SK5632003A3 - Cyanopyrrolidine derivatives - Google Patents

Cyanopyrrolidine derivatives Download PDF

Info

Publication number: SK5632003A3
Authority: SK; Slovakia
Prior art keywords: group; carbon atoms; optionally substituted; hydrogen; alkyl
Prior art date: 2000-11-10

Application number

SK563-2003A

Other languages

English (en)

Slovak (sk)

Inventor

Hiroshi Fukushima

Akira Hiratate

Masato Takahashi

Kazuya Kameo

Original Assignee

Taisho Pharmaceutical Co Ltd

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.)

2000-11-10

Filing date

2001-11-09

Publication date

2003-12-02

2001-11-09 Application filed by Taisho Pharmaceutical Co Ltd filed Critical Taisho Pharmaceutical Co Ltd

2003-12-02 Publication of SK5632003A3 publication Critical patent/SK5632003A3/sk

Links

QJRYYOWARFCJQZ-UHFFFAOYSA-N pyrrolidine-1-carbonitrile Chemical class N#CN1CCCC1 QJRYYOWARFCJQZ-UHFFFAOYSA-N 0.000 title claims abstract description 30
-1 hydroxyimino group Chemical group 0.000 claims abstract description 144
125000004432 carbon atom Chemical group C* 0.000 claims abstract description 85
125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 63
150000003839 salts Chemical class 0.000 claims abstract description 42
125000000217 alkyl group Chemical group 0.000 claims abstract description 40
125000005843 halogen group Chemical group 0.000 claims abstract description 40
125000003277 amino group Chemical group 0.000 claims abstract description 29
125000003545 alkoxy group Chemical group 0.000 claims abstract description 23
125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 23
125000004122 cyclic group Chemical group 0.000 claims abstract description 15
125000000392 cycloalkenyl group Chemical group 0.000 claims abstract description 9
150000001602 bicycloalkyls Chemical group 0.000 claims abstract description 8
229910052799 carbon Inorganic materials 0.000 claims abstract description 7
229910052757 nitrogen Inorganic materials 0.000 claims abstract description 7
125000001118 alkylidene group Chemical group 0.000 claims abstract description 4
150000001721 carbon Chemical group 0.000 claims abstract description 4
229910052717 sulfur Chemical group 0.000 claims abstract description 4
OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims abstract description 3
150000001875 compounds Chemical class 0.000 claims description 179
229910052739 hydrogen Inorganic materials 0.000 claims description 52
239000001257 hydrogen Substances 0.000 claims description 52
125000001424 substituent group Chemical group 0.000 claims description 44
125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 34
125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 34
RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 33
150000002431 hydrogen Chemical class 0.000 claims description 32
229910052736 halogen Inorganic materials 0.000 claims description 27
125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 25
125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 22
UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 21
125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 claims description 21
150000002367 halogens Chemical class 0.000 claims description 20
125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 15
UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 claims description 15
125000004076 pyridyl group Chemical group 0.000 claims description 15
230000005764 inhibitory process Effects 0.000 claims description 13
102000016622 Dipeptidyl Peptidase 4 Human genes 0.000 claims description 12
101000930822 Giardia intestinalis Dipeptidyl-peptidase 4 Proteins 0.000 claims description 12
125000001309 chloro group Chemical group Cl* 0.000 claims description 12
239000008194 pharmaceutical composition Substances 0.000 claims description 12
125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 claims description 10
125000001041 indolyl group Chemical group 0.000 claims description 10
230000002401 inhibitory effect Effects 0.000 claims description 10
125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 claims description 10
PXQLVRUNWNTZOS-UHFFFAOYSA-N sulfanyl Chemical class [SH] PXQLVRUNWNTZOS-UHFFFAOYSA-N 0.000 claims description 10
125000001153 fluoro group Chemical group F* 0.000 claims description 9
201000010099 disease Diseases 0.000 claims description 8
208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 8
125000006527 (C1-C5) alkyl group Chemical group 0.000 claims description 6
230000001668 ameliorated effect Effects 0.000 claims description 6
208000026278 immune system disease Diseases 0.000 claims description 6
QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 5
125000006165 cyclic alkyl group Chemical group 0.000 claims description 5
229910052760 oxygen Inorganic materials 0.000 claims description 5
239000001301 oxygen Substances 0.000 claims description 5
230000002265 prevention Effects 0.000 claims description 5
125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 5
125000000008 (C1-C10) alkyl group Chemical group 0.000 claims description 4
125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 4
NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 4
206010012601 diabetes mellitus Diseases 0.000 claims description 4
125000006374 C2-C10 alkenyl group Chemical group 0.000 claims description 3
125000003342 alkenyl group Chemical group 0.000 claims description 3
150000001356 alkyl thiols Chemical class 0.000 claims description 3
125000002768 hydroxyalkyl group Chemical group 0.000 claims description 3
IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 3
QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 3
239000011593 sulfur Chemical group 0.000 claims description 3
239000004480 active ingredient Substances 0.000 claims description 2
125000004429 atom Chemical group 0.000 claims 2
239000000825 pharmaceutical preparation Substances 0.000 claims 1
125000000547 substituted alkyl group Chemical group 0.000 abstract description 4
125000000676 alkoxyimino group Chemical group 0.000 abstract description 3
125000004433 nitrogen atom Chemical group N* 0.000 abstract description 3
125000004430 oxygen atom Chemical group O* 0.000 abstract description 2
125000005017 substituted alkenyl group Chemical group 0.000 abstract 1
125000005346 substituted cycloalkyl group Chemical group 0.000 abstract 1
125000004434 sulfur atom Chemical group 0.000 abstract 1
238000003786 synthesis reaction Methods 0.000 description 160
XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 159
230000015572 biosynthetic process Effects 0.000 description 158
239000011734 sodium Substances 0.000 description 120
238000000034 method Methods 0.000 description 111
238000006243 chemical reaction Methods 0.000 description 99
239000000243 solution Substances 0.000 description 98
WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 96
ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 92
YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 91
OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 81
HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 78
239000000843 powder Substances 0.000 description 69
VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 68
YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 48
RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 45
LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 45
VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 44
XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 44
YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 42
238000001816 cooling Methods 0.000 description 41
FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 40
239000000126 substance Substances 0.000 description 37
RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 35
239000000203 mixture Substances 0.000 description 35
239000000460 chlorine Substances 0.000 description 33
238000003756 stirring Methods 0.000 description 33
229920006395 saturated elastomer Polymers 0.000 description 29
239000002904 solvent Substances 0.000 description 27
QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 25
JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 24
ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 24
VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 23
239000000741 silica gel Substances 0.000 description 23
229910002027 silica gel Inorganic materials 0.000 description 23
UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 22
QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 21
239000011780 sodium chloride Substances 0.000 description 20
WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 18
BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 16
108010067722 Dipeptidyl Peptidase 4 Proteins 0.000 description 15
102100025012 Dipeptidyl peptidase 4 Human genes 0.000 description 15
HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
239000012442 inert solvent Substances 0.000 description 15
239000002274 desiccant Substances 0.000 description 14
239000012074 organic phase Substances 0.000 description 14
RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 14
PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 13
238000001914 filtration Methods 0.000 description 13
239000002198 insoluble material Substances 0.000 description 13
WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 12
RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 12
239000000706 filtrate Substances 0.000 description 12
125000006633 tert-butoxycarbonylamino group Chemical group 0.000 description 12
WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 11
125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 11
239000008103 glucose Substances 0.000 description 11
235000017557 sodium bicarbonate Nutrition 0.000 description 11
229910000030 sodium bicarbonate Inorganic materials 0.000 description 11
229910021529 ammonia Inorganic materials 0.000 description 10
210000004369 blood Anatomy 0.000 description 10
239000008280 blood Substances 0.000 description 10
125000004744 butyloxycarbonyl group Chemical group 0.000 description 10
239000007810 chemical reaction solvent Substances 0.000 description 10
239000007787 solid Substances 0.000 description 10
238000012360 testing method Methods 0.000 description 10
QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 description 10
125000004063 butyryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 9
229910052731 fluorine Inorganic materials 0.000 description 9
239000012071 phase Substances 0.000 description 9
230000008569 process Effects 0.000 description 9
ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 8
DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 8
230000009435 amidation Effects 0.000 description 8
238000007112 amidation reaction Methods 0.000 description 8
150000001412 amines Chemical class 0.000 description 8
239000003795 chemical substances by application Substances 0.000 description 8
150000002148 esters Chemical class 0.000 description 8
XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 8
229910000027 potassium carbonate Inorganic materials 0.000 description 8
125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 8
125000006239 protecting group Chemical group 0.000 description 8
125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 8
FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 8
229940126062 Compound A Drugs 0.000 description 7
IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 7
NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 description 7
KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical group CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 7
239000002253 acid Substances 0.000 description 7
150000001732 carboxylic acid derivatives Chemical class 0.000 description 7
230000000052 comparative effect Effects 0.000 description 7
125000000753 cycloalkyl group Chemical group 0.000 description 7
YIEACUBSPQGCLW-MMALYQPHSA-N (2s,4s)-4-fluoropyrrolidine-2-carboxamide;hydrochloride Chemical compound Cl.NC(=O)[C@@H]1C[C@H](F)CN1 YIEACUBSPQGCLW-MMALYQPHSA-N 0.000 description 6
YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 6
239000005977 Ethylene Substances 0.000 description 6
WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 6
AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 6
JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 6
125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 6
230000037396 body weight Effects 0.000 description 6
125000006630 butoxycarbonylamino group Chemical group 0.000 description 6
125000004093 cyano group Chemical group *C#N 0.000 description 6
UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 6
230000000694 effects Effects 0.000 description 6
238000002474 experimental method Methods 0.000 description 6
FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 6
125000003104 hexanoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 6
VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 6
238000005160 1H NMR spectroscopy Methods 0.000 description 5
AGXOAHRFTPHJPH-UHFFFAOYSA-N C(=O)=C1C(NCC1F)C#N Chemical compound C(=O)=C1C(NCC1F)C#N AGXOAHRFTPHJPH-UHFFFAOYSA-N 0.000 description 5
ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 5
239000007864 aqueous solution Substances 0.000 description 5
GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical compound BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 5
229910052801 chlorine Inorganic materials 0.000 description 5
239000013078 crystal Substances 0.000 description 5
125000000031 ethylamino group Chemical group [H]C([H])([H])C([H])([H])N([H])[*] 0.000 description 5
150000007529 inorganic bases Chemical class 0.000 description 5
239000011591 potassium Substances 0.000 description 5
229910052700 potassium Inorganic materials 0.000 description 5
238000000746 purification Methods 0.000 description 5
OLZBUMFLINUMEV-FHAQVOQBSA-N (2s,4s)-4-fluoropyrrolidine-2-carbonitrile;hydrochloride Chemical compound Cl.F[C@@H]1CN[C@H](C#N)C1 OLZBUMFLINUMEV-FHAQVOQBSA-N 0.000 description 4
VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 4
FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 4
DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 4
MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 4
KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 4
229910052794 bromium Inorganic materials 0.000 description 4
238000005660 chlorination reaction Methods 0.000 description 4
238000009833 condensation Methods 0.000 description 4
230000005494 condensation Effects 0.000 description 4
HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 4
CSJLBAMHHLJAAS-UHFFFAOYSA-N diethylaminosulfur trifluoride Chemical compound CCN(CC)S(F)(F)F CSJLBAMHHLJAAS-UHFFFAOYSA-N 0.000 description 4
229940079593 drug Drugs 0.000 description 4
239000003814 drug Substances 0.000 description 4
239000011737 fluorine Substances 0.000 description 4
NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 4
KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 description 4
ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 4
230000004060 metabolic process Effects 0.000 description 4
230000036470 plasma concentration Effects 0.000 description 4
239000011541 reaction mixture Substances 0.000 description 4
229910052708 sodium Inorganic materials 0.000 description 4
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238000006386 neutralization reaction Methods 0.000 description 1
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YBYUZZMVUSJRQP-BQBZGAKWSA-N tert-butyl (2s,3s)-2-carbamoyl-3-hydroxypyrrolidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CC[C@H](O)[C@H]1C(N)=O YBYUZZMVUSJRQP-BQBZGAKWSA-N 0.000 description 1
ISGKNURQVBUGBO-RQJHMYQMSA-N tert-butyl (2s,4r)-2-carbamoyl-4-hydroxypyrrolidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1C(N)=O ISGKNURQVBUGBO-RQJHMYQMSA-N 0.000 description 1
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TVJJWGOMPPPJNW-SDDRHHMPSA-N tert-butyl n-[(2s)-1-[(2s,4s)-2-cyano-4-fluoropyrrolidin-1-yl]-3,3-dimethyl-1-oxobutan-2-yl]carbamate Chemical compound CC(C)(C)OC(=O)N[C@@H](C(C)(C)C)C(=O)N1C[C@@H](F)C[C@H]1C#N TVJJWGOMPPPJNW-SDDRHHMPSA-N 0.000 description 1
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LLBGGNURMOZNGM-RNJOBUHISA-N tert-butyl n-[(2s,3s)-1-[(2s,3r)-2-cyano-3-fluoropyrrolidin-1-yl]-3-methyl-1-oxopentan-2-yl]carbamate Chemical compound CC(C)(C)OC(=O)N[C@@H]([C@@H](C)CC)C(=O)N1CC[C@@H](F)[C@@H]1C#N LLBGGNURMOZNGM-RNJOBUHISA-N 0.000 description 1
LXTBAJPSXZAOFY-BJDJZHNGSA-N tert-butyl n-[(2s,3s)-1-[(2s,4s)-2-carbamoyl-4-fluoropyrrolidin-1-yl]-3-methyl-1-oxopentan-2-yl]carbamate Chemical compound CC(C)(C)OC(=O)N[C@@H]([C@@H](C)CC)C(=O)N1C[C@@H](F)C[C@H]1C(N)=O LXTBAJPSXZAOFY-BJDJZHNGSA-N 0.000 description 1
DZLFLBLQUQXARW-UHFFFAOYSA-N tetrabutylammonium Chemical compound CCCC[N+](CCCC)(CCCC)CCCC DZLFLBLQUQXARW-UHFFFAOYSA-N 0.000 description 1
125000001391 thioamide group Chemical group 0.000 description 1
238000002054 transplantation Methods 0.000 description 1
125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
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Classifications

- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon 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]
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
- A61P31/18—Antivirals for RNA viruses for HIV
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/04—Antineoplastic agents specific for metastasis
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- 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
- C07D207/10—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 hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

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Chemical Kinetics & Catalysis (AREA)
Medicinal Chemistry (AREA)
Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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Molecular Biology (AREA)
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Tropical Medicine & Parasitology (AREA)
Obesity (AREA)
Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Plural Heterocyclic Compounds (AREA)
Nitrogen Condensed Heterocyclic Rings (AREA)
Pyrrole Compounds (AREA)
Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

SK563-2003A 2000-11-10 2001-11-09 Cyanopyrrolidine derivatives SK5632003A3 (en)

Applications Claiming Priority (3)

Application Number	Priority Date	Filing Date	Title
JP2000344036		2000-11-10
JP2001215766		2001-07-16
PCT/JP2001/009818 WO2002038541A1 (en)	2000-11-10	2001-11-09	Cyanopyrrolidine derivatives

Publications (1)

Publication Number	Publication Date
SK5632003A3 true SK5632003A3 (en)	2003-12-02

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SK563-2003A SK5632003A3 (en)	2000-11-10	2001-11-09	Cyanopyrrolidine derivatives

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US (3)	US20040072892A1 (no)
EP (2)	EP1746086A1 (no)
JP (1)	JP3987890B2 (no)
KR (3)	KR100680079B1 (no)
CN (1)	CN1298703C (no)
AU (2)	AU2002212745B2 (no)
BG (1)	BG107799A (no)
BR (1)	BR0114851A (no)
CA (1)	CA2428271C (no)
CZ (1)	CZ20031250A3 (no)
EA (2)	EA006204B1 (no)
EE (1)	EE200300175A (no)
HR (2)	HRP20070116A2 (no)
HU (1)	HUP0302248A2 (no)
IL (2)	IL155776A0 (no)
MX (1)	MXPA03004114A (no)
NO (2)	NO20031949L (no)
NZ (1)	NZ525705A (no)
PL (1)	PL361463A1 (no)
SK (1)	SK5632003A3 (no)
TW (1)	TWI243162B (no)
WO (1)	WO2002038541A1 (no)

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ATE380175T1 (de)	2001-06-27	2007-12-15	Smithkline Beecham Corp	Pyrrolidine als dipeptidyl peptidase inhibitoren
ATE370943T1 (de)	2001-06-27	2007-09-15	Smithkline Beecham Corp	Fluoropyrrolidine als dipeptidyl-peptidase inhibitoren
JP3909056B2 (ja) *	2001-06-27	2007-04-25	スミスクラインビーチャムコーポレーション	ジペプチジルペプチダーゼ阻害剤としてのフルオロピロリジン類
GB0125445D0 (en) *	2001-10-23	2001-12-12	Ferring Bv	Protease Inhibitors
WO2003057144A2 (en) *	2001-12-26	2003-07-17	Guilford Pharmaceuticals	Change inhibitors of dipeptidyl peptidase iv
DE60304911D1 (de)	2002-02-25	2006-06-08	Eisai Co Ltd	Xanthin-Derivate als DPP-IV-Inhibitoren
HUP0200849A2 (hu) *	2002-03-06	2004-08-30	Sanofi-Synthelabo	N-aminoacetil-2-ciano-pirrolidin-származékok, e vegyületeket tartalmazó gyógyszerkészítmények és eljárás előállításukra
WO2003095425A1 (en) *	2002-05-09	2003-11-20	Taisho Pharmaceutical Co.,Ltd.	Cyanopyrrolidine derivatives
JP2005533771A (ja) *	2002-06-04	2005-11-10	ファイザー・プロダクツ・インク	ジペプチジルペプチダーゼｉｖ阻害剤としてのフッ素化環式アミド
AU2003248259A1 (en) *	2002-07-10	2004-02-02	Yamanouchi Pharmaceutical Co., Ltd.	Novel azetidine derivative or salt thereof
TW200401635A (en) *	2002-07-23	2004-02-01	Yamanouchi Pharma Co Ltd	2-Cyano-4-fluoropyrrolidine derivative or salt thereof
PL374664A1 (en) *	2002-08-29	2005-10-31	Taisho Pharmaceutical Co, Ltd.	Benzenesulfonate of 4-fluoro-2-cyanopyrrolidine derivative
JP2006508975A (ja) *	2002-11-18	2006-03-16	ファイザー・プロダクツ・インク	ジペプチジルペプチダーゼｉｖを阻害するフッ素化環状アミド
JP2005170792A (ja) *	2002-11-22	2005-06-30	Mitsubishi Pharma Corp	Ｌ−プロリン誘導体およびその医薬としての用途。
DE10308355A1 (de)	2003-02-27	2004-12-23	Aventis Pharma Deutschland Gmbh	Aryl-cycloalkyl substituierte Alkansäurederivate, Verfahren zu ihrer Herstellung und ihre Anwendung als Arzneimittel
DE10308352A1 (de)	2003-02-27	2004-09-09	Aventis Pharma Deutschland Gmbh	Arylcycloalkylderivate mit verzweigten Seitenketten, Verfahren zu ihrer Herstellung und ihre Anwendung als Arzneimittel
US7148246B2 (en)	2003-02-27	2006-12-12	Sanofi-Aventis Deutschland Gmbh	Cycloalkyl derivatives having bioisosteric carboxylic acid groups, processes for their preparation and their use as pharmaceuticals
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KR100620944B1 (ko)	2006-09-19
IL155776A0 (en)	2003-12-23
BG107799A (bg)	2004-08-31
EA200500852A1 (ru)	2006-02-24
TWI243162B (en)	2005-11-11
KR100680079B1 (ko)	2007-02-09
KR100680081B1 (ko)	2007-02-09
JP3987890B2 (ja)	2007-10-10
WO2002038541A1 (en)	2002-05-16
NO20031949L (no)	2003-07-08
US20070112205A1 (en)	2007-05-17
BR0114851A (pt)	2003-09-16
NZ525705A (en)	2004-04-30
NO20054429L (no)	2003-07-08
CA2428271C (en)	2005-12-27
EP1333025A4 (en)	2004-03-24
HK1061688A1 (zh)	2004-09-30
PL361463A1 (en)	2004-10-04
MXPA03004114A (es)	2003-08-19
EA006204B1 (ru)	2005-10-27
US20040072892A1 (en)	2004-04-15
AU2002212745B2 (en)	2007-01-04
CA2428271A1 (en)	2002-05-16
KR20060061410A (ko)	2006-06-07
AU1274502A (en)	2002-05-21
HUP0302248A2 (hu)	2003-10-28
CZ20031250A3 (cs)	2003-08-13
EE200300175A (et)	2003-06-16
KR20050096206A (ko)	2005-10-05
WO2002038541A9 (en)	2002-08-08
EP1746086A1 (en)	2007-01-24
US20070112059A1 (en)	2007-05-17
EP1333025A1 (en)	2003-08-06
CN1474809A (zh)	2004-02-11
EA008226B1 (ru)	2007-04-27
JPWO2002038541A1 (ja)	2004-03-18
KR20030059232A (ko)	2003-07-07
CN1298703C (zh)	2007-02-07
EA200300559A1 (ru)	2003-10-30
IL182030A0 (en)	2007-07-24
HRP20070116A2 (hr)	2007-07-31
HRP20030366A2 (en)	2004-08-31
NO20031949D0 (no)	2003-04-29

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AU2002212745B2 (en)	2007-01-04	Cyanopyrrolidine derivatives
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EP2460798B1 (en)	2019-02-27	Apaf-1 inhibitor compounds
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