UA74849C2 - Lactam - Google Patents

Lactam Download PDF

Info

Publication number: UA74849C2
Authority: UA; Ukraine
Prior art keywords: methyl; benzazepin; tetrahydro; amino; formula
Prior art date: 2000-11-17

Application number

UA2003054408A

Other languages

English (en)

Ukrainian (uk)

Inventor

James Edmund Audia

Jeffrey S Nissen

Original Assignee

Lilly Co Eli

Elan Pharm Inc

Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)

2000-11-17

Filing date

2001-05-11

Publication date

2006-02-15

2001-05-11 Application filed by Lilly Co Eli, Elan Pharm Inc filed Critical Lilly Co Eli

2006-02-15 Publication of UA74849C2 publication Critical patent/UA74849C2/uk

Links

150000003951 lactams Chemical class 0.000 title description 5
150000001875 compounds Chemical class 0.000 claims abstract description 93
238000000034 method Methods 0.000 claims abstract description 51
238000003786 synthesis reaction Methods 0.000 claims description 24
230000015572 biosynthetic process Effects 0.000 claims description 22
108090000765 processed proteins & peptides Proteins 0.000 claims description 19
208000024827 Alzheimer disease Diseases 0.000 claims description 16
239000003085 diluting agent Substances 0.000 claims description 11
230000002401 inhibitory effect Effects 0.000 claims description 8
230000005764 inhibitory process Effects 0.000 claims description 8
239000008194 pharmaceutical composition Substances 0.000 claims description 8
238000011161 development Methods 0.000 claims description 5
230000002265 prevention Effects 0.000 claims description 2
239000000203 mixture Substances 0.000 abstract description 68
XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 60
YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 54
238000006243 chemical reaction Methods 0.000 description 54
239000000243 solution Substances 0.000 description 53
OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 48
WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 36
XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 34
LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 28
239000002253 acid Substances 0.000 description 25
HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 24
239000002904 solvent Substances 0.000 description 24
238000002425 crystallisation Methods 0.000 description 22
230000008025 crystallization Effects 0.000 description 22
-1 for example Substances 0.000 description 22
239000004480 active ingredient Substances 0.000 description 21
150000003839 salts Chemical class 0.000 description 19
UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 16
239000000725 suspension Substances 0.000 description 16
238000001914 filtration Methods 0.000 description 15
239000000047 product Substances 0.000 description 15
239000011541 reaction mixture Substances 0.000 description 15
239000010410 layer Substances 0.000 description 14
238000003756 stirring Methods 0.000 description 13
239000003826 tablet Substances 0.000 description 13
CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 12
BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 12
238000000605 extraction Methods 0.000 description 12
RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 11
KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 11
ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 11
239000007864 aqueous solution Substances 0.000 description 11
239000002585 base Substances 0.000 description 11
210000004027 cell Anatomy 0.000 description 11
239000004615 ingredient Substances 0.000 description 11
239000012265 solid product Substances 0.000 description 11
JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-diisopropylethylamine Substances CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 10
235000001014 amino acid Nutrition 0.000 description 10
150000001413 amino acids Chemical class 0.000 description 10
238000005859 coupling reaction Methods 0.000 description 10
HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 10
239000012044 organic layer Substances 0.000 description 10
238000002360 preparation method Methods 0.000 description 10
WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
239000000872 buffer Chemical class 0.000 description 9
238000001556 precipitation Methods 0.000 description 9
230000008569 process Effects 0.000 description 9
VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
239000002775 capsule Substances 0.000 description 8
238000004587 chromatography analysis Methods 0.000 description 8
238000007796 conventional method Methods 0.000 description 8
229910000030 sodium bicarbonate Inorganic materials 0.000 description 8
235000017557 sodium bicarbonate Nutrition 0.000 description 8
235000011121 sodium hydroxide Nutrition 0.000 description 8
239000000126 substance Substances 0.000 description 8
238000001665 trituration Methods 0.000 description 8
NAWXUBYGYWOOIX-SFHVURJKSA-N (2s)-2-[[4-[2-(2,4-diaminoquinazolin-6-yl)ethyl]benzoyl]amino]-4-methylidenepentanedioic acid Chemical compound C1=CC2=NC(N)=NC(N)=C2C=C1CCC1=CC=C(C(=O)N[C@@H](CC(=C)C(O)=O)C(O)=O)C=C1 NAWXUBYGYWOOIX-SFHVURJKSA-N 0.000 description 7
CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 7
KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 7
150000003934 aromatic aldehydes Chemical class 0.000 description 7
239000005018 casein Substances 0.000 description 7
BECPQYXYKAMYBN-UHFFFAOYSA-N casein, tech. Chemical compound NCCCCC(C(O)=O)N=C(O)C(CC(O)=O)N=C(O)C(CCC(O)=N)N=C(O)C(CC(C)C)N=C(O)C(CCC(O)=O)N=C(O)C(CC(O)=O)N=C(O)C(CCC(O)=O)N=C(O)C(C(C)O)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=O)N=C(O)C(CCC(O)=O)N=C(O)C(COP(O)(O)=O)N=C(O)C(CCC(O)=N)N=C(O)C(N)CC1=CC=CC=C1 BECPQYXYKAMYBN-UHFFFAOYSA-N 0.000 description 7
235000021240 caseins Nutrition 0.000 description 7
239000002609 medium Substances 0.000 description 7
239000007787 solid Substances 0.000 description 7
YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 7
RETLCOJLSHBJEZ-UHFFFAOYSA-N 5-amino-3-methyl-2,5-dihydro-1h-3-benzazepin-4-one Chemical compound NC1C(=O)N(C)CCC2=CC=CC=C21 RETLCOJLSHBJEZ-UHFFFAOYSA-N 0.000 description 6
QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
ZRALSGWEFCBTJO-UHFFFAOYSA-N Guanidine Chemical compound NC(N)=N ZRALSGWEFCBTJO-UHFFFAOYSA-N 0.000 description 6
241000282414 Homo sapiens Species 0.000 description 6
VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 6
FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
229920002472 Starch Polymers 0.000 description 6
ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
239000012267 brine Substances 0.000 description 6
208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 6
239000001257 hydrogen Substances 0.000 description 6
229910052739 hydrogen Inorganic materials 0.000 description 6
VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
238000010992 reflux Methods 0.000 description 6
229920006395 saturated elastomer Polymers 0.000 description 6
HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 6
239000008107 starch Substances 0.000 description 6
235000019698 starch Nutrition 0.000 description 6
NAUWUGHLFUVNQH-UHFFFAOYSA-N 3-methyl-2,5-dihydro-1h-3-benzazepin-4-one Chemical compound C1C(=O)N(C)CCC2=CC=CC=C21 NAUWUGHLFUVNQH-UHFFFAOYSA-N 0.000 description 5
KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical class OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 5
UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 5
PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 5
238000004458 analytical method Methods 0.000 description 5
150000001540 azides Chemical class 0.000 description 5
239000003153 chemical reaction reagent Substances 0.000 description 5
201000010099 disease Diseases 0.000 description 5
239000000945 filler Substances 0.000 description 5
235000019359 magnesium stearate Nutrition 0.000 description 5
239000000463 material Substances 0.000 description 5
238000000926 separation method Methods 0.000 description 5
239000011975 tartaric acid Substances 0.000 description 5
AZKSAVLVSZKNRD-UHFFFAOYSA-M 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide Chemical compound [Br-].S1C(C)=C(C)N=C1[N+]1=NC(C=2C=CC=CC=2)=NN1C1=CC=CC=C1 AZKSAVLVSZKNRD-UHFFFAOYSA-M 0.000 description 4
108091003079 Bovine Serum Albumin Proteins 0.000 description 4
IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
229920000168 Microcrystalline cellulose Polymers 0.000 description 4
241000699670 Mus sp. Species 0.000 description 4
229930006000 Sucrose Natural products 0.000 description 4
CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 4
QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
150000001412 amines Chemical class 0.000 description 4
125000003277 amino group Chemical group 0.000 description 4
239000003125 aqueous solvent Substances 0.000 description 4
210000004556 brain Anatomy 0.000 description 4
239000002285 corn oil Substances 0.000 description 4
235000005687 corn oil Nutrition 0.000 description 4
239000007903 gelatin capsule Substances 0.000 description 4
OWFXIOWLTKNBAP-UHFFFAOYSA-N isoamyl nitrite Chemical compound CC(C)CCON=O OWFXIOWLTKNBAP-UHFFFAOYSA-N 0.000 description 4
JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 description 4
229940011051 isopropyl acetate Drugs 0.000 description 4
GWYFCOCPABKNJV-UHFFFAOYSA-M isovalerate Chemical compound CC(C)CC([O-])=O GWYFCOCPABKNJV-UHFFFAOYSA-M 0.000 description 4
229960002510 mandelic acid Drugs 0.000 description 4
238000004519 manufacturing process Methods 0.000 description 4
239000012907 medicinal substance Substances 0.000 description 4
229940016286 microcrystalline cellulose Drugs 0.000 description 4
235000019813 microcrystalline cellulose Nutrition 0.000 description 4
239000008108 microcrystalline cellulose Substances 0.000 description 4
238000002156 mixing Methods 0.000 description 4
239000012299 nitrogen atmosphere Substances 0.000 description 4
150000002923 oximes Chemical class 0.000 description 4
239000000546 pharmaceutical excipient Substances 0.000 description 4
239000002244 precipitate Substances 0.000 description 4
239000005720 sucrose Substances 0.000 description 4
238000012360 testing method Methods 0.000 description 4
238000012546 transfer Methods 0.000 description 4
MSXVEPNJUHWQHW-UHFFFAOYSA-N 2-methylbutan-2-ol Chemical compound CCC(C)(C)O MSXVEPNJUHWQHW-UHFFFAOYSA-N 0.000 description 3
ZJSQZQMVXKZAGW-UHFFFAOYSA-N 2H-benzotriazol-4-ol hydrate Chemical compound O.OC1=CC=CC2=C1N=NN2 ZJSQZQMVXKZAGW-UHFFFAOYSA-N 0.000 description 3
GUERDLPJJJMIEU-UHFFFAOYSA-N 3-methylphenethylamine Chemical compound CC1=CC=CC(CCN)=C1 GUERDLPJJJMIEU-UHFFFAOYSA-N 0.000 description 3
AGMHHPHTPYMULW-UHFFFAOYSA-N 5-hydroxyimino-3-methyl-1,2-dihydro-3-benzazepin-4-one Chemical compound ON=C1C(=O)N(C)CCC2=CC=CC=C21 AGMHHPHTPYMULW-UHFFFAOYSA-N 0.000 description 3
101710137189 Amyloid-beta A4 protein Proteins 0.000 description 3
101710151993 Amyloid-beta precursor protein Proteins 0.000 description 3
102100022704 Amyloid-beta precursor protein Human genes 0.000 description 3
WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 3
GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 3
241001465754 Metazoa Species 0.000 description 3
CHJJGSNFBQVOTG-UHFFFAOYSA-N N-methyl-guanidine Natural products CNC(N)=N CHJJGSNFBQVOTG-UHFFFAOYSA-N 0.000 description 3
KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 description 3
150000001241 acetals Chemical class 0.000 description 3
DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 3
235000004279 alanine Nutrition 0.000 description 3
150000001298 alcohols Chemical class 0.000 description 3
DZHSAHHDTRWUTF-SIQRNXPUSA-N amyloid-beta polypeptide 42 Chemical compound C([C@@H](C(=O)N[C@@H](C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@H](C(=O)NCC(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](C)C(=O)N[C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](C(C)C)C(=O)NCC(=O)NCC(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(O)=O)[C@@H](C)CC)C(C)C)NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@@H](NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)CNC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC(O)=O)C(C)C)C(C)C)C1=CC=CC=C1 DZHSAHHDTRWUTF-SIQRNXPUSA-N 0.000 description 3
238000003556 assay Methods 0.000 description 3
229940098773 bovine serum albumin Drugs 0.000 description 3
239000000969 carrier Substances 0.000 description 3
238000003776 cleavage reaction Methods 0.000 description 3
238000001816 cooling Methods 0.000 description 3
150000004683 dihydrates Chemical class 0.000 description 3
SWSQBOPZIKWTGO-UHFFFAOYSA-N dimethylaminoamidine Natural products CN(C)C(N)=N SWSQBOPZIKWTGO-UHFFFAOYSA-N 0.000 description 3
239000003814 drug Substances 0.000 description 3
238000001035 drying Methods 0.000 description 3
229960004198 guanidine Drugs 0.000 description 3
238000010438 heat treatment Methods 0.000 description 3
238000011534 incubation Methods 0.000 description 3
238000002955 isolation Methods 0.000 description 3
239000008101 lactose Substances 0.000 description 3
239000007788 liquid Substances 0.000 description 3
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125000006239 protecting group Chemical group 0.000 description 3
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230000007017 scission Effects 0.000 description 3
239000000829 suppository Substances 0.000 description 3
230000037317 transdermal delivery Effects 0.000 description 3
SPEUIVXLLWOEMJ-UHFFFAOYSA-N 1,1-dimethoxyethane Chemical compound COC(C)OC SPEUIVXLLWOEMJ-UHFFFAOYSA-N 0.000 description 2
RFFLAFLAYFXFSW-UHFFFAOYSA-N 1,2-dichlorobenzene Chemical compound ClC1=CC=CC=C1Cl RFFLAFLAYFXFSW-UHFFFAOYSA-N 0.000 description 2
NEONZQLZBJJYCB-UHFFFAOYSA-N 3-methyl-6,7-dihydro-1h-3-benzazepin-2-one Chemical compound C1C(=O)N(C)C=CC2=C1C=CCC2 NEONZQLZBJJYCB-UHFFFAOYSA-N 0.000 description 2
SFWWGMKXCYLZEG-UHFFFAOYSA-N 3-methylmorpholine Chemical compound CC1COCCN1 SFWWGMKXCYLZEG-UHFFFAOYSA-N 0.000 description 2
IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 2
LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 2
OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 2
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NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 2
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CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
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UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 2
DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 2
150000007513 acids Chemical class 0.000 description 2
230000003213 activating effect Effects 0.000 description 2
150000001295 alanines Chemical class 0.000 description 2
150000001299 aldehydes Chemical class 0.000 description 2
VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 2
125000006242 amine protecting group Chemical group 0.000 description 2
239000012298 atmosphere Substances 0.000 description 2
125000000852 azido group Chemical group *N=[N+]=[N-] 0.000 description 2
210000004369 blood Anatomy 0.000 description 2
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BTANRVKWQNVYAZ-UHFFFAOYSA-N butan-2-ol Chemical compound CCC(C)O BTANRVKWQNVYAZ-UHFFFAOYSA-N 0.000 description 2
239000003054 catalyst Substances 0.000 description 2
150000001805 chlorine compounds Chemical class 0.000 description 2
229940075614 colloidal silicon dioxide Drugs 0.000 description 2
238000004040 coloring Methods 0.000 description 2
239000003636 conditioned culture medium Substances 0.000 description 2
230000008878 coupling Effects 0.000 description 2
238000010168 coupling process Methods 0.000 description 2
239000011549 crystallization solution Substances 0.000 description 2
LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 2
239000006185 dispersion Substances 0.000 description 2
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239000008387 emulsifying waxe Substances 0.000 description 2
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125000005456 glyceride group Chemical group 0.000 description 2
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239000012312 sodium hydride Substances 0.000 description 1
229910000104 sodium hydride Inorganic materials 0.000 description 1
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Classifications

- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
- C07D223/14—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
- C07D223/16—Benzazepines; Hydrogenated benzazepines
- 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
- A61P25/28—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
- 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)
Medicinal Chemistry (AREA)
General Health & Medical Sciences (AREA)
Life Sciences & Earth Sciences (AREA)
Engineering & Computer Science (AREA)
Bioinformatics & Cheminformatics (AREA)
Biomedical Technology (AREA)
Neurology (AREA)
Neurosurgery (AREA)
Animal Behavior & Ethology (AREA)
Molecular Biology (AREA)
General Chemical & Material Sciences (AREA)
Pharmacology & Pharmacy (AREA)
Chemical Kinetics & Catalysis (AREA)
Proteomics, Peptides & Aminoacids (AREA)
Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
Public Health (AREA)
Veterinary Medicine (AREA)
Biochemistry (AREA)
Biophysics (AREA)
Genetics & Genomics (AREA)
Hospice & Palliative Care (AREA)
Psychiatry (AREA)
Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Plural Heterocyclic Compounds (AREA)
Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Peptides Or Proteins (AREA)
Other In-Based Heterocyclic Compounds (AREA)
Medicinal Preparation (AREA)
Hydrogenated Pyridines (AREA)

UA2003054408A 2000-11-17 2001-05-11 Lactam UA74849C2 (en)

Applications Claiming Priority (2)

Application Number	Priority Date	Filing Date	Title
US24955200P	2000-11-17	2000-11-17
PCT/US2001/027799 WO2002047671A2 (en)	2000-11-17	2001-11-05	Lactam compound to inhibit beta-amyloid peptide release or synthesis

Publications (1)

Publication Number	Publication Date
UA74849C2 true UA74849C2 (en)	2006-02-15

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ID=22943982

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UA2003054408A UA74849C2 (en)	2000-11-17	2001-05-11	Lactam

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US (1)	US20050261495A1 (pl)
EP (1)	EP1341531B1 (pl)
JP (1)	JP4116437B2 (pl)
KR (1)	KR100819679B1 (pl)
CN (1)	CN1486184A (pl)
AR (1)	AR035927A1 (pl)
AU (2)	AU2002243192B2 (pl)
BR (1)	BR0115427A (pl)
CA (1)	CA2427227C (pl)
CY (1)	CY1106366T1 (pl)
CZ (1)	CZ20031351A3 (pl)
DE (1)	DE60126132T2 (pl)
DK (1)	DK1341531T3 (pl)
DZ (1)	DZ3453A1 (pl)
EA (1)	EA005954B1 (pl)
EC (1)	ECSP034600A (pl)
ES (1)	ES2278804T3 (pl)
HR (1)	HRP20030383B1 (pl)
HU (1)	HU228117B1 (pl)
IL (2)	IL155960A0 (pl)
MX (1)	MXPA03004292A (pl)
MY (1)	MY134559A (pl)
NO (1)	NO324324B1 (pl)
NZ (1)	NZ525854A (pl)
PE (1)	PE20020802A1 (pl)
PL (1)	PL212199B1 (pl)
PT (1)	PT1341531E (pl)
SI (1)	SI1341531T1 (pl)
SK (1)	SK288065B6 (pl)
TW (1)	TWI305204B (pl)
UA (1)	UA74849C2 (pl)
WO (1)	WO2002047671A2 (pl)
ZA (1)	ZA200303789B (pl)

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BR112021002267A8 (pt)	2018-08-07	2023-02-07	Merck Sharp & Dohme	Inibidores de prmt5
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BR112022012015A2 (pt)	2019-12-17	2022-08-30	Merck Sharp & Dohme Llc	Inibidores de prmt5
EP4076459B1 (en)	2019-12-17	2026-04-29	Merck Sharp & Dohme LLC	Prmt5 inhibitors
CA3160153A1 (en)	2019-12-17	2021-06-24	Michelle Machacek	Prmt5 inhibitors
EP4076460B1 (en)	2019-12-17	2026-01-21	Merck Sharp & Dohme LLC	1,4-dihydro-2h-spiro[isoquinoline-3,4'-piperidine derivatives as prmt5 inhibitors for the treatment of cancer
KR20250053961A (ko)	2022-09-02	2025-04-22	머크 샤프 앤드 돔 엘엘씨	엑사테칸-유래 토포이소머라제-1 억제제 제약 조성물 및 그의 용도
TW202432099A (zh)	2022-10-25	2024-08-16	美商默沙東有限責任公司	源自依克沙替康(exatecan)之adc連接子-載藥(payload)、醫藥組合物及其用途
IL321395A (en)	2022-12-14	2025-08-01	Merck Sharp & Dohme Llc	Auristatin cargo-linkers, pharmaceutical compounds, and their uses

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2001
- 2001-05-11 UA UA2003054408A patent/UA74849C2/uk unknown
- 2001-11-05 CZ CZ20031351A patent/CZ20031351A3/cs unknown
- 2001-11-05 SK SK559-2003A patent/SK288065B6/sk not_active IP Right Cessation
- 2001-11-05 ES ES01989070T patent/ES2278804T3/es not_active Expired - Lifetime
- 2001-11-05 KR KR1020037006721A patent/KR100819679B1/ko not_active Expired - Fee Related
- 2001-11-05 IL IL15596001A patent/IL155960A0/xx unknown
- 2001-11-05 PL PL362688A patent/PL212199B1/pl unknown
- 2001-11-05 AU AU2002243192A patent/AU2002243192B2/en not_active Ceased
- 2001-11-05 HU HU0301842A patent/HU228117B1/hu not_active IP Right Cessation
- 2001-11-05 WO PCT/US2001/027799 patent/WO2002047671A2/en not_active Ceased
- 2001-11-05 HR HR20030383A patent/HRP20030383B1/xx not_active IP Right Cessation
- 2001-11-05 MX MXPA03004292A patent/MXPA03004292A/es active IP Right Grant
- 2001-11-05 CA CA2427227A patent/CA2427227C/en not_active Expired - Fee Related
- 2001-11-05 AU AU4319202A patent/AU4319202A/xx active Pending
- 2001-11-05 DK DK01989070T patent/DK1341531T3/da active
- 2001-11-05 DE DE60126132T patent/DE60126132T2/de not_active Expired - Lifetime
- 2001-11-05 JP JP2002549245A patent/JP4116437B2/ja not_active Expired - Fee Related
- 2001-11-05 NZ NZ525854A patent/NZ525854A/en not_active IP Right Cessation
- 2001-11-05 EP EP01989070A patent/EP1341531B1/en not_active Expired - Lifetime
- 2001-11-05 US US10/416,771 patent/US20050261495A1/en not_active Abandoned
- 2001-11-05 CN CNA018221009A patent/CN1486184A/zh active Pending
- 2001-11-05 PT PT01989070T patent/PT1341531E/pt unknown
- 2001-11-05 EA EA200300580A patent/EA005954B1/ru not_active IP Right Cessation
- 2001-11-05 DZ DZ013453A patent/DZ3453A1/fr active
- 2001-11-05 SI SI200130701T patent/SI1341531T1/sl unknown
- 2001-11-05 BR BR0115427-3A patent/BR0115427A/pt not_active IP Right Cessation
- 2001-11-12 TW TW090128005A patent/TWI305204B/zh not_active IP Right Cessation
- 2001-11-14 AR ARP010105312A patent/AR035927A1/es not_active Application Discontinuation
- 2001-11-15 MY MYPI20015236A patent/MY134559A/en unknown
- 2001-11-16 PE PE2001001142A patent/PE20020802A1/es not_active Application Discontinuation
2003
- 2003-05-13 EC EC2003004600A patent/ECSP034600A/es unknown
- 2003-05-15 ZA ZA200303789A patent/ZA200303789B/en unknown
- 2003-05-15 IL IL155960A patent/IL155960A/en not_active IP Right Cessation
- 2003-05-16 NO NO20032236A patent/NO324324B1/no not_active IP Right Cessation
2007
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Also Published As

Publication number	Publication date
BR0115427A (pt)	2003-10-07
EA200300580A1 (ru)	2003-10-30
EA005954B1 (ru)	2005-08-25
PL212199B1 (pl)	2012-08-31
US20050261495A1 (en)	2005-11-24
ES2278804T3 (es)	2007-08-16
NO324324B1 (no)	2007-09-24
HUP0301842A2 (hu)	2003-09-29
HK1059731A1 (en)	2004-07-16
MXPA03004292A (es)	2004-02-12
IL155960A0 (en)	2003-12-23
AU4319202A (en)	2002-06-24
MY134559A (en)	2007-12-31
KR100819679B1 (ko)	2008-04-04
DE60126132D1 (de)	2007-03-08
DZ3453A1 (fr)	2002-06-20
JP2004517090A (ja)	2004-06-10
CY1106366T1 (el)	2011-10-12
EP1341531B1 (en)	2007-01-17
AR035927A1 (es)	2004-07-28
CA2427227A1 (en)	2002-06-20
JP4116437B2 (ja)	2008-07-09
DE60126132T2 (de)	2007-10-18
KR20030051846A (ko)	2003-06-25
CN1486184A (zh)	2004-03-31
IL155960A (en)	2009-06-15
PL362688A1 (pl)	2004-11-02
SK5592003A3 (en)	2003-12-02
HRP20030383B1 (hr)	2007-12-31
ZA200303789B (en)	2004-08-16
CZ20031351A3 (cs)	2003-11-12
DK1341531T3 (da)	2007-05-14
SI1341531T1 (sl)	2007-06-30
PE20020802A1 (es)	2002-09-10
ECSP034600A (es)	2003-06-25
WO2002047671A3 (en)	2003-03-06
NZ525854A (en)	2004-06-25
NO20032236L (no)	2003-07-10
AU2002243192B2 (en)	2006-07-20
NO20032236D0 (no)	2003-05-16
WO2002047671A2 (en)	2002-06-20
PT1341531E (pt)	2007-04-30
TWI305204B (en)	2009-01-11
HUP0301842A3 (en)	2010-03-29
HRP20030383A2 (en)	2005-10-31
SK288065B6 (sk)	2013-04-03
CA2427227C (en)	2010-08-17
EP1341531A2 (en)	2003-09-10
HU228117B1 (en)	2012-11-28

Publication	Publication Date	Title
JP4116437B2 (ja)	2008-07-09	β−アミロイドペプチドの放出および／または合成を阻害するラクタム化合物
AU2002243192A1 (en)	2002-08-29	Lactam compound to inhibit beta-amyloid peptide release or synthesis
US7468365B2 (en)	2008-12-23	Lactam compound
AU2002224321B2 (en)	2006-10-19	Lactam compound
JP2004521084A5 (pl)	2005-12-22
AU2002224321A1 (en)	2002-08-01	Lactam compound
CA2390376A1 (en)	2001-05-17	.beta.-aminoacid compounds useful for inhibiting .beta.-amyloid peptide release and/or its synthesis
EP1345955A2 (en)	2003-09-24	Lactam dipeptide and its use in inhibiting beta-amyloid peptide release
US20040077627A1 (en)	2004-04-22	Lactam compound
HK1059731B (en)	2007-08-24	Lactam compound to inhibit beta-amyloid peptide release or synthesis
MXPA99004527A (en)	2000-07-01	N-(ARYL/HETEROARYL) AMINO ACID DERIVATIVES, PHARMACEUTICAL COMPOSITIONS COMPRISING SAME, AND METHODS FOR INHIBITING&bgr;-AMYLOID PEPTIDE RELEASE AND/OR ITS SYNTHESIS BY USE OF SUCH COMPOUNDS
JPH0224265B2 (pl)	1990-05-29