CA2267634A1 - Methods and compounds for inhibiting .beta.-amyloid peptide release and/or synthesis - Google Patents

Methods and compounds for inhibiting .beta.-amyloid peptide release and/or synthesis Download PDF

Info

Publication number: CA2267634A1
Authority: CA; Canada
Prior art keywords: alaninyl; difluorophenylacetyl; methyl ester; hydrogen; butyl
Prior art date: 1996-11-22
Legal status (The legal status 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 status listed.): Abandoned

Application number

CA002267634A

Other languages

English (en)

French (fr)

Inventor

James E. Audia

Thomas C. Britton

James J. Droste

Beverly K. Folmer

George W. Huffman

Varghese John

Lee H. Latimer

Thomas E. Mabry

Jeffrey S. Nissen

Warren J. Porter

Jon K. Reel

Eugene D. Thorsett

Jay S. Tung

Jing Wu

Clark Norman Eid

William Leonard Scott

Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)

Elan Pharmaceuticals LLC

Eli Lilly and Co

Original Assignee

Individual

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.)

1996-11-22

Filing date

1997-11-21

Publication date

1998-05-28

1997-11-21 Application filed by Individual filed Critical Individual

1998-05-28 Publication of CA2267634A1 publication Critical patent/CA2267634A1/en

Status Abandoned legal-status Critical Current

Links

238000000034 method Methods 0.000 title claims abstract description 296
150000001875 compounds Chemical class 0.000 title claims abstract description 210
230000015572 biosynthetic process Effects 0.000 title claims abstract description 130
238000003786 synthesis reaction Methods 0.000 title claims abstract description 127
108090000765 processed proteins & peptides Proteins 0.000 title claims abstract description 31
230000002401 inhibitory effect Effects 0.000 title claims description 11
239000008194 pharmaceutical composition Substances 0.000 claims abstract description 47
-1 3-nitrophenyl Chemical group 0.000 claims description 777
229910052739 hydrogen Inorganic materials 0.000 claims description 342
239000001257 hydrogen Substances 0.000 claims description 340
125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 330
125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 200
XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 142
125000000217 alkyl group Chemical group 0.000 claims description 118
125000003118 aryl group Chemical group 0.000 claims description 118
125000001072 heteroaryl group Chemical group 0.000 claims description 112
239000000203 mixture Substances 0.000 claims description 99
125000000753 cycloalkyl group Chemical group 0.000 claims description 90
125000000547 substituted alkyl group Chemical group 0.000 claims description 90
125000000623 heterocyclic group Chemical group 0.000 claims description 88
KIYRSYYOVDHSPG-ZETCQYMHSA-N (2s)-2-amino-2-phenylacetamide Chemical compound NC(=O)[C@@H](N)C1=CC=CC=C1 KIYRSYYOVDHSPG-ZETCQYMHSA-N 0.000 claims description 86
125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 80
125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 57
125000003342 alkenyl group Chemical group 0.000 claims description 55
150000004702 methyl esters Chemical class 0.000 claims description 50
229910052757 nitrogen Chemical group 0.000 claims description 48
125000004211 3,5-difluorophenyl group Chemical group [H]C1=C(F)C([H])=C(*)C([H])=C1F 0.000 claims description 47
125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 46
125000005017 substituted alkenyl group Chemical group 0.000 claims description 46
GXBRYTMUEZNYJT-UHFFFAOYSA-N 2-anilinoacetamide Chemical compound NC(=O)CNC1=CC=CC=C1 GXBRYTMUEZNYJT-UHFFFAOYSA-N 0.000 claims description 45
125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 43
125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 42
125000003545 alkoxy group Chemical group 0.000 claims description 39
IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical group N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 38
125000005309 thioalkoxy group Chemical group 0.000 claims description 38
BEBCJVAWIBVWNZ-UHFFFAOYSA-N glycinamide Chemical compound NCC(N)=O BEBCJVAWIBVWNZ-UHFFFAOYSA-N 0.000 claims description 36
125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 34
YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 32
150000002148 esters Chemical class 0.000 claims description 32
125000000304 alkynyl group Chemical group 0.000 claims description 31
125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 30
125000004432 carbon atom Chemical group C* 0.000 claims description 28
125000005415 substituted alkoxy group Chemical group 0.000 claims description 24
125000000392 cycloalkenyl group Chemical group 0.000 claims description 23
125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 23
125000001424 substituent group Chemical group 0.000 claims description 23
125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 23
125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 22
125000004426 substituted alkynyl group Chemical group 0.000 claims description 22
ZGUNAGUHMKGQNY-ZETCQYMHSA-N L-alpha-phenylglycine zwitterion Chemical compound OC(=O)[C@@H](N)C1=CC=CC=C1 ZGUNAGUHMKGQNY-ZETCQYMHSA-N 0.000 claims description 20
125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 20
VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 19
ZGUNAGUHMKGQNY-SSDOTTSWSA-N D-alpha-phenylglycine Chemical compound OC(=O)[C@H](N)C1=CC=CC=C1 ZGUNAGUHMKGQNY-SSDOTTSWSA-N 0.000 claims description 18
DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 claims description 18
125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 17
125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 claims description 17
125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 17
125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 17
125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 17
RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 16
125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 16
229910052760 oxygen Inorganic materials 0.000 claims description 16
QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 15
125000004122 cyclic group Chemical group 0.000 claims description 15
VSDUZFOSJDMAFZ-VIFPVBQESA-N methyl L-phenylalaninate Chemical compound COC(=O)[C@@H](N)CC1=CC=CC=C1 VSDUZFOSJDMAFZ-VIFPVBQESA-N 0.000 claims description 15
239000001301 oxygen Substances 0.000 claims description 15
229960005190 phenylalanine Drugs 0.000 claims description 15
125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 claims description 14
NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 14
125000001153 fluoro group Chemical group F* 0.000 claims description 14
229910052717 sulfur Inorganic materials 0.000 claims description 14
239000011593 sulfur Chemical group 0.000 claims description 14
125000001541 3-thienyl group Chemical group S1C([H])=C([*])C([H])=C1[H] 0.000 claims description 13
QNAYBMKLOCPYGJ-UWTATZPHSA-N D-alanine Chemical compound C[C@@H](N)C(O)=O QNAYBMKLOCPYGJ-UWTATZPHSA-N 0.000 claims description 13
QNAYBMKLOCPYGJ-UHFFFAOYSA-N D-alpha-Ala Natural products CC([NH3+])C([O-])=O QNAYBMKLOCPYGJ-UHFFFAOYSA-N 0.000 claims description 13
125000004181 carboxyalkyl group Chemical group 0.000 claims description 13
125000002877 alkyl aryl group Chemical group 0.000 claims description 12
125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 12
125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims description 12
KQSSATDQUYCRGS-UHFFFAOYSA-N methyl glycinate Chemical compound COC(=O)CN KQSSATDQUYCRGS-UHFFFAOYSA-N 0.000 claims description 12
239000004471 Glycine Substances 0.000 claims description 11
150000003839 salts Chemical class 0.000 claims description 11
125000002941 2-furyl group Chemical group O1C([*])=C([H])C([H])=C1[H] 0.000 claims description 10
125000004200 2-methoxyethyl group Chemical group [H]C([H])([H])OC([H])([H])C([H])([H])* 0.000 claims description 10
125000000094 2-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 10
125000000590 4-methylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 claims description 10
UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 10
125000004494 ethyl ester group Chemical group 0.000 claims description 10
125000003107 substituted aryl group Chemical group 0.000 claims description 10
150000003573 thiols Chemical class 0.000 claims description 10
125000004485 2-pyrrolidinyl group Chemical group [H]N1C([H])([H])C([H])([H])C([H])([H])C1([H])* 0.000 claims description 9
125000004180 3-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(F)=C1[H] 0.000 claims description 9
125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims description 9
125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 9
125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims description 9
125000004800 4-bromophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Br 0.000 claims description 8
125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims description 8
DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 claims description 8
125000005842 heteroatom Chemical group 0.000 claims description 8
229960004452 methionine Drugs 0.000 claims description 8
125000000636 p-nitrophenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)[N+]([O-])=O 0.000 claims description 8
QLNJFJADRCOGBJ-UHFFFAOYSA-N propionamide Chemical compound CCC(N)=O QLNJFJADRCOGBJ-UHFFFAOYSA-N 0.000 claims description 8
229940080818 propionamide Drugs 0.000 claims description 8
125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 claims description 8
SJMDMGHPMLKLHQ-UHFFFAOYSA-N tert-butyl 2-aminoacetate Chemical compound CC(C)(C)OC(=O)CN SJMDMGHPMLKLHQ-UHFFFAOYSA-N 0.000 claims description 8
125000004179 3-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(Cl)=C1[H] 0.000 claims description 7
125000001637 1-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C(*)=C([H])C([H])=C([H])C2=C1[H] 0.000 claims description 6
125000004198 2-fluorophenyl group Chemical group [H]C1=C([H])C(F)=C(*)C([H])=C1[H] 0.000 claims description 6
125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 6
AYFVYJQAPQTCCC-STHAYSLISA-N D-threonine Chemical compound C[C@H](O)[C@@H](N)C(O)=O AYFVYJQAPQTCCC-STHAYSLISA-N 0.000 claims description 6
229930182822 D-threonine Natural products 0.000 claims description 6
AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 claims description 6
125000004429 atom Chemical group 0.000 claims description 6
125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 claims description 6
125000004433 nitrogen atom Chemical group N* 0.000 claims description 6
125000004043 oxo group Chemical group O=* 0.000 claims description 6
125000006503 p-nitrobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1[N+]([O-])=O)C([H])([H])* 0.000 claims description 6
125000004076 pyridyl group Chemical group 0.000 claims description 6
238000006467 substitution reaction Methods 0.000 claims description 6
OGYGFUAIIOPWQD-UHFFFAOYSA-N 1,3-thiazolidine Chemical compound C1CSCN1 OGYGFUAIIOPWQD-UHFFFAOYSA-N 0.000 claims description 5
125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 claims description 5
125000004189 3,4-dichlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(Cl)C([H])=C1* 0.000 claims description 5
125000004207 3-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(OC([H])([H])[H])=C1[H] 0.000 claims description 5
125000000219 ethylidene group Chemical group [H]C(=[*])C([H])([H])[H] 0.000 claims description 5
229960004295 valine Drugs 0.000 claims description 5
PZUOEYPTQJILHP-GBXIJSLDSA-N (2s,3r)-2-amino-3-hydroxybutanamide Chemical compound C[C@@H](O)[C@H](N)C(N)=O PZUOEYPTQJILHP-GBXIJSLDSA-N 0.000 claims description 4
125000004201 2,4-dichlorophenyl group Chemical group [H]C1=C([H])C(*)=C(Cl)C([H])=C1Cl 0.000 claims description 4
125000004182 2-chlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(*)C([H])=C1[H] 0.000 claims description 4
125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 4
125000006275 3-bromophenyl group Chemical group [H]C1=C([H])C(Br)=C([H])C(*)=C1[H] 0.000 claims description 4
125000006291 3-hydroxybenzyl group Chemical group [H]OC1=C([H])C([H])=C([H])C(=C1[H])C([H])([H])* 0.000 claims description 4
125000005917 3-methylpentyl group Chemical group 0.000 claims description 4
125000004860 4-ethylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])C([H])([H])[H] 0.000 claims description 4
125000003143 4-hydroxybenzyl group Chemical group [H]C([*])([H])C1=C([H])C([H])=C(O[H])C([H])=C1[H] 0.000 claims description 4
QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 4
JXYACYYPACQCDM-UHFFFAOYSA-N Benzyl glycinate Chemical compound NCC(=O)OCC1=CC=CC=C1 JXYACYYPACQCDM-UHFFFAOYSA-N 0.000 claims description 4
OBSIQMZKFXFYLV-QMMMGPOBSA-N L-phenylalanine amide Chemical compound NC(=O)[C@@H](N)CC1=CC=CC=C1 OBSIQMZKFXFYLV-QMMMGPOBSA-N 0.000 claims description 4
ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 claims description 4
125000004202 aminomethyl group Chemical group [H]N([H])C([H])([H])* 0.000 claims description 4
HONIICLYMWZJFZ-UHFFFAOYSA-N azetidine Chemical compound C1CNC1 HONIICLYMWZJFZ-UHFFFAOYSA-N 0.000 claims description 4
125000004244 benzofuran-2-yl group Chemical group [H]C1=C(*)OC2=C([H])C([H])=C([H])C([H])=C12 0.000 claims description 4
125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 4
230000001413 cellular effect Effects 0.000 claims description 4
125000006378 chloropyridyl group Chemical group 0.000 claims description 4
125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 4
NTNZTEQNFHNYBC-UHFFFAOYSA-N ethyl 2-aminoacetate Chemical compound CCOC(=O)CN NTNZTEQNFHNYBC-UHFFFAOYSA-N 0.000 claims description 4
125000006379 fluoropyridyl group Chemical group 0.000 claims description 4
229960000310 isoleucine Drugs 0.000 claims description 4
125000000040 m-tolyl group Chemical group [H]C1=C([H])C(*)=C([H])C(=C1[H])C([H])([H])[H] 0.000 claims description 4
WBLGPKGZZDMIPA-YJBOKZPZSA-N methyl (2s)-3-phenyl-2-[[(2s)-2-[(2-phenylacetyl)amino]propanoyl]amino]propanoate Chemical compound C([C@@H](C(=O)OC)NC(=O)[C@H](C)NC(=O)CC=1C=CC=CC=1)C1=CC=CC=C1 WBLGPKGZZDMIPA-YJBOKZPZSA-N 0.000 claims description 4
BLWYXBNNBYXPPL-YFKPBYRVSA-N methyl (2s)-pyrrolidine-2-carboxylate Chemical compound COC(=O)[C@@H]1CCCN1 BLWYXBNNBYXPPL-YFKPBYRVSA-N 0.000 claims description 4
SZJUWKPNWWCOPG-UHFFFAOYSA-N methyl 2-anilinoacetate Chemical compound COC(=O)CNC1=CC=CC=C1 SZJUWKPNWWCOPG-UHFFFAOYSA-N 0.000 claims description 4
125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 claims description 4
125000003261 o-tolyl group Chemical group [H]C1=C([H])C(*)=C(C([H])=C1[H])C([H])([H])[H] 0.000 claims description 4
125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 claims description 4
MDHYEMXUFSJLGV-UHFFFAOYSA-N phenethyl acetate Chemical compound CC(=O)OCCC1=CC=CC=C1 MDHYEMXUFSJLGV-UHFFFAOYSA-N 0.000 claims description 4
125000004574 piperidin-2-yl group Chemical group N1C(CCCC1)* 0.000 claims description 4
229960002429 proline Drugs 0.000 claims description 4
125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 claims description 4
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 4
125000004299 tetrazol-5-yl group Chemical group [H]N1N=NC(*)=N1 0.000 claims description 4
125000004265 thionaphthen-2-yl group Chemical group [H]C1=C(*)SC2=C([H])C([H])=C([H])C([H])=C12 0.000 claims description 4
230000006866 deterioration Effects 0.000 claims description 3
FBEHFRAORPEGFH-UHFFFAOYSA-N Allyxycarb Chemical group CNC(=O)OC1=CC(C)=C(N(CC=C)CC=C)C(C)=C1 FBEHFRAORPEGFH-UHFFFAOYSA-N 0.000 claims description 2
125000000341 threoninyl group Chemical group [H]OC([H])(C([H])([H])[H])C([H])(N([H])[H])C(*)=O 0.000 claims 3
NBLJHBLKFTVEBO-UHFFFAOYSA-N 2-amino-N-[2-[[2-(3,5-difluorophenyl)acetyl]amino]-2-phenylacetyl]-2-phenylacetamide Chemical compound FC=1C=C(C=C(C=1)F)CC(=O)NC(C1=CC=CC=C1)C(=O)NC(C(N)C1=CC=CC=C1)=O NBLJHBLKFTVEBO-UHFFFAOYSA-N 0.000 claims 1
125000003412 L-alanyl group Chemical group [H]N([H])[C@@](C([H])([H])[H])(C(=O)[*])[H] 0.000 claims 1
YQNVZFSYQODYOG-UHFFFAOYSA-N N-(2-amino-2-phenylacetyl)-2-[[2-(3,5-difluorophenyl)acetyl]amino]-3-methylbutanamide Chemical compound FC=1C=C(C=C(C=1)F)CC(=O)NC(C(C)C)C(=O)NC(C(N)C1=CC=CC=C1)=O YQNVZFSYQODYOG-UHFFFAOYSA-N 0.000 claims 1
KXKVLQRXCPHEJC-UHFFFAOYSA-N methyl acetate Chemical compound COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 claims 1
VMWJCFLUSKZZDX-UHFFFAOYSA-N n,n-dimethylmethanamine Chemical compound [CH2]N(C)C VMWJCFLUSKZZDX-UHFFFAOYSA-N 0.000 claims 1
IYDBQCZYZKQGCD-YWZLYKJASA-N tert-butyl (2s)-2-[[(2s)-2-[[2-(3,5-difluorophenyl)acetyl]amino]propanoyl]amino]-3-phenylpropanoate Chemical compound N([C@@H](C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)OC(C)(C)C)C(=O)CC1=CC(F)=CC(F)=C1 IYDBQCZYZKQGCD-YWZLYKJASA-N 0.000 claims 1
JAELLLITIZHOGQ-UHFFFAOYSA-N tert-butyl propanoate Chemical compound CCC(=O)OC(C)(C)C JAELLLITIZHOGQ-UHFFFAOYSA-N 0.000 claims 1
208000024827 Alzheimer disease Diseases 0.000 abstract description 41
238000006243 chemical reaction Methods 0.000 description 124
238000005481 NMR spectroscopy Methods 0.000 description 87
VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 86
238000000746 purification Methods 0.000 description 84
239000000741 silica gel Substances 0.000 description 76
229910002027 silica gel Inorganic materials 0.000 description 76
YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 66
VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 60
239000007787 solid Substances 0.000 description 59
235000019439 ethyl acetate Nutrition 0.000 description 57
238000004949 mass spectrometry Methods 0.000 description 57
HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 53
239000000243 solution Substances 0.000 description 51
OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 48
238000001914 filtration Methods 0.000 description 47
229940024606 amino acid Drugs 0.000 description 43
235000001014 amino acid Nutrition 0.000 description 42
230000002829 reductive effect Effects 0.000 description 42
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239000003765 sweetening agent Substances 0.000 description 1
230000009885 systemic effect Effects 0.000 description 1
239000007916 tablet composition Substances 0.000 description 1
229940095064 tartrate Drugs 0.000 description 1
CLOXAWYNXXEWBT-UHFFFAOYSA-N tert-butyl n-(3-oxocyclopentyl)carbamate Chemical compound CC(C)(C)OC(=O)NC1CCC(=O)C1 CLOXAWYNXXEWBT-UHFFFAOYSA-N 0.000 description 1
GJJMACLSYWGZLO-QMMMGPOBSA-N tert-butyl n-[(2s)-2-aminohexanoyl]carbamate Chemical compound CCCC[C@H](N)C(=O)NC(=O)OC(C)(C)C GJJMACLSYWGZLO-QMMMGPOBSA-N 0.000 description 1
238000012360 testing method Methods 0.000 description 1
125000005207 tetraalkylammonium group Chemical group 0.000 description 1
WHRNULOCNSKMGB-UHFFFAOYSA-N tetrahydrofuran thf Chemical compound C1CCOC1.C1CCOC1 WHRNULOCNSKMGB-UHFFFAOYSA-N 0.000 description 1
125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
WROMPOXWARCANT-UHFFFAOYSA-N tfa trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.OC(=O)C(F)(F)F WROMPOXWARCANT-UHFFFAOYSA-N 0.000 description 1
125000004495 thiazol-4-yl group Chemical group S1C=NC(=C1)* 0.000 description 1
238000004809 thin layer chromatography Methods 0.000 description 1
DUYAAUVXQSMXQP-UHFFFAOYSA-M thioacetate Chemical compound CC([S-])=O DUYAAUVXQSMXQP-UHFFFAOYSA-M 0.000 description 1
125000005296 thioaryloxy group Chemical group 0.000 description 1
125000005404 thioheteroaryloxy group Chemical group 0.000 description 1
ZPHGMBGIFODUMF-UHFFFAOYSA-N thiophen-2-ylmethanol Chemical compound OCC1=CC=CS1 ZPHGMBGIFODUMF-UHFFFAOYSA-N 0.000 description 1
ZKQMGZYLARVFFJ-NSHDSACASA-N thiophen-2-ylmethyl (2s)-2-[[2-(3-chlorophenyl)acetyl]amino]propanoate Chemical compound N([C@@H](C)C(=O)OCC=1SC=CC=1)C(=O)CC1=CC=CC(Cl)=C1 ZKQMGZYLARVFFJ-NSHDSACASA-N 0.000 description 1
JEPPWCFIANJOGN-NSHDSACASA-N thiophen-3-ylmethyl (2s)-2-[[2-(3-chlorophenyl)acetyl]amino]propanoate Chemical compound N([C@@H](C)C(=O)OCC1=CSC=C1)C(=O)CC1=CC=CC(Cl)=C1 JEPPWCFIANJOGN-NSHDSACASA-N 0.000 description 1
VXUYXOFXAQZZMF-UHFFFAOYSA-N titanium(IV) isopropoxide Chemical compound CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C VXUYXOFXAQZZMF-UHFFFAOYSA-N 0.000 description 1
239000012049 topical pharmaceutical composition Substances 0.000 description 1
235000010487 tragacanth Nutrition 0.000 description 1
239000000196 tragacanth Substances 0.000 description 1
229940116362 tragacanth Drugs 0.000 description 1
VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
230000037317 transdermal delivery Effects 0.000 description 1
230000009466 transformation Effects 0.000 description 1
238000000844 transformation Methods 0.000 description 1
QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
BKOOMYPCSUNDGP-UHFFFAOYSA-N trimethyl-ethylene Natural products CC=C(C)C BKOOMYPCSUNDGP-UHFFFAOYSA-N 0.000 description 1
SEDZOYHHAIAQIW-UHFFFAOYSA-N trimethylsilyl azide Chemical compound C[Si](C)(C)N=[N+]=[N-] SEDZOYHHAIAQIW-UHFFFAOYSA-N 0.000 description 1
238000009827 uniform distribution Methods 0.000 description 1
238000005292 vacuum distillation Methods 0.000 description 1
239000004474 valine Substances 0.000 description 1
230000002792 vascular Effects 0.000 description 1
239000003981 vehicle Substances 0.000 description 1
239000003039 volatile agent Substances 0.000 description 1
239000000080 wetting agent Substances 0.000 description 1
239000011592 zinc chloride Substances 0.000 description 1
235000005074 zinc chloride Nutrition 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
- C07K5/08—Tripeptides
- C07K5/0827—Tripeptides containing heteroatoms different from O, S, or N
- 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
- 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
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
- 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
- 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
- C07K5/06034—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 2 to 4 carbon atoms
- 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
- C07K5/06034—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 2 to 4 carbon atoms
- C07K5/06043—Leu-amino acid
- 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
- C07K5/0606—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing heteroatoms not provided for by C07K5/06086 - C07K5/06139, e.g. Ser, Met, Cys, Thr
- 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
- C07K5/06078—Dipeptides with the first amino acid being neutral and aromatic or cycloaliphatic
- 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
- C07K5/06191—Dipeptides containing heteroatoms different from O, S, or N
- 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
- C07K5/08—Tripeptides
- C07K5/0802—Tripeptides with the first amino acid being neutral
- C07K5/0804—Tripeptides with the first amino acid being neutral and aliphatic
- C07K5/0806—Tripeptides with the first amino acid being neutral and aliphatic the side chain containing 0 or 1 carbon atoms, i.e. Gly, Ala
- 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
- C07K5/08—Tripeptides
- C07K5/0802—Tripeptides with the first amino acid being neutral
- C07K5/0804—Tripeptides with the first amino acid being neutral and aliphatic
- C07K5/0808—Tripeptides with the first amino acid being neutral and aliphatic the side chain containing 2 to 4 carbon atoms, e.g. Val, Ile, Leu
- 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
- C07K5/08—Tripeptides
- C07K5/0802—Tripeptides with the first amino acid being neutral
- C07K5/0812—Tripeptides with the first amino acid being neutral and aromatic or cycloaliphatic
- 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)
Organic Chemistry (AREA)
Health & Medical Sciences (AREA)
General Health & Medical Sciences (AREA)
Life Sciences & Earth Sciences (AREA)
Medicinal Chemistry (AREA)
Proteomics, Peptides & Aminoacids (AREA)
Molecular Biology (AREA)
Genetics & Genomics (AREA)
Biophysics (AREA)
Biochemistry (AREA)
Bioinformatics & Cheminformatics (AREA)
Neurosurgery (AREA)
Engineering & Computer Science (AREA)
Neurology (AREA)
Biomedical Technology (AREA)
Veterinary Medicine (AREA)
General Chemical & Material Sciences (AREA)
Public Health (AREA)
Psychiatry (AREA)
Pharmacology & Pharmacy (AREA)
Hospice & Palliative Care (AREA)
Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
Animal Behavior & Ethology (AREA)
Chemical Kinetics & Catalysis (AREA)
Peptides Or Proteins (AREA)
Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Plural Heterocyclic Compounds (AREA)
Hydrogenated Pyridines (AREA)

CA002267634A 1996-11-22 1997-11-21 Methods and compounds for inhibiting .beta.-amyloid peptide release and/or synthesis Abandoned CA2267634A1 (en)

Applications Claiming Priority (9)

Application Number	Priority Date	Filing Date	Title
US75544296A	1996-11-22	1996-11-22
US08/755,442		1996-11-22
US80752897A	1997-02-28	1997-02-28
US80852897A	1997-02-28	1997-02-28
US80742797A	1997-02-28	1997-02-28
US08/808,528		1997-02-28
US08/807,528		1997-02-28
US08/807,427		1997-02-28
PCT/US1997/020804 WO1998022494A2 (en)	1996-11-22	1997-11-21	METHODS AND COMPOUNDS FOR INHIBITING β-AMYLOID PEPTIDE RELEASE AND/OR SYNTHESIS

Publications (1)

Publication Number	Publication Date
CA2267634A1 true CA2267634A1 (en)	1998-05-28

Family

ID=27505670

Family Applications (1)

Application Number	Title	Priority Date	Filing Date
CA002267634A Abandoned CA2267634A1 (en)	1996-11-22	1997-11-21	Methods and compounds for inhibiting .beta.-amyloid peptide release and/or synthesis

Country Status (21)

Country	Link
EP (1)	EP0942924A2 (cs)
JP (1)	JP2001503782A (cs)
KR (1)	KR20000069064A (cs)
CN (1)	CN1238779A (cs)
AR (1)	AR016751A1 (cs)
AU (1)	AU5356198A (cs)
BR (1)	BR9713400A (cs)
CA (1)	CA2267634A1 (cs)
CO (1)	CO4910156A1 (cs)
CZ (1)	CZ122899A3 (cs)
EA (1)	EA199900490A1 (cs)
HR (1)	HRP970627A2 (cs)
HU (1)	HUP0100270A3 (cs)
ID (1)	ID22044A (cs)
IL (1)	IL129083A0 (cs)
NO (1)	NO992368L (cs)
NZ (1)	NZ334690A (cs)
PE (1)	PE16999A1 (cs)
TR (3)	TR199902938T2 (cs)
WO (1)	WO1998022494A2 (cs)
YU (1)	YU46097A (cs)

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WO1999066934A1 (en) *	1998-06-22	1999-12-29	Elan Pharmaceuticals, Inc.	CYCLIC AMINO ACID COMPOUNDS, PHARMACEUTICAL COMPOSITIONS COMPRISING SAME, AND METHODS FOR INHIBITING β-AMYLOID PEPTIDE RELEASE AND/OR ITS SYNTHESIS BY USE OF SUCH COMPOUNDS
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AU2001254763A1 (en)	2000-03-31	2001-10-08	Prosidion Limited	Method for the improvement of islet signaling in diabetes mellitus and for its prevention
WO2001087354A2 (en)	2000-05-17	2001-11-22	Bristol-Myers Squibb Pharma Company	Use of small molecule radioligands for diagnostic imaging
CN1386118A (zh)	2000-06-01	2002-12-18	布里斯托尔-迈尔斯斯奎布药品公司	作为Aβ蛋白产生抑制剂的被环状琥珀酸酯取代的内酰胺类化合物
FR2832152A1 (fr) *	2001-11-09	2003-05-16	Aventis Pharma Sa	Utilisation de derives de 2-amino-thiazoline comme inhibiteurs de no-synthase inductible
US6432944B1 (en)	2000-07-06	2002-08-13	Bristol-Myers Squibb Company	Benzodiazepinone β-amyloid inhibitors: arylacetamidoalanyl derivatives
GB0016681D0 (en)	2000-07-06	2000-08-23	Merck Sharp & Dohme	Therapeutic compounds
US7132104B1 (en)	2000-10-27	2006-11-07	Probiodrug Ag	Modulation of central nervous system (CNS) dipeptidyl peptidase IV (DPIV) -like activity for the treatment of neurological and neuropsychological disorders
US6890905B2 (en)	2001-04-02	2005-05-10	Prosidion Limited	Methods for improving islet signaling in diabetes mellitus and for its prevention
US7368421B2 (en)	2001-06-27	2008-05-06	Probiodrug Ag	Use of dipeptidyl peptidase IV inhibitors in the treatment of multiple sclerosis
US20030130199A1 (en)	2001-06-27	2003-07-10	Von Hoersten Stephan	Dipeptidyl peptidase IV inhibitors and their uses as anti-cancer agents
DE10150203A1 (de)	2001-10-12	2003-04-17	Probiodrug Ag	Peptidylketone als Inhibitoren der DPIV
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DE10143840A1 (de) *	2001-09-06	2003-03-27	Probiodrug Ag	Neue Inhibitoren der Dipeptidylpeptidase I
US6844316B2 (en)	2001-09-06	2005-01-18	Probiodrug Ag	Inhibitors of dipeptidyl peptidase I
JP2005526005A (ja)	2001-11-09	2005-09-02	アベンティス・ファーマ・ソシエテ・アノニム	誘導型ｎｏシンターゼの阻害剤としての２−アミノ−チアゾリン誘導体及びその使用
SK3622004A3 (sk)	2002-02-28	2005-02-04	Prosidion Limited	Inhibítory DPIV na báze glutaminylu
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1997
- 1997-11-18 AR ARP970105393A patent/AR016751A1/es not_active Application Discontinuation
- 1997-11-19 HR HR08/808,528A patent/HRP970627A2/hr not_active Application Discontinuation
- 1997-11-20 PE PE1997001056A patent/PE16999A1/es not_active Application Discontinuation
- 1997-11-21 KR KR1019997004486A patent/KR20000069064A/ko not_active Withdrawn
- 1997-11-21 CZ CZ991228A patent/CZ122899A3/cs unknown
- 1997-11-21 JP JP52375698A patent/JP2001503782A/ja active Pending
- 1997-11-21 EP EP97950601A patent/EP0942924A2/en not_active Withdrawn
- 1997-11-21 BR BR9713400-7A patent/BR9713400A/pt not_active IP Right Cessation
- 1997-11-21 TR TR1999/02938T patent/TR199902938T2/xx unknown
- 1997-11-21 NZ NZ334690A patent/NZ334690A/en unknown
- 1997-11-21 AU AU53561/98A patent/AU5356198A/en not_active Abandoned
- 1997-11-21 IL IL12908397A patent/IL129083A0/xx unknown
- 1997-11-21 CO CO97068215A patent/CO4910156A1/es unknown
- 1997-11-21 CN CN97199803A patent/CN1238779A/zh active Pending
- 1997-11-21 TR TR1999/02937T patent/TR199902937T2/xx unknown
- 1997-11-21 CA CA002267634A patent/CA2267634A1/en not_active Abandoned
- 1997-11-21 YU YU46097A patent/YU46097A/sh unknown
- 1997-11-21 WO PCT/US1997/020804 patent/WO1998022494A2/en not_active Ceased
- 1997-11-21 EA EA199900490A patent/EA199900490A1/ru unknown
- 1997-11-21 ID IDW990394A patent/ID22044A/id unknown
- 1997-11-21 TR TR1999/01133T patent/TR199901133T2/xx unknown
- 1997-11-21 HU HU0100270A patent/HUP0100270A3/hu unknown
1999
- 1999-05-14 NO NO992368A patent/NO992368L/no not_active Application Discontinuation

Also Published As

Publication number	Publication date
NZ334690A (en)	2001-09-28
AU5356198A (en)	1998-06-10
YU46097A (sh)	2000-10-30
HRP970627A2 (en)	1998-08-31
WO1998022494A2 (en)	1998-05-28
TR199901133T2 (xx)	1999-07-21
IL129083A0 (en)	2000-02-17
EP0942924A2 (en)	1999-09-22
ID22044A (id)	1999-08-26
TR199902937T2 (xx)	2001-01-22
TR199902938T2 (xx)	2002-06-21
HUP0100270A3 (en)	2001-09-28
KR20000069064A (ko)	2000-11-25
NO992368D0 (no)	1999-05-14
EA199900490A1 (ru)	2000-02-28
JP2001503782A (ja)	2001-03-21
NO992368L (no)	1999-06-21
CN1238779A (zh)	1999-12-15
HUP0100270A2 (hu)	2001-08-28
CZ122899A3 (cs)	1999-10-13
PE16999A1 (es)	1999-02-19
WO1998022494A3 (en)	1998-11-26
CO4910156A1 (es)	2000-04-24
AR016751A1 (es)	2001-08-01
BR9713400A (pt)	2000-01-25

Legal Events

Date	Code	Title	Description
2002-11-21	EEER	Examination request
2005-11-21	FZDE	Discontinued

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