FI105190B - Menetelmä terapeuttisesti käyttökelpoisten pyrrolidiinijohdannaisten valmistamiseksi - Google Patents

Menetelmä terapeuttisesti käyttökelpoisten pyrrolidiinijohdannaisten valmistamiseksi Download PDF

Info

Publication number: FI105190B
Authority: FI; Finland
Prior art keywords: phenyl; tert; alk; ureido; radical
Prior art date: 1991-07-10

Application number

FI940072A

Other languages

English (en)

Finnish (fi)

Swedish (sv)

Other versions

FI940072A0 (fi

FI940072L (fi

Inventor

Claude Cotrel

Claude Guyon

Gerard Roussel

Marc Capet

Marie-Christine Dubroeucq

Michel Cheve

Gilles Dutruc-Rosset

Michel Joannic

Franco Manfre

Original Assignee

Rhone Poulenc Rorer Sa

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.)

1991-07-10

Filing date

1994-01-07

Publication date

2000-06-30

1994-01-07 Application filed by Rhone Poulenc Rorer Sa filed Critical Rhone Poulenc Rorer Sa

1994-01-07 Publication of FI940072A0 publication Critical patent/FI940072A0/fi

1994-01-07 Publication of FI940072L publication Critical patent/FI940072L/fi

2000-06-30 Application granted granted Critical

2000-06-30 Publication of FI105190B publication Critical patent/FI105190B/fi

Links

238000002360 preparation method Methods 0.000 title claims abstract description 10
238000000034 method Methods 0.000 title claims description 113
230000008569 process Effects 0.000 title claims description 8
150000003235 pyrrolidines Chemical class 0.000 title claims description 3
150000001875 compounds Chemical class 0.000 claims abstract description 198
150000003839 salts Chemical class 0.000 claims abstract description 22
-1 pyridyl radical Chemical class 0.000 claims description 553
XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 154
125000001951 carbamoylamino group Chemical group C(N)(=O)N* 0.000 claims description 122
239000000203 mixture Substances 0.000 claims description 98
229910052757 nitrogen Inorganic materials 0.000 claims description 61
125000004198 2-fluorophenyl group Chemical group [H]C1=C([H])C(F)=C(*)C([H])=C1[H] 0.000 claims description 60
125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 50
125000000217 alkyl group Chemical group 0.000 claims description 50
239000002253 acid Substances 0.000 claims description 47
150000003254 radicals Chemical class 0.000 claims description 47
125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 42
125000003545 alkoxy group Chemical group 0.000 claims description 37
125000001424 substituent group Chemical group 0.000 claims description 34
125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 31
CIUQDSCDWFSTQR-UHFFFAOYSA-N [C]1=CC=CC=C1 Chemical group [C]1=CC=CC=C1 CIUQDSCDWFSTQR-UHFFFAOYSA-N 0.000 claims description 30
XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims description 28
229920006395 saturated elastomer Polymers 0.000 claims description 27
239000005711 Benzoic acid Substances 0.000 claims description 25
125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 24
229910052717 sulfur Inorganic materials 0.000 claims description 24
125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 22
125000004434 sulfur atom Chemical group 0.000 claims description 19
125000004432 carbon atom Chemical group C* 0.000 claims description 18
IYABWNGZIDDRAK-UHFFFAOYSA-N allene Chemical group C=C=C IYABWNGZIDDRAK-UHFFFAOYSA-N 0.000 claims description 16
125000005843 halogen group Chemical group 0.000 claims description 16
239000001257 hydrogen Substances 0.000 claims description 16
229910052739 hydrogen Inorganic materials 0.000 claims description 16
125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 16
235000019260 propionic acid Nutrition 0.000 claims description 14
238000004587 chromatography analysis Methods 0.000 claims description 13
HZVOZRGWRWCICA-UHFFFAOYSA-N methanediyl Chemical group [CH2] HZVOZRGWRWCICA-UHFFFAOYSA-N 0.000 claims description 12
125000000719 pyrrolidinyl group Chemical group 0.000 claims description 12
125000004001 thioalkyl group Chemical group 0.000 claims description 12
125000002252 acyl group Chemical group 0.000 claims description 11
125000003884 phenylalkyl group Chemical group 0.000 claims description 11
VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 claims description 9
HCUYBXPSSCRKRF-UHFFFAOYSA-N diphosgene Chemical compound ClC(=O)OC(Cl)(Cl)Cl HCUYBXPSSCRKRF-UHFFFAOYSA-N 0.000 claims description 9
XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 claims description 9
125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 8
239000005977 Ethylene Substances 0.000 claims description 7
125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 7
HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 claims description 6
125000004433 nitrogen atom Chemical group N* 0.000 claims description 6
101100244083 Arabidopsis thaliana PKL gene Proteins 0.000 claims description 5
125000000753 cycloalkyl group Chemical group 0.000 claims description 5
150000002148 esters Chemical class 0.000 claims description 5
229910052736 halogen Inorganic materials 0.000 claims description 5
150000002367 halogens Chemical class 0.000 claims description 5
125000001624 naphthyl group Chemical group 0.000 claims description 5
PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 claims description 4
NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 4
125000004666 alkoxyiminoalkyl group Chemical group 0.000 claims description 4
125000002947 alkylene group Chemical group 0.000 claims description 4
125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 4
125000001316 cycloalkyl alkyl group Chemical group 0.000 claims description 4
125000004663 dialkyl amino group Chemical group 0.000 claims description 4
125000005842 heteroatom Chemical group 0.000 claims description 4
125000001041 indolyl group Chemical group 0.000 claims description 4
229910052760 oxygen Inorganic materials 0.000 claims description 4
DGTNSSLYPYDJGL-UHFFFAOYSA-N phenyl isocyanate Chemical compound O=C=NC1=CC=CC=C1 DGTNSSLYPYDJGL-UHFFFAOYSA-N 0.000 claims description 4
125000005493 quinolyl group Chemical group 0.000 claims description 4
125000000020 sulfo group Chemical group O=S(=O)([*])O[H] 0.000 claims description 4
239000011593 sulfur Substances 0.000 claims description 4
125000004694 alkoxyaminocarbonyl group Chemical group 0.000 claims description 3
125000004644 alkyl sulfinyl group Chemical group 0.000 claims description 3
125000002768 hydroxyalkyl group Chemical group 0.000 claims description 3
238000011065 in-situ storage Methods 0.000 claims description 3
125000002911 monocyclic heterocycle group Chemical group 0.000 claims description 3
125000004585 polycyclic heterocycle group Chemical group 0.000 claims description 3
IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 claims description 3
NXLNNXIXOYSCMB-UHFFFAOYSA-N (4-nitrophenyl) carbonochloridate Chemical compound [O-][N+](=O)C1=CC=C(OC(Cl)=O)C=C1 NXLNNXIXOYSCMB-UHFFFAOYSA-N 0.000 claims description 2
YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 claims description 2
125000004183 alkoxy alkyl group Chemical group 0.000 claims description 2
BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 claims description 2
LEVJVKGPFAQPOI-UHFFFAOYSA-N phenylmethanone Chemical compound O=[C]C1=CC=CC=C1 LEVJVKGPFAQPOI-UHFFFAOYSA-N 0.000 claims description 2
125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 claims 2
CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 claims 2
XVVPHRVTUJRMNJ-UHFFFAOYSA-N 2-[3-[[2-[2-(2-hydroxyphenyl)-5-phenylpyrrolidin-1-yl]-2-oxoethyl]carbamoylamino]phenyl]acetic acid Chemical compound OC(=O)CC1=CC=CC(NC(=O)NCC(=O)N2C(CCC2C=2C=CC=CC=2)C=2C(=CC=CC=2)O)=C1 XVVPHRVTUJRMNJ-UHFFFAOYSA-N 0.000 claims 1
229910006069 SO3H Inorganic materials 0.000 claims 1
239000004760 aramid Substances 0.000 claims 1
229920003235 aromatic polyamide Polymers 0.000 claims 1
125000004093 cyano group Chemical group *C#N 0.000 claims 1
125000002887 hydroxy group Chemical group [H]O* 0.000 claims 1
239000003814 drug Substances 0.000 abstract description 2
OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 211
XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 205
239000000243 solution Substances 0.000 description 205
238000003786 synthesis reaction Methods 0.000 description 190
YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 186
WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 174
239000007858 starting material Substances 0.000 description 138
WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 125
KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 118
CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 116
LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 111
IUGYQRQAERSCNH-UHFFFAOYSA-N pivalic acid Chemical compound CC(C)(C)C(O)=O IUGYQRQAERSCNH-UHFFFAOYSA-N 0.000 description 108
HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 106
239000003480 eluent Substances 0.000 description 106
239000011541 reaction mixture Substances 0.000 description 106
238000010898 silica gel chromatography Methods 0.000 description 106
239000003921 oil Substances 0.000 description 97
235000019198 oils Nutrition 0.000 description 97
HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 93
239000012043 crude product Substances 0.000 description 80
QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 79
IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 75
ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 71
RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 69
QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 67
239000000155 melt Substances 0.000 description 67
YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 64
VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 61
125000003118 aryl group Chemical group 0.000 description 61
VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 60
239000000126 substance Substances 0.000 description 60
238000002329 infrared spectrum Methods 0.000 description 58
229910052943 magnesium sulfate Inorganic materials 0.000 description 57
235000019341 magnesium sulphate Nutrition 0.000 description 57
YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 54
239000007787 solid Substances 0.000 description 53
238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 52
230000008018 melting Effects 0.000 description 51
238000002844 melting Methods 0.000 description 51
239000012074 organic phase Substances 0.000 description 51
QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 50
WACQKHWOTAEEFS-UHFFFAOYSA-N cyclohexane;ethyl acetate Chemical compound CCOC(C)=O.C1CCCCC1 WACQKHWOTAEEFS-UHFFFAOYSA-N 0.000 description 47
ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 45
WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 36
239000002904 solvent Substances 0.000 description 35
KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 34
UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 34
RWRDLPDLKQPQOW-UHFFFAOYSA-N tetrahydropyrrole Natural products C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 34
VQTUBCCKSQIDNK-UHFFFAOYSA-N Isobutene Chemical compound CC(C)=C VQTUBCCKSQIDNK-UHFFFAOYSA-N 0.000 description 33
230000004927 fusion Effects 0.000 description 32
238000003756 stirring Methods 0.000 description 32
WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 31
IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 31
VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 31
125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 31
XUJNEKJLAYXESH-REOHCLBHSA-N L-Cysteine Chemical compound SC[C@H](N)C(O)=O XUJNEKJLAYXESH-REOHCLBHSA-N 0.000 description 30
238000001953 recrystallisation Methods 0.000 description 30
FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 30
CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 27
239000000377 silicon dioxide Substances 0.000 description 27
238000006243 chemical reaction Methods 0.000 description 25
238000002425 crystallisation Methods 0.000 description 24
230000008025 crystallization Effects 0.000 description 24
238000010992 reflux Methods 0.000 description 24
235000010233 benzoic acid Nutrition 0.000 description 23
239000000725 suspension Substances 0.000 description 23
JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 22
239000000706 filtrate Substances 0.000 description 22
239000012442 inert solvent Substances 0.000 description 20
239000000843 powder Substances 0.000 description 20
ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 19
235000019502 Orange oil Nutrition 0.000 description 18
125000000040 m-tolyl group Chemical group [H]C1=C([H])C(*)=C([H])C(=C1[H])C([H])([H])[H] 0.000 description 18
239000010502 orange oil Substances 0.000 description 18
239000008346 aqueous phase Substances 0.000 description 17
WGLUMOCWFMKWIL-UHFFFAOYSA-N dichloromethane;methanol Chemical compound OC.ClCCl WGLUMOCWFMKWIL-UHFFFAOYSA-N 0.000 description 16
238000001914 filtration Methods 0.000 description 16
229910000030 sodium bicarbonate Inorganic materials 0.000 description 16
235000017557 sodium bicarbonate Nutrition 0.000 description 16
RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 15
239000004201 L-cysteine Substances 0.000 description 15
235000013878 L-cysteine Nutrition 0.000 description 15
WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 15
FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 15
DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 14
BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 14
UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 13
MTZQAGJQAFMTAQ-UHFFFAOYSA-N benzoic acid ethyl ester Natural products CCOC(=O)C1=CC=CC=C1 MTZQAGJQAFMTAQ-UHFFFAOYSA-N 0.000 description 13
229910052799 carbon Inorganic materials 0.000 description 13
238000004898 kneading Methods 0.000 description 13
125000001637 1-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C(*)=C([H])C([H])=C([H])C2=C1[H] 0.000 description 12
125000004208 3-hydroxyphenyl group Chemical group [H]OC1=C([H])C([H])=C([H])C(*)=C1[H] 0.000 description 12
NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 12
MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 12
DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 12
239000003054 catalyst Substances 0.000 description 12
239000006196 drop Substances 0.000 description 12
OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 11
XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 11
238000009835 boiling Methods 0.000 description 11
239000003795 chemical substances by application Substances 0.000 description 11
125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 11
WLJVXDMOQOGPHL-UHFFFAOYSA-N phenylacetic acid Chemical compound OC(=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-UHFFFAOYSA-N 0.000 description 11
FKRCODPIKNYEAC-UHFFFAOYSA-N propionic acid ethyl ester Natural products CCOC(=O)CC FKRCODPIKNYEAC-UHFFFAOYSA-N 0.000 description 11
UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 11
230000009467 reduction Effects 0.000 description 11
BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 11
FJTZTYQQQLLMQR-UHFFFAOYSA-N 2-[[3-(2-methoxy-2-oxoethyl)phenyl]carbamoylamino]acetic acid Chemical compound COC(=O)CC1=CC=CC(NC(=O)NCC(O)=O)=C1 FJTZTYQQQLLMQR-UHFFFAOYSA-N 0.000 description 10
239000012298 atmosphere Substances 0.000 description 10
HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 10
UHOVQNZJYSORNB-UHFFFAOYSA-N benzene Substances C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 10
238000001816 cooling Methods 0.000 description 10
239000012153 distilled water Substances 0.000 description 10
125000003261 o-tolyl group Chemical group [H]C1=C([H])C(*)=C(C([H])=C1[H])C([H])([H])[H] 0.000 description 10
239000012071 phase Substances 0.000 description 10
XJJBXZIKXFOMLP-UHFFFAOYSA-N tert-butyl pyrrolidine-2-carboxylate Chemical compound CC(C)(C)OC(=O)C1CCCN1 XJJBXZIKXFOMLP-UHFFFAOYSA-N 0.000 description 10
125000004204 2-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C(OC([H])([H])[H])C([H])=C1[H] 0.000 description 9
QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 9
239000002585 base Substances 0.000 description 9
FATAVLOOLIRUNA-UHFFFAOYSA-N formylmethyl Chemical group [CH2]C=O FATAVLOOLIRUNA-UHFFFAOYSA-N 0.000 description 9
229960003424 phenylacetic acid Drugs 0.000 description 9
239000003279 phenylacetic acid Substances 0.000 description 9
DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 9
238000010626 work up procedure Methods 0.000 description 9
VRPJIFMKZZEXLR-UHFFFAOYSA-N 2-[(2-methylpropan-2-yl)oxycarbonylamino]acetic acid Chemical compound CC(C)(C)OC(=O)NCC(O)=O VRPJIFMKZZEXLR-UHFFFAOYSA-N 0.000 description 8
230000005526 G1 to G0 transition Effects 0.000 description 8
IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 8
WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 8
UREBWPXBXRYXRJ-UHFFFAOYSA-N ethyl acetate;methanol Chemical compound OC.CCOC(C)=O UREBWPXBXRYXRJ-UHFFFAOYSA-N 0.000 description 8
IIEWJVIFRVWJOD-UHFFFAOYSA-N ethyl cyclohexane Natural products CCC1CCCCC1 IIEWJVIFRVWJOD-UHFFFAOYSA-N 0.000 description 8
239000000463 material Substances 0.000 description 8
108090000765 processed proteins & peptides Proteins 0.000 description 8
125000006239 protecting group Chemical group 0.000 description 8
239000000741 silica gel Substances 0.000 description 8
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229910000077 silane Inorganic materials 0.000 description 1
229910052709 silver Inorganic materials 0.000 description 1
239000004332 silver Substances 0.000 description 1
239000001632 sodium acetate Substances 0.000 description 1
235000017281 sodium acetate Nutrition 0.000 description 1
QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
159000000000 sodium salts Chemical class 0.000 description 1
235000010265 sodium sulphite Nutrition 0.000 description 1
238000010183 spectrum analysis Methods 0.000 description 1
238000006467 substitution reaction Methods 0.000 description 1
KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
208000011580 syndromic disease Diseases 0.000 description 1
SKAUYPOIIAWYGC-UHFFFAOYSA-N tert-butyl 2-(tert-butylcarbamoyl)-5-phenylpyrrolidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1C(C(=O)NC(C)(C)C)CCC1C1=CC=CC=C1 SKAUYPOIIAWYGC-UHFFFAOYSA-N 0.000 description 1
KFPXIANZWRZFRU-DJNXLDHESA-N tert-butyl n-[2-[(2s)-2-(tert-butylcarbamoyl)-5-phenylpyrrolidin-1-yl]-2-oxoethyl]carbamate Chemical compound CC(C)(C)OC(=O)NCC(=O)N1[C@H](C(=O)NC(C)(C)C)CCC1C1=CC=CC=C1 KFPXIANZWRZFRU-DJNXLDHESA-N 0.000 description 1
DZPLZVUGKLPAFF-BGYRXZFFSA-N tert-butyl n-[2-[(2s,5r)-2,5-diphenylpyrrolidin-1-yl]-2-oxoethyl]carbamate Chemical compound C1([C@@H]2CC[C@@H](N2C(=O)CNC(=O)OC(C)(C)C)C=2C=CC=CC=2)=CC=CC=C1 DZPLZVUGKLPAFF-BGYRXZFFSA-N 0.000 description 1
YBRBMKDOPFTVDT-UHFFFAOYSA-N tert-butylamine Chemical compound CC(C)(C)N YBRBMKDOPFTVDT-UHFFFAOYSA-N 0.000 description 1
125000001984 thiazolidinyl group Chemical group 0.000 description 1
150000003573 thiols Chemical class 0.000 description 1
125000005505 thiomorpholino group Chemical group 0.000 description 1
DZLNHFMRPBPULJ-UHFFFAOYSA-N thioproline Chemical compound OC(=O)C1CSCN1 DZLNHFMRPBPULJ-UHFFFAOYSA-N 0.000 description 1
230000007704 transition Effects 0.000 description 1
210000003462 vein Anatomy 0.000 description 1
125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
229920002554 vinyl polymer Polymers 0.000 description 1
238000005406 washing Methods 0.000 description 1

Classifications

- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C07K5/06008—Dipeptides with the first amino acid being neutral
- C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
- C07K5/06026—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 0 or 1 carbon atom, i.e. Gly or Ala
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
- A61P25/16—Anti-Parkinson drugs
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
- 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
- A61P35/00—Antineoplastic agents
- 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
- 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
- C07D207/04—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 no double bonds between ring members or between ring members and non-ring members
- C07D207/06—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 no double bonds between ring members or between ring members and non-ring members with radicals, containing only hydrogen and carbon atoms, attached to ring carbon atoms
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
- C07K1/14—Extraction; Separation; Purification
- C07K1/16—Extraction; Separation; Purification by chromatography
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides

Landscapes

Chemical & Material Sciences (AREA)
Health & Medical Sciences (AREA)
Organic Chemistry (AREA)
General Health & Medical Sciences (AREA)
Medicinal Chemistry (AREA)
Life Sciences & Earth Sciences (AREA)
General Chemical & Material Sciences (AREA)
Pharmacology & Pharmacy (AREA)
Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
Animal Behavior & Ethology (AREA)
Chemical Kinetics & Catalysis (AREA)
Public Health (AREA)
Veterinary Medicine (AREA)
Engineering & Computer Science (AREA)
Bioinformatics & Cheminformatics (AREA)
Biomedical Technology (AREA)
Genetics & Genomics (AREA)
Proteomics, Peptides & Aminoacids (AREA)
Neurology (AREA)
Neurosurgery (AREA)
Molecular Biology (AREA)
Biochemistry (AREA)
Biophysics (AREA)
Analytical Chemistry (AREA)
Psychology (AREA)
Rheumatology (AREA)
Pain & Pain Management (AREA)
Psychiatry (AREA)
Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Plural Heterocyclic Compounds (AREA)
Pyrrole Compounds (AREA)
Thiazole And Isothizaole Compounds (AREA)
Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
Peptides Or Proteins (AREA)
Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Nitrogen Condensed Heterocyclic Rings (AREA)

FI940072A 1991-07-10 1994-01-07 Menetelmä terapeuttisesti käyttökelpoisten pyrrolidiinijohdannaisten valmistamiseksi FI105190B (fi)

Applications Claiming Priority (4)

Application Number	Priority Date	Filing Date	Title
FR9108675		1991-07-10
FR9108675A FR2678938B1 (fr)	1991-07-10	1991-07-10	Derives de pyrrolidine, leur preparation et les medicaments les contenant.
PCT/FR1992/000626 WO1993001167A1 (fr)	1991-07-10	1992-07-03	Derives de pyrrolidine et thiazolidine, leur preparation et les medicaments les contenant
FR9200626		1992-07-03

Publications (3)

Publication Number	Publication Date
FI940072A0 FI940072A0 (fi)	1994-01-07
FI940072L FI940072L (fi)	1994-01-07
FI105190B true FI105190B (fi)	2000-06-30

Family

ID=9414933

Family Applications (1)

Application Number	Title	Priority Date	Filing Date
FI940072A FI105190B (fi)	1991-07-10	1994-01-07	Menetelmä terapeuttisesti käyttökelpoisten pyrrolidiinijohdannaisten valmistamiseksi

Country Status (23)

Country	Link
US (1)	US5610144A (cs)
EP (2)	EP0593639B1 (cs)
JP (1)	JP3034043B2 (cs)
KR (1)	KR100234927B1 (cs)
AT (1)	ATE120732T1 (cs)
AU (1)	AU662345B2 (cs)
BR (1)	BR1100717A (cs)
CA (1)	CA2102697C (cs)
CZ (1)	CZ283602B6 (cs)
DE (1)	DE69201956T2 (cs)
DK (1)	DK0593639T3 (cs)
ES (1)	ES2071510T3 (cs)
FI (1)	FI105190B (cs)
FR (1)	FR2678938B1 (cs)
HU (1)	HU223470B1 (cs)
IE (1)	IE66331B1 (cs)
NO (1)	NO180166C (cs)
NZ (1)	NZ243514A (cs)
PL (5)	PL171112B1 (cs)
RU (1)	RU2118316C1 (cs)
SK (1)	SK1694A3 (cs)
WO (1)	WO1993001167A1 (cs)
ZA (1)	ZA925128B (cs)

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FR2700167B1 (fr) *	1993-01-07	1995-02-03	Rhone Poulenc Rorer Sa	Dérivés de pyrrolidine et thiazolidine, leur préparation et les médicaments les contenant.
FR2700165B1 (fr) *	1993-01-07	1995-02-17	Rhone Poulenc Rorer Sa	Dérivés de pyrrolidine, leur préparation et les médicaments les contenant.
FR2700166B1 (fr) *	1993-01-07	1995-02-17	Rhone Poulenc Rorer Sa	Dérivés de pyrrolidine, leur préparation et les médicaments les contenant.
FR2700168B1 (fr) *	1993-01-07	1995-02-03	Rhone Poulenc Rorer Sa	Dérivés de thiazolidine, leur préparation et les médicaments les contenant.
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FR2721314B1 (fr) *	1994-06-20	1996-07-19	Rhone Poulenc Rorer Sa	Dérivés de pyrrolidine, leur préparation et les médicaments les contenant.
FR2721608B1 (fr) *	1994-06-22	1996-07-19	Rhone Poulenc Rorer Sa	Dérivés de thiazolidine, leur préparation et les médicaments les contenant.
FR2734724B1 (fr) *	1995-06-01	1997-07-04	Rhone Poulenc Rorer Sa	Application de derives de pyrrolidine a la preparation de medicaments destines au traitement de l'alcoolisme
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FR2744361B1 (fr) *	1996-02-07	1998-02-27	Rhone Poulenc Rorer Sa	Application de derives de pyrrolidine a la preparation de medicaments destines au traitement de l'abus de drogues ou de substances donnant lieu a des pharmacomanies ou a un usage excessif
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DE60128731T2 (de)	2000-10-30	2008-02-07	Janssen Pharmaceutica N.V.	Tripeptidylpeptidase-hemmer
US7105556B2 (en)	2001-05-30	2006-09-12	Bristol-Myers Squibb Company	Conformationally constrained analogs useful as antidiabetic and antiobesity agents and method
US7262207B2 (en)	2002-09-19	2007-08-28	Abbott Laboratories	Pharmaceutical compositions as inhibitors of dipeptidyl peptidase-IV (DPP-IV)
CA2768674A1 (en) *	2002-09-19	2004-04-01	Abbott Laboratories	Pharmaceutical compositions as inhibitors of dipeptidyl peptidase-iv (dpp-iv)
US7238724B2 (en)	2002-09-19	2007-07-03	Abbott Laboratories	Pharmaceutical compositions as inhibitors of dipeptidyl peptidase-IV (DPP-IV)
US6846836B2 (en) *	2003-04-18	2005-01-25	Bristol-Myers Squibb Company	N-substituted phenylurea inhibitors of mitochondrial F1F0 ATP hydrolase
US7230002B2 (en)	2004-02-03	2007-06-12	Glenmark Pharmaceuticals Ltd.	Dipeptidyl peptidase IV inhibitors; processes for their preparation and compositions thereof
BRPI0507612A (pt) *	2004-02-11	2007-07-03	Univ Ohio State Res Found	análogos exibindo inibição de proliferação de célula e métodos para fabricação e uso destes
WO2007086584A1 (ja) *	2006-01-30	2007-08-02	Meiji Seika Kaisha, Ltd.	新規ＦａｂＫおよびＦａｂＩ／Ｋ阻害剤
EP2057145B1 (en) *	2006-07-20	2012-08-22	Abbott Laboratories	Synthesis of (2s,5r)-5-ethynyl-1-{n-(4-methyl-1-(4-carboxy-pyridin-2-yl)piperidin-4-yl)glycyl}pyrrolidine-2-carbonitrile
US8247438B2 (en)	2008-02-27	2012-08-21	Neuropill, Inc.	Methods for treating schizophrenia
CN101407502B (zh) *	2008-11-21	2010-12-22	南京大学	一类n-(叔丁氧基羰基)噻唑烷酸类化合物及其制法和用途
DE102009004204A1 (de) *	2009-01-09	2010-07-15	Christian-Albrechts-Universität Zu Kiel	Verfahren zur verbesserten Bioaktivierung von Arzneistoffen
CN102812003B (zh) *	2009-12-18	2015-01-21	欧洲筛选有限公司	吡咯烷羧酸衍生物、药物组合物以及在代谢紊乱中作为g-蛋白偶联受体43(gpr43)激动剂使用的方法
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CN105916500A (zh)	2013-11-27	2016-08-31	欧洲筛选有限公司	用于治疗炎性疾病的化合物、药物组合物和方法
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1991
- 1991-07-10 FR FR9108675A patent/FR2678938B1/fr not_active Expired - Fee Related
1992
- 1992-07-03 HU HU9400061A patent/HU223470B1/hu active IP Right Grant
- 1992-07-03 US US08/175,381 patent/US5610144A/en not_active Expired - Lifetime
- 1992-07-03 CZ CZ9449A patent/CZ283602B6/cs not_active IP Right Cessation
- 1992-07-03 PL PL92313381A patent/PL171112B1/pl unknown
- 1992-07-03 JP JP5502018A patent/JP3034043B2/ja not_active Expired - Lifetime
- 1992-07-03 AT AT92915456T patent/ATE120732T1/de active
- 1992-07-03 PL PL92313382A patent/PL171095B1/pl unknown
- 1992-07-03 ES ES92915456T patent/ES2071510T3/es not_active Expired - Lifetime
- 1992-07-03 CA CA002102697A patent/CA2102697C/fr not_active Expired - Lifetime
- 1992-07-03 KR KR1019940700052A patent/KR100234927B1/ko not_active Expired - Lifetime
- 1992-07-03 WO PCT/FR1992/000626 patent/WO1993001167A1/fr not_active Ceased
- 1992-07-03 EP EP92915456A patent/EP0593639B1/fr not_active Expired - Lifetime
- 1992-07-03 SK SK16-94A patent/SK1694A3/sk unknown
- 1992-07-03 EP EP92401904A patent/EP0527069A1/fr active Pending
- 1992-07-03 DK DK92915456.5T patent/DK0593639T3/da active
- 1992-07-03 AU AU23275/92A patent/AU662345B2/en not_active Expired
- 1992-07-03 DE DE69201956T patent/DE69201956T2/de not_active Expired - Lifetime
- 1992-07-03 PL PL92302029A patent/PL171333B1/pl unknown
- 1992-07-03 PL PL92313379A patent/PL171094B1/pl unknown
- 1992-07-03 PL PL92313380A patent/PL171054B1/pl unknown
- 1992-07-09 ZA ZA925128A patent/ZA925128B/xx unknown
- 1992-07-09 IE IE922244A patent/IE66331B1/en not_active IP Right Cessation
- 1992-07-10 NZ NZ243514A patent/NZ243514A/en not_active IP Right Cessation
1993
- 1993-01-21 RU RU94015258/04A patent/RU2118316C1/ru active
- 1993-11-26 NO NO934300A patent/NO180166C/no not_active IP Right Cessation
1994
- 1994-01-07 FI FI940072A patent/FI105190B/fi not_active IP Right Cessation
1997
- 1997-05-04 BR BR1100717-6A patent/BR1100717A/pt active IP Right Grant

Also Published As

Publication number	Publication date
AU662345B2 (en)	1995-08-31
NO934300D0 (no)	1993-11-26
CZ4994A3 (en)	1994-04-13
FR2678938A1 (fr)	1993-01-15
EP0593639B1 (fr)	1995-04-05
EP0593639A1 (fr)	1994-04-27
PL171095B1 (pl)	1997-03-28
PL171094B1 (pl)	1997-03-28
DE69201956T2 (de)	1995-11-30
PL171333B1 (pl)	1997-04-30
RU2118316C1 (ru)	1998-08-27
WO1993001167A1 (fr)	1993-01-21
JP3034043B2 (ja)	2000-04-17
PL171112B1 (pl)	1997-03-28
JPH06509331A (ja)	1994-10-20
HU223470B1 (hu)	2004-07-28
DK0593639T3 (da)	1995-07-03
HU9400061D0 (en)	1994-05-30
ZA925128B (en)	1993-04-28
ES2071510T3 (es)	1995-06-16
US5610144A (en)	1997-03-11
AU2327592A (en)	1993-02-11
ATE120732T1 (de)	1995-04-15
NO180166C (no)	1997-02-26
FR2678938B1 (fr)	1993-10-08
NO180166B (no)	1996-11-18
CZ283602B6 (cs)	1998-05-13
HUT70403A (en)	1995-10-30
CA2102697A1 (fr)	1993-01-11
FI940072A0 (fi)	1994-01-07
SK1694A3 (en)	1994-12-07
IE66331B1 (en)	1995-12-27
KR100234927B1 (ko)	2000-02-01
IE922244A1 (en)	1993-01-13
EP0527069A1 (fr)	1993-02-10
BR1100717A (pt)	2000-03-14
NZ243514A (en)	1995-03-28
PL171054B1 (pl)	1997-02-28
CA2102697C (fr)	2003-09-30
FI940072L (fi)	1994-01-07
NO934300L (no)	1993-11-26
DE69201956D1 (de)	1995-05-11

Legal Events

Date	Code	Title	Description
2004-11-10	PC	Transfer of assignment of patent	Owner name: AVENTIS PHARMA S.A.
2012-08-10	MA	Patent expired

Publication	Publication Date	Title
FI105190B (fi)	2000-06-30	Menetelmä terapeuttisesti käyttökelpoisten pyrrolidiinijohdannaisten valmistamiseksi
US5637602A (en)	1997-06-10	Pyrrolidine and thiazolidine derivatives, their preparation and drugs containing same
DE68913988T2 (de)	1994-07-28	Hydroxamsäure enthaltende collagenase-inhibitoren.
CA2093221C (en)	1998-09-22	N-sulfonylindoline derivatives carrying an amide functional group, their preparation, and the pharmaceutical compositions in which they are present
AU639706B2 (en)	1993-08-05	Hydroxamic acid based collagenase inhibitors
IL104582A (en)	1998-10-30	Opioid compounds Pharmacological preparations containing them and the process for making certain such compounds
JP2005523248A (ja)	2005-08-04	ジペプチジルペプチダーゼｉｖの阻害剤
NZ259530A (en)	1996-06-25	Thiazolidine compounds n-acylated by an alpha-amino acid derivative; pharmaceutical compositions thereof
CA2380578A1 (en)	2001-02-08	Ring opened cpis
HUT74094A (en)	1996-11-28	Pyrrolidine derivatives, pharmaceutical compositions containing them and process for producing them
JPH02200668A (ja)	1990-08-08	向精神作用を有するピロリドン‐２‐カルボン酸誘導体