-methyl- 5-p-chlorobenzoyl-2-pyrryl)butan-2-one; 4-(1-methyl- 5-p-chlorobenzoyl-2-pyrxyl)butan-2-ol; 2-a.cetoxy-4-(i-m ethyl- 5-p-chlorobenzoyl-2-pyrryl)butane; 4-(1-methyl-5-thien-2 ’-oyl-2-pyrryl)butan-2-one; 4-(1 -methyl-5-thien-2*-oyl-2-pyrryl)butan-2-ol; 2-a,cetoxy-4-(1-m ethyl-5-thien-2 ’-oyl-2-pyrryl)- butane. 4-(1-methyl-5-p-toluoyl-2-pyrryl)butan-2-ol. '7 - 8 46825 In a further aspect this invention provides a pharmaceutical composition which comprises a compound of the formula (II) and a pharmaceutically acceptable carrier.
The compositions of this invention are useful in treating rheumatic and arthritic conditions because of their anti-inflammatory and analgesic properties. The compositions may be adapted for administration via the oral, rectal or injection routes but since the compositions of this invention do not excessively irritate the gastro-intestinal tract it is preferred that they are adapted for oral administration.
The compositions of this invention may contain diluents, binders, fillers, disintegrants, flavouring agents, colouring agents, lubricants or preservatives in conventional manner. These conventional excipients may be employed in conventional manner, for example as in the preparation of compositions of ketoprofen, indomethacin, naproxen, acetylsalicylic acid or other anti-inflammatory analgesic agent.
Most suitably the composition of this invention will be in the form of a unit dose such as a tablet, capsule or reconstitutable powder in a sachet. Such unit doses will generally contain from 20mg to lOQmg and more suitably will contain from about 30mg to 500mg for example 50mg to 250mg of active agent, for example about 50, 100, 150, 200, 250, 300, 350, 400, 450 or 500mg. These compositions may be administered once or more times a day , for example 2, 3 or 4 times daily, so that the total - 9 46825 daily dose for a 7OKg adult will usually be in the range 200 ' to 400mg and more usually in the range 300 to 3000mg for example 500 to 2000mg. Alternatively the unit dose may contain from 2-20mg of active agent and may be administered in multiples if desired to give the preceeding daily dose.
A favoured form of the composition of this invention is a hard gelatin capsule containing the active agent. The active agent may be in the form of a powder, pr granulate and may advantageously be in intimate mixture with a lubricant 10 such as magnesium stearate.
A further favoured form of the composition of this invention is a tablet containing the active agent. The active agent may be in the form of a recompressed granulate-of the active ingredient in intimate mixture with a lubricant such as magnesium staarate,a filler such as microcrystalline cellulose and a disintegrant such as sodium starch glycollate.
The present invention also provides a method of treating inf lanmatcmy and/or painful conditions in non-human mammals which comprises administering per day from 200 to 4000mg of a compound of this invention and more usually from 300 to 3000mg for example from 500 to 2000mg of a compound of this invention.
Non-human manmals which may be thus treated include domestic animals such as dogs, cats or horses. - 10 4 6 8 2 5 Most suitably the medicament will be administered orally as 2, 3, or 4 doses per day at the dose level previously indicated.
Often the condition treated will be arthritis.
The present invention provides a process for the preparation of a compound of the formula (il) or a pro-drug thereof which process comprises the reaction of a compound of the formula (VII): Ar.CO.Cl (VII) cr an equivalent agent- for the acylation of nucleophilic aromatic nuclei wherein Ar is as defined in relation to formula (II), with a cotpound of the formula (IX): ch3 wherein Q;is a group of the sub-formulae (a) - (d) as hereinbefore 15 defined or a group of the sub-formula (e): -CHR1-CH2-CO-CH3 (e) wherein R^ is a hydrogen atom or a methyl group; and thereafter if desired reducing the carbonyl present in a group of the subformula (e) to a CHOH group.
The present invention also provides a process for the preparation of the compounds of the formula (II) which process comprises the reaction of.a compound of the formula (VII): Ar.CO.Cl (VII) or an equivalent agent far the acylation of nucleophilic aranatic nuclei wherein Ar is as defined in relation to formula (II), with a canpound of the formula (X): CHR1 - CH2 - CO - CH^ (X) wherein is as defined in relation to formula (II) arid thereafter if desired reducing the carbonyl group X to a CHOH group X and/or thereafter converting the CO or CHOH group X to a pro-drug thereof.
The present invention also provides a process for the preparation of the pro-drugs of the compounds of the formula (II) which process comprises the reaction of a compound of the . formula (VII) as hereinbefore defined or an equivalent agent for the acylation of nucleophilic aromatic nuclei with a compound of the formula (XI): (XI) CH, ί wherein Q is a group of the sub-formulae (a) - (d) as hereinbefore defined. - 12 46825 Suitable equivalents of the compounds of the formula (VII) for acylation include the corresponding bromide and anhydride for example the corresponding azide or mixed anhydride.
The reaction of the compounds of the formulae (VII) and 5 (IX), (X) or (XI) takes place in an inert solvent or under conventional Friedel-Crafts acylation conditions, for example in an inert solvent and optionally in the presence of a Lewis acid such as aluminium chloride.
The acylation reaction is normally carried out at a non10 extreme temperature for example from 5°c to 5o°c and more usually from 1O°C to 3O°C if a Lewis acid is used. If no catalyst is used the acylation reaction is normally carried out at a higher temperature than 5O°C e.g. 1OO°C.
Suitable solvents for carrying out the acylation include tetrachloroethylene, chloroform, dichloromethane, dichloroethane, chlorobenzene or benzene, toluene or nitrobenzene.
The solvent system used for the process of this invention will be homogenous and will advantageously comprise an inert component and a tertiary amine. In general the inert component 2o will predominate, for example it will comprise 60%-90% v/v of the total system and more usually from 80% to 92% v/v. Toluene and tetrachloroethylene are favoured inert solvents. Suitable tertiary amines include conventional weak tertiary amines such as pyridine, When the solvent system employed, contains a tertiary amine it is frequently advantageous not to employ a Lewis acid catalyst as acceptable yields are obtained in the absence of said catalyst. This form of the reaction may be performed at a low, ambient or elevated temperature but in general it is preferred to use a somewhat elevated temperature to ensure that the reaction is over in a reasonably short period. Thus, for example, a temperature of 40-140°C is generally suitable, for example 80-120°C.
The product produced by acylation in the presence of a Lewis acid may be isolated in conventional manner, for example I by diluting with an aqueous acid, extracting into an organic I solvent, washing and drying the organic phase and thereafter evaporating the solvent? The resulting ketone may then be purified by chromatography and/or recrystallisation.
The product produced by acylation in the absence of a Lewis acid may often be obtained simply by the evaporation of the solvents. If the resulting product is required in a purer form it - may normally be further purified by chromatography in conventional manner.
The diketones of the formula (II) may be converted to the corresponding compounds wherein X is a CHOH hy careful reduction with a complex hydride such as sodium borohydride. The resulting compound may be separated by conventional methods of column chromatography from any contaminant resulting from reduction of the aromatic ketone. - 14 4 6 8 2 5 The compounds wherein X is a CHOH group may be acylated in conventional manner, for example, by reaction with the acid R2C0,H in the presence of a condensation promoting agent such as dieyclohexylcarbodiimide in an aprotic solvent such as dichloromethane or tetrahydrofuran or by reaction with an acyl halide in the presence of an acid acceptor such as pyridine.
The conventional pro-drugs of the compounds of the formula (II) may be prepared from the compounds of the formula (II) In conventional manner.
Thus, for example, those compounds containing a side chain Q of the sub-formula (a) may be prepared by the acylation of a corresponding compound containing a side chain of the sub-formula Suitable methods of acylation include those described in 15 Belgian Patent No: 854429.
Also for example, those compounds containing a side chain q of the sub-formulae (b), (c) or (d) may be prepared by the enol acylation or enol etherification of a corresponding compound containing a side chain of the sub-formula (f): R Suitable methods of enol acylation or enol etherification include those described in West German Application P2647966.3. - 15 46825 Description 1 4-(1-Methyl-2-pyrryl )-butan-2-one I A mixture of 4-;(1-Methyl-2-pyrryl)-but-3-en-2-one (2.98g) and 10% palladium on charcoal (0.2g) was hydrogenated in ethyl acetate (50ml) at room temperature and. atmospheric pressure.
The catalyst was removed by filtration the solvent evaporated, and the resulting oil left overnight to solidify in a refrigerator.
The long, colourless needles which formed were washed with cold 60-80° petrol to give 4-(1-Methyl-2-pyrryl)-butan-2-one (2.46g). - 16 46825 Example 1 4-(1-Methyl-5-P~toluovl-2-pyrryl)butan-2-one To a solution of 4-(1-Methyl-2-pyrryl)-butan-2-one (2.46g) in 5 dichloroethane (10ml) at room temperature was added over 40 minutes a solution of dichloroethane (10ml) containing aluminium chloride (2.17g: 0.016 mole) and p-toluoyl chloride (2.52gi0.0l6 mole). After a further 20 minutes the mixture was treated with dilute hydrochloric acid (5N, 10ml) and extracted with dichloro10 methane (50ml). The organic layer was washed with water (20ml), aqueous unsymmetrical-dimethylethylenediamine (20% 20ml), dilute hydrochloric acid (5N, 10ml) and extracted with dichloromethane (50ml). The organic layer was washed with water (20ml), aqueous unsymmetrical-dimethylethylenediamine (20% 20ml), dilute hydrochloric acid (1N.20ml) and finally brine (20ml). After drying (NagSO^) the mixture was concentrated to give a dark oil which was then chromatographed on alumina (150g) using benzene as eluant. Recrystallisation of the solid fraction from 60-80° petrol gave pure 4-(1-methyl-5-p-toluoyl-2-pyrryl)20 butan-2-one, m.p. 103-4°.
N.m.r. (CDClj) $= 7.65 (2H, d, £ = 8Hz), 7.17 (2H, d, £ = 8Hz), 6.6 (1H, d, J = 4Hz), 5.87 (1H, d, J = 4Hz), 3.92 (3H, s), 3.0 2.7 (4H, m), 2.38 (3H, s), 2.17 (3H, s). - 17 4 6825 Example 2 ϊ 4-(1-Metfayl-5-P-toluoyl-2-pyrryl)butan-2-one 4-(1-Methyl-2-pyrryl)-butan-2-one (15g) and. p-toloyl chloride (37.5 ml) were dissolved in toluene (200ml) and pyridine (30ml). The mixture was heated under reflux for 7 hours. The resulting mixture was filtered and the filtrate evaporated ( 50°C 15mm/Hg) to leave an oil. The oil was extracted into hot 60-80°C petrol (4 x 250ml) and the solution cooled (-30°C)causing a solid to precipitate. This solid was purified hy column chromatography (detection by t.l.c. using u.v.) to yield after evaporation of the solvent the desired 4-(1-methyl-5-p-toluoyl~2-pyrryl)-butan10 2-one (40% yield) as a white solid, m.p. 1O3-1O4°C.
N.m.r. - as described in Example 1.
(The chromatographic system employed 300g silica eluting with / ethyl acetate/60-80°petrol mixtures. The initial eluting solvent contained 10% ethyl acetate and brought through the benzophenone impurity. Increasing the concentration of the ethyl acetate to 20% then brought through the desired product). - 18 46825 Example 5 4-(1-Methyl-5-p-chlorobenzoyl-2-pyrryl)butan-2-one CHz CH, The title compound was prepared by the process as described in Example 2 except that p-chlorobenzoyl chloride was used as acylating agent and tetrachloroethylene as solvent. The crude product was purified by passage through alumina using methylene chloride as solvent, followed by recrystallisation from carbon tetrachloride to give pure 4-(1-methyl~5-p-chlorobenzoyl-2-pyrryl) butan-2-one as colourless needles, m.p. 108-109 C.
N.m.r. (CDC15) S= 7.7 (2H, d, J=9Hz), 7.35 (2H, d, J=9Hz), 6.53 (1H, d, J=4Hz), 5.85 (1H, d, J=4Hz), 5.93 (3H, s), 3.0-2.7 (4H, m), 2.15 (3H, s). - 19 46825 Example 4 4-(1-Methyl-5-thien-2 i-oyl-2-pyrryl)butan-2-one ch2ch2coch3 CH, •Nf CH, :h2ch2coch.
The title compound was prepared by the process described in Example 3 except that thien-2-oyl chloride was used as acylating agent. Recrystallisation from diethyl ether gave pure 4-(1methyl-5-thien-2,-oyl-2-pyri,yl)butan-2-one as rhombic crystals, m.p. 78-79°C.
N.m.r. (CDC13) S= 8.1-6.9 (4H, m), 6.92 (1H, d, J = 4Hz), 3.87 (3H, s), 3.0-2.7 (4H, m), 2.19 (3H, s). - 20 46825 Example 5 4-(1-Me thvJ.-5-p-toluoyl-2-pyrryl)butan-2-ol A mixture of 4-(1-methyl-5-p-toluoyl-2-pyrryl)-butan-2-one (2.35g), sodium borohydride (0.4g) and ethanol (350ml) was stirred for 1 hour at room temperature before being treated with a saturated, aqueous solution of ammonium chloride (20ml). This mixture was concentrated and then partitioned between water (50ml) and methylene chloride (100ml). The aqueous layer was extracted with methylene chloride (3 x 50 ml) and the combined organic layers were then washed with water (50ml), dried (Na2S0^) and concentrated to afford somewhat crude 4-(1-methyl-5-p-toluoyl-210 pyrryl)butan-2-ol as a pale purple oil (2.06g). ^6 8 25 Example 6 2-Acetoxy-4-(1-in3thyl-5-P-toluoyl-2-pyrryl )butane The product of Example 5 was taken up in toluene (100ml) containing pyridine (4ml), treated dropwise at 5°C with acetyl chloride (2ml) and then stirred at room temperature for 1 hour. The resulting mixture was added to cold water (100ml) and extracted with diethyl ether (3 x 100ml). The combined organic layers· were washed with 1N HCl (50ml)and water (2x50ml)and dried (NagSO^) and concentrated to give a pale purple oil which slowly solidified on standing. Recrystallisation of this · solid from diethyl ether gave pure 2-acetoxy-4-(l-methyl-5-p10 toluoyl-2-pyrryl)butane as colourless needles, m.p. 88-89°.
N.m.r. (CDClj) S= 7.65 (2H, d, J = 8Hz), 7.2 (2H, d, J = 8Hz), _ 6.64 (1H, d, J = 4Hz), 5.94 (1H, d, J=4Hz), 4.97 (1H, q, J=6Hz), 3.91 (3H, s), 2.9-1.7 (4H, m), 2.34 (3H, s), 2.03 (3H, s), 1.27 (3H, d, J= 6Hz). - 22 46825 Example γ 2-Methyl-2-[2-(1-methyl-5-P-toluoyl-2-pyrryl)ethyl]-1,g-dioxolane A mixture of 4-(1-Methyl-5-p-toluoyl-2-pyrryl)butan-2-one (1.0g), ethylene glycol (6ml), p-toluene-sulphonic acid (40mg) and benzene (100ml) was refluxed for 5 hours with constant separation of HgO by means of a Dean-Stark trap. The mixture was cooled to room temperature, basified with 1N sodium bicarbonate solution (20ml) and extracted with chloroform (3 x 50ml). The organic layer was washed with H20 (2 x 50ml), dried (NagSO^) and concentrated to give a purple oil. This was chromatographed on alumina using ether as eluant to give pure 2-methyl-2-[2-(1methyl-5-p-toluoyl-2-pyrryl)ethyl]1,3-dioxolane as a colourless oil.
N.m.r. x(CDC13), d= 7.69 (2H, d, J = 8Hz), 7.20 (2H, d, J=8Hz), 6.64 (1H. d, J=4Hz), 5.95 (1H, d,z J= 4Hz), 3.99 (4H, s), 3.95 (3H, s), 3.ΟΙ.8 (4H, m), 2.40 (3H, s), 1.39 (3H, s). - 23 4 6825 Example 8 Compositions (a) Tablets of the following composition may be prepared: 4-(1-Methyl-5-p-toluoyl2-pyrryl)butan-2-one 25 mg Microcrystalline cellulose 123 mg 5 Magnesium Stearate 2 mg (b) Hard gelatin capsules may be prepared containing the following: 4-(1-Methyl-5-p-toluoyl2-pyrryl)butan-2-one 50 mg 10 Lactose 75 mg Sodium lauryl sulphate 5 mg - 24 46825 Example 9 Compositions (a) Tablets of the following composition may be prepared: 4-(1-Methyl-5-p-chlorobenzoyl2-pyrryl)butan-2-one 25 mg Microcrystalline cellulose 123 mg Magnesium Stearate 2 mg (b) Hard gelatin capsules may be prepared containing the following: 4-(1-Methyl-5-thien-2’-oyl2-pyrryl)butan-2-one 50 mg Lactose 75 mg Sodium lauryl sulphate 5 mg (c) Hard gelatin capsules may bs prepared containing the following: 4-(1-Methyl-5-p-chlorobenzoyl2-pyrryl)butan-2-one 100 mg Lactose 25 mg Sodium lauryl sulphate 5 mg - 25 4 6 8 2 5' Demonstration 1 a. When tested on a conventional phenylquinone induced writhing test for analgesic activity, the compound of Example 1 and tolmetin produced the following values when administered orally to mice: COMPOUND ED5o (mg/kg) Test A_Test B Comp. Example 1 6.7 5.3 Tolmetin 4.3 2.3 These results indicate that the compound of Example 1 is about half as potent as tolmetin as an analgesic agent. b. . Groups of 10 rats were starved overnight and then dosed orally with the test compound suspended in 0.7% methylcellulose.
After a 4 hour contact time the animals were killed and the stomachs removed, inflated with 0.9% saline, cut open ? after 30 minutes and examined for erosions. The following results, expressed as the number of animals in each group showing damage, were obtained: Dose (mg/kg) No. of Animals Showing Erosions Tolmetin . 90 30 10 10 6 2 Compound of Example 1 270 1 90 1 30 0 - 26 - This test indicates that tolmetin is probably at least 10 times as gastric irritant as the compound of Example 1. c. When tested on a conventional carrageenin induced oedema test for anti-inflamnatcry activity, the compound of Example 1 was classed as active at 10mg/kg per oral in rats (as compared to about 5mg/kg for tolmetin). d. No drug-induced lethalities have been observed with the compound of Example 1 during testing in rats at dosages up to 100mg/kg per day for 6 days. The compound did not reduce body weight increase at this dose nor did it increase thymus weight. - 27 4 68 2 6 Demonstration 2 When tested on a conventional cotton pellet induced granuloma test the results shown hereafter were obtained. In these tests hydrocortisone (HC) was used as a positive control .
Compound Dose Inhibition a. Comp. Example 3 HC 10mg/kg 1Omg/kg 42% 43% b. Comp. Example 4 HC 10mg/kg 10mg/kg 24% 43% c. Comp, Example 6 HC 50mg/kg 10mg/kg 34% 43% d. Comp. Example 7 HC 50mg/kg 10mg/kg 43% 43% The compounds of Examples 3. 4, 6 and 7 were not found to exhibit any overt toxic effects during testing, for example no drug-induced lethalities were observed, no reduction in body weight gain was observed and no change in thymus weight was observed.
Claims (13)
1. CLAIMS :1. A compound of the formula (II): CH, wherein is a hydrogen atom or a methyl group; Ar is a phenyl 5 group or is a phenyl group substituted by one or two groups selected from fluorine, chlorine, bromine, methyl, methoxyl or trifluoromethyl or is a thienyl group; and X is a CO or CHOH group; or a pro-drug therefore.
2. A compound as claimed in claim 1 wherein R^ and X are as 10 defined in claim 1 and Ar is a phenyl or substituted phenyl group.
3. A compound as claimed in claim 1 or 2 wherein Ar is a phenyl or mono-substituted phenyl group.
4. A compound as claimed in claims 1 or 2 wherein Ar is a phenyl, methylphenyl, fluorophenyl, chlorophenyl, methoxy15 phenyl or a dichlorophenyl group.
5. A compound as claimed in claim 1 or 2 wherein Ar is a dichlorophenyl group.
6. A compound as claimed in claim 1 wherein Ar is a thienyl group. 20
7. A compound as claimed in any of claims 1-4 wherein Ar is a phenyl group. - 29
8. A compound as claimed in claim 1 wherein Ar is a methylphenyl group.
9. A compound as claimed in claim 1 wherein Ar is a methoxyphenyl group. 5 1Q A compound as claimed in claim 1 wherein Ar is a chlorophenyl group. 11 . A compound as claimed in claim 1 wherein Ar is a fluorophenyl group. 12 . A compound as claimed in claim 6 wherein Ar is a 2-thienyl
10. Group . 13· A compound as claimed in claim 6 wherein Ar is a 3-thienyl group.
11. 14 . A compound as claimed in claim 8 wherein Ar is a 4-methylphenyl group. 15 15 . A compound, as claimed in claim 9 wherein Ar is a 4-methoxyphenyl group. 16 . A compound as claimed in claim 10 wherein Ar is a 4-chlorophenyl group. 17 . A compound as claimed in claim 11 wherein Ar is a 20 4-fluorophenyl group. - 30 46825 18. A compound as claimed in any of claims 1-17 wherein R^ is a hydrogen atom. 19. A compound as claimed in any of claims 1-17 wherein is a methyl group. 5 20. A compound as claimed in any of claims 1-17 wherein X is a CO group. 21. A compound as claimed in any of claims 1-19 wherein X is a CHOH group. 22. A compound as claimed in any of claims 1-17 wherein 10 the CHR^-CH^-X-CH^ side chain is a group of the sub-formulae (a)-(d): wherein R 1 is a hydrogen atom or a methyl group; R 2 is a - 31 46825 group GO.Rg wherein Rg is th·.- residue of a pharmaceutically acceptable carboxylic acid of up to 9 carbon atoms of the formula RgCOOlI; R- is a C 1 _ Zj alkyl group or a CO.Rg group; R^ ic a methyl, ethyl or propyl group and R Z| is a methyl, 5 ethyl or propyl group or Rg is joined to R, ( so that ’they together represent a CH^CHg or CHgCHgCHg group. 2p. A compound as claimed in any of claims 1- 19 wherein the 2-position side chain is a CHg.CHp.CO.CIL· group. • 24. A compound as claimed in any of claims 1-19 wherein the l 0 2-position side chain is a CI^.CHg.CHOH.CHg group. 25. A compound as claimed in any of claims 1-19 wherein the 2-position side chain ic a CH.,.CHj.Cn(O.CO.Rg)CH 3 group wherein Rg is as defined in claim 21. 26. A compound is claimed in claims 22 or 25 wherein Rg is
12. 15 a phenyl group , an alkyl group of 1-4 carbon atoms, an alkyl group of 1-4 carbon atoms substituted by a phenyl group, or one of the aforementioned groups substituted by a hydroxyl, acetoxyl, rnethoxyl, acetamido, optionally salted amino or alkylamino or optionally salted carboxyl group.
13. 20 27. A compound as claimed in claims 22 or 25 wherein Rg ic a methyl, ethyl, n-propyl, iso-propyl, t-butyl, phenyl, benzyl, phenylethyl, acetoxymethyl, methoxymethyl, hydroxymethyl optionally salted aminoethyl, α-acetoxyphenyl, 4-methoxyphenyl, 3,4-dimethoxyphenyl or 3)4,5-trimethoxyphenyl group. - 32 46825 28. A compound as claimed ;n claims 22 or --5 wherein is a methyj, ethyl, benzyl, 2-methoxyphenyl, phenyl or 3,4,5-trime thoxypheny l, gj oup. 29. A compound as claimed in claims 22 or 2 5 wherein Rg is 5 a methyl group. 30. A compound as claimed in any of claims 1-19 wherein the 2-position side chain is a CH 0 .CHp.CH(O.CO.CH 3 ).CH- group. 31. A compound as claimed in any of claims 1-19 wherein the 2-position side chain is a CH^CHg.X CIU group wherein X' is a 10 CO, CHOH or CHOCOR? group R? is an alkyl group of 1-4 carbon atoms. 32. A compound as claimed in claim 1 of the formula (IV): (IV) wherein Rj is a hydrogen atom or methyl group and X is a CO, 15 CHOH or CH.OCOCH^ group. 33. A compound as claimed in claim 32 wherein is a hydrogen a tom. - 33 46828 34. A compound as claimed in claim 33 wherein R^ is a methyl group. 35. A compound, as claimed in claims 32-34 wherein X is a CO group. '26. A compound as claimed in claims 32-34 wherein X is a CHOH group. 37. A compound as claimed in claims 32-34 wherein X is a CH.OCOCH^ group. 38. A compound as claimed in claim 1 of the formula (V): Cl CO wherein R^ is a hydrogen atom or a methyl group and X is a CO, CHOH or CH.O.CO.CHj group. 39. A compound as claimed in claim 38 wherein R^ is a hydrogen atom. 40. A compound as claimed in claim 38 wherein is a methyl group. 4682S 41. Λ compound as c1uirncd any oi c1 aims 38-40 wherein X ic a CO group). 42. A compound as claimed in any of cluj ms 38-40 wherein X is a CHOH group. 43. A compound as claimed in any of claims 38-40 wherein X is a CHOCOSH, group. 44. A compound as claimed in claim 1 of the formula (VI): wherein R^ is a hydrogen atom or a methyl group and X is a 10 CO, CHOH or CHOCOCH- group. 45. A compound as claimed in claim 44 wherein R 1 is a hydrogen atom. 46. A compound as claimed in claim 44 wherein R^ is a methyl group 47. A compound as claimed in any of claims 44-46 wherein X 15 is a CO group;. 48. A compound as claimed in any of claims 44-46 wherein X is a CHOH group. - 35 46825 49. Λ compound as claimed m any of cJaims 44-46 whoroin X a CHOCOCH-j group. . 50. 4-(1-Met.hyl-5-p- fcoluoyl-2-pyrryl) butan-2-one. 51. ' 4-(1-Methyl-5-p-toluoyl-2-pryyrl)butan-2-ol. 5 52. 2-Acetoxy-4-,(1-B.ethyl-5-p-toluoyl-2-pyrryl)butane I 5 3. 4-(1 -Methyl-5-p- chlorcbenzcyl -2-pyrryl )butan-2-one. 54. 4-(1-Methyl-5-p- chlorcbenzcyl -2-pyrryl)butan-2-ol. 5 5. 2-Acetoxy-4- (1 -methyl-5-p- chlorcbenzcyl -2-pyrryl )butane. 5 6. 4-(1-Methyl-5-thien-2’-oyl-2-pyrryl)butan-2-one. 10 57. 4-(1*-Methyl-5-'thien-2 , -oyl-2-pyrryl)butan-2-ol. ( Γ 58. 2-Acetoxy-4-(1-B,ethyl-5-thien-2 , -oyl-2-pyrryl)butane. - 56 4682S 59. A compound as claimed in any of claims 1, 16-30 wherein Ar is a di-halogenated phenyl group. 60. A compound as claimed in claim 59 wherein Ar is a dichlorophenyl group. 5 61. A compound as claimed in claim 60 wherein Ar is a 2,4-dichlorophenyl group. 62. A pharmaceutical composition which comprises a compound as claimed in any of claims 1-61 and a pharmaceutically acceptable carrier. 10 63. A composition as claimed in claim 62 adapted, for oral administration. 64. A composition as claimed in claims 61 or 62 which is in the form of a unit dose containing from 20 to 1000mg of a compound as claimed in any of claims 1-61. 15 65. A composition as claimed in claim 64 which comprises from 30 to 500 mg of a compound as claimed in any of claims 1-61. 66. A caiposition as claimed in claim 65 which comprises fran 50 to 25Qrg of a caipound as claimed in any of claims 1-61, 67. A process for the preparation of a composition according to any me of 2q claims 62-66 which process ccnpriseg hringing together the caipound and the carrier. 68. A method cf treating inflammatory and/or painful conditions in non-human manmals which canprises the administration per day of fran 200 to 4000 ng of a canpcund of any of claims 1-61 said caipound being present in a composition as claimed in any of claims 62-66- 37 468 2S 69. A method as claimed in claim 67 which utilizes 300 to 3000 mg of a compound of any of claims 1-61. 70. A method as claimed in claim 68 which utilizes 500 to 2000 mg of a compound of any of claims 1-61. 5 71. A process for the preparation of a qompound of the formula (II) as' claimed in claim 1 or a pro-drug thereof which process comprises the reaction of a compound of the formula (VII): Ar.CO.Cl (VII) or an equivalent agent for the acylation of nucleophilic 10 aromatic nuclei wherein Ar is as defined in relation to formula (II), with a compound of the formula (IX): ch 3 wherein Q is a group of the sub-formulae (a) - (d) as hereinbefore defined or a group of the sub-formula (e): -CH^-CHg-CO-CHj (e) wherein R 1 is a hydrogen atom or a methyl group; and thereafter if desired reducing the carbonyl present in a group of the subformula (e) to a CHOH group. - 38 72. A process as claimed in claim 70 which comprises the reaction of a compound of the formula (VII): Ar.CO.Cl (VII) or an equivalent agent for the acylaticn of nucleophilic aranatic nuclei 5 wherein Ar is as defined in relation to formula, (ii) , with a canpound of the formula (X): wherein R^ is as defined in relation to formula (II) and thereafter if desired reducing the carbonyl group X to a CHOH 10 group X and/or thereafter converting the CO or CHOH group X to a pro-drug thereof. 73. A process as claimed in claim 70 for the present invention also provides a process for the preparation of the pro-drugs of the compounds of the formula (II) which process comprises the 15 reaction of a compound of the formula (VII) as hereinbefore defined or an equivalent agent for the acylation of nucleophilic aromatic nuclei with a compound of the formula (XI): (XI) CH, wherein q' is a group of the sub-formulae (a) - (d) as hereinbefore defined. - 39 46825 74. . A process as claimed in any of claims 70-72 wherein the condensation is effected at a temperature of 5°to 50°C in the presence of a Lewis acid. 75. A process as claimed in any of claims 70-72 in the absence of a Lewis acid at a temperature above 50°C. 76. A process as claimed in any of claims 70-72 or 74 carried out in a solvent comprising an inert organic solvent and a tertiary amine. 77. A process as claimed in claim 75 wherein the amine is 10 pyridine. 78. A compound as claimed in any of claims 1-61 when prepared by a process as claimed in any of claims 70-76. 79. ' A compound substantially as described with reference to any of Examples 1-7 herein. 80. A composition substantially as described with reference to either of Examples 8 or 9 herein. 81 A process according to any one of claims 71 to 77 substantially as described with reference to any of Examples 1-7 herein.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB19465/77A GB1601107A (en) | 1977-05-10 | 1977-05-10 | Pyrrole derivatives |
| GB352978 | 1978-01-28 | ||
| GB575178 | 1978-02-14 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| IE780942L IE780942L (en) | 1978-11-10 |
| IE46825B1 true IE46825B1 (en) | 1983-10-05 |
Family
ID=27254285
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| IE942/78A IE46825B1 (en) | 1977-05-10 | 1978-05-09 | Pyrrole derivatives |
Country Status (12)
| Country | Link |
|---|---|
| JP (1) | JPS53141268A (en) |
| AU (1) | AU526256B2 (en) |
| CA (1) | CA1100142A (en) |
| CH (1) | CH640225A5 (en) |
| DE (1) | DE2819463A1 (en) |
| DK (1) | DK204078A (en) |
| ES (1) | ES469631A1 (en) |
| FR (1) | FR2390431A1 (en) |
| IE (1) | IE46825B1 (en) |
| IL (1) | IL54642A (en) |
| NL (1) | NL7804942A (en) |
| SE (1) | SE7805282L (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0032314A1 (en) * | 1980-01-09 | 1981-07-22 | Beecham Group Plc | Aroylpyrrole derivatives, processes for their preparation and their use |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3752826A (en) * | 1970-01-26 | 1973-08-14 | Mcneilab Inc | Aroyl substituted pyrroles |
-
1978
- 1978-05-03 DE DE19782819463 patent/DE2819463A1/en not_active Withdrawn
- 1978-05-04 IL IL54642A patent/IL54642A/en unknown
- 1978-05-05 FR FR7813338A patent/FR2390431A1/en active Granted
- 1978-05-09 IE IE942/78A patent/IE46825B1/en unknown
- 1978-05-09 NL NL7804942A patent/NL7804942A/en not_active Application Discontinuation
- 1978-05-09 CH CH503078A patent/CH640225A5/en not_active IP Right Cessation
- 1978-05-09 CA CA302,893A patent/CA1100142A/en not_active Expired
- 1978-05-09 DK DK204078A patent/DK204078A/en unknown
- 1978-05-09 SE SE7805282A patent/SE7805282L/en unknown
- 1978-05-09 ES ES469631A patent/ES469631A1/en not_active Expired
- 1978-05-10 AU AU35990/78A patent/AU526256B2/en not_active Expired
- 1978-05-10 JP JP5539178A patent/JPS53141268A/en active Pending
Also Published As
| Publication number | Publication date |
|---|---|
| IE780942L (en) | 1978-11-10 |
| FR2390431B1 (en) | 1981-11-06 |
| CA1100142A (en) | 1981-04-28 |
| NL7804942A (en) | 1978-11-14 |
| IL54642A (en) | 1982-03-31 |
| JPS53141268A (en) | 1978-12-08 |
| DK204078A (en) | 1978-11-11 |
| AU526256B2 (en) | 1982-12-23 |
| CH640225A5 (en) | 1983-12-30 |
| ES469631A1 (en) | 1980-03-01 |
| FR2390431A1 (en) | 1978-12-08 |
| IL54642A0 (en) | 1978-07-31 |
| AU3599078A (en) | 1979-11-15 |
| SE7805282L (en) | 1978-11-11 |
| DE2819463A1 (en) | 1978-11-16 |
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