ES2264124T3 - Acilacion selectiva de grupos epsilon-amino de insulina. - Google Patents
Acilacion selectiva de grupos epsilon-amino de insulina.Info
- Publication number
- ES2264124T3 ES2264124T3 ES95308167T ES95308167T ES2264124T3 ES 2264124 T3 ES2264124 T3 ES 2264124T3 ES 95308167 T ES95308167 T ES 95308167T ES 95308167 T ES95308167 T ES 95308167T ES 2264124 T3 ES2264124 T3 ES 2264124T3
- Authority
- ES
- Spain
- Prior art keywords
- insulin
- fatty acid
- amino
- epsilon
- ester
- Prior art date
- 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.)
- Expired - Lifetime
Links
- 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 claims abstract description 114
- 229940125396 insulin Drugs 0.000 claims abstract description 49
- 102000004877 Insulin Human genes 0.000 claims abstract description 43
- 108090001061 Insulin Proteins 0.000 claims abstract description 43
- 238000000034 method Methods 0.000 claims abstract description 29
- 108010076181 Proinsulin Chemical class 0.000 claims abstract description 24
- 102000004169 proteins and genes Human genes 0.000 claims abstract description 11
- 108090000623 proteins and genes Proteins 0.000 claims abstract description 11
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical group CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 75
- 230000010933 acylation Effects 0.000 claims description 31
- 238000005917 acylation reaction Methods 0.000 claims description 31
- 235000014113 dietary fatty acids Nutrition 0.000 claims description 31
- 229930195729 fatty acid Natural products 0.000 claims description 31
- 239000000194 fatty acid Substances 0.000 claims description 31
- -1 fatty acid ester Chemical class 0.000 claims description 22
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 20
- 239000004026 insulin derivative Substances 0.000 claims description 15
- 150000004665 fatty acids Chemical class 0.000 claims description 14
- 239000002904 solvent Substances 0.000 claims description 13
- PBGKTOXHQIOBKM-FHFVDXKLSA-N insulin (human) Chemical group C([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@H]1CSSC[C@H]2C(=O)N[C@H](C(=O)N[C@@H](CO)C(=O)N[C@H](C(=O)N[C@H](C(N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC=3C=CC(O)=CC=3)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=3C=CC(O)=CC=3)C(=O)N[C@@H](CSSC[C@H](NC(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=3C=CC(O)=CC=3)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](C)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=3NC=NC=3)NC(=O)[C@H](CO)NC(=O)CNC1=O)C(=O)NCC(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)O)C(O)=O)C(=O)N[C@@H](CC(N)=O)C(O)=O)=O)CSSC[C@@H](C(N2)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@@H](NC(=O)CN)[C@@H](C)CC)[C@@H](C)CC)[C@@H](C)O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H](NC(=O)[C@@H](N)CC=1C=CC=CC=1)C(C)C)C1=CN=CN1 PBGKTOXHQIOBKM-FHFVDXKLSA-N 0.000 claims description 12
- 229950004152 insulin human Drugs 0.000 claims description 12
- ODIGIKRIUKFKHP-UHFFFAOYSA-N (n-propan-2-yloxycarbonylanilino) acetate Chemical compound CC(C)OC(=O)N(OC(C)=O)C1=CC=CC=C1 ODIGIKRIUKFKHP-UHFFFAOYSA-N 0.000 claims description 11
- 101000976075 Homo sapiens Insulin Proteins 0.000 claims description 9
- 239000003125 aqueous solvent Substances 0.000 claims description 9
- 239000002798 polar solvent Substances 0.000 claims description 9
- WSXGQYDHJZKQQB-UHFFFAOYSA-N 3-pyridin-4-ylpropanoic acid Chemical group OC(=O)CCC1=CC=NC=C1 WSXGQYDHJZKQQB-UHFFFAOYSA-N 0.000 claims description 8
- 239000002253 acid Substances 0.000 claims description 8
- IPCSVZSSVZVIGE-UHFFFAOYSA-N hexadecanoic acid Chemical compound CCCCCCCCCCCCCCCC(O)=O IPCSVZSSVZVIGE-UHFFFAOYSA-N 0.000 claims description 6
- 235000021314 Palmitic acid Nutrition 0.000 claims description 3
- WQEPLUUGTLDZJY-UHFFFAOYSA-N n-Pentadecanoic acid Natural products CCCCCCCCCCCCCCC(O)=O WQEPLUUGTLDZJY-UHFFFAOYSA-N 0.000 claims description 3
- 239000003960 organic solvent Substances 0.000 claims description 3
- TUNFSRHWOTWDNC-UHFFFAOYSA-N tetradecanoic acid Chemical compound CCCCCCCCCCCCCC(O)=O TUNFSRHWOTWDNC-UHFFFAOYSA-N 0.000 claims description 2
- NMHMNPHRMNGLLB-UHFFFAOYSA-N phloretic acid Chemical compound OC(=O)CCC1=CC=C(O)C=C1 NMHMNPHRMNGLLB-UHFFFAOYSA-N 0.000 claims 5
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 claims 1
- 229940105132 myristate Drugs 0.000 claims 1
- 239000011356 non-aqueous organic solvent Substances 0.000 claims 1
- WWZKQHOCKIZLMA-UHFFFAOYSA-M octanoate Chemical compound CCCCCCCC([O-])=O WWZKQHOCKIZLMA-UHFFFAOYSA-M 0.000 claims 1
- 239000000243 solution Substances 0.000 description 49
- 238000006243 chemical reaction Methods 0.000 description 41
- 150000002148 esters Chemical class 0.000 description 34
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 24
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 18
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 18
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 17
- 230000001851 biosynthetic effect Effects 0.000 description 16
- 125000003277 amino group Chemical group 0.000 description 15
- 239000013078 crystal Substances 0.000 description 12
- 239000000047 product Substances 0.000 description 12
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 description 10
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 10
- 230000015572 biosynthetic process Effects 0.000 description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- IPCSVZSSVZVIGE-UHFFFAOYSA-M hexadecanoate Chemical compound CCCCCCCCCCCCCCCC([O-])=O IPCSVZSSVZVIGE-UHFFFAOYSA-M 0.000 description 9
- 235000018102 proteins Nutrition 0.000 description 9
- NQTADLQHYWFPDB-UHFFFAOYSA-N N-Hydroxysuccinimide Chemical class ON1C(=O)CCC1=O NQTADLQHYWFPDB-UHFFFAOYSA-N 0.000 description 8
- 239000000203 mixture Substances 0.000 description 8
- 238000003756 stirring Methods 0.000 description 8
- 238000003786 synthesis reaction Methods 0.000 description 8
- 238000011179 visual inspection Methods 0.000 description 8
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Natural products NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 6
- 125000000539 amino acid group Chemical group 0.000 description 6
- 239000003795 chemical substances by application Substances 0.000 description 6
- 239000002245 particle Substances 0.000 description 6
- 239000004471 Glycine Substances 0.000 description 5
- 235000001014 amino acid Nutrition 0.000 description 5
- 229940024606 amino acid Drugs 0.000 description 5
- 238000004128 high performance liquid chromatography Methods 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- KYVBNYUBXIEUFW-UHFFFAOYSA-N 1,1,3,3-tetramethylguanidine Chemical group CN(C)C(=N)N(C)C KYVBNYUBXIEUFW-UHFFFAOYSA-N 0.000 description 4
- 239000004472 Lysine Substances 0.000 description 4
- LINDOXZENKYESA-UHFFFAOYSA-N TMG Natural products CNC(N)=NC LINDOXZENKYESA-UHFFFAOYSA-N 0.000 description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 4
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 description 4
- 239000004327 boric acid Substances 0.000 description 4
- 235000018417 cysteine Nutrition 0.000 description 4
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 description 4
- 125000000151 cysteine group Chemical group N[C@@H](CS)C(=O)* 0.000 description 4
- 239000012071 phase Substances 0.000 description 4
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 4
- 239000011541 reaction mixture Substances 0.000 description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- 125000002252 acyl group Chemical group 0.000 description 3
- 150000001413 amino acids Chemical class 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 238000004108 freeze drying Methods 0.000 description 3
- 108090000765 processed proteins & peptides Proteins 0.000 description 3
- 125000006239 protecting group Chemical group 0.000 description 3
- 241000894007 species Species 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- 108020004511 Recombinant DNA Proteins 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 230000002209 hydrophobic effect Effects 0.000 description 2
- 150000002632 lipids Chemical class 0.000 description 2
- 239000007791 liquid phase Substances 0.000 description 2
- 230000007935 neutral effect Effects 0.000 description 2
- 238000010915 one-step procedure Methods 0.000 description 2
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 230000009257 reactivity Effects 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 238000010561 standard procedure Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- VDZOOKBUILJEDG-UHFFFAOYSA-M tetrabutylammonium hydroxide Chemical compound [OH-].CCCC[N+](CCCC)(CCCC)CCCC VDZOOKBUILJEDG-UHFFFAOYSA-M 0.000 description 2
- SIFCHNIAAPMMKG-UHFFFAOYSA-N (2,5-dioxopyrrolidin-1-yl) acetate Chemical compound CC(=O)ON1C(=O)CCC1=O SIFCHNIAAPMMKG-UHFFFAOYSA-N 0.000 description 1
- XGFQVJQXCLZRFH-ZDUSSCGKSA-N (2s)-2-(dodecanoylamino)-3-hydroxypropanoic acid Chemical compound CCCCCCCCCCCC(=O)N[C@@H](CO)C(O)=O XGFQVJQXCLZRFH-ZDUSSCGKSA-N 0.000 description 1
- NQBRFIXRZDTIRQ-UHFFFAOYSA-N (4-methoxyphenyl)methyl n-diazocarbamate Chemical compound COC1=CC=C(COC(=O)N=[N+]=[N-])C=C1 NQBRFIXRZDTIRQ-UHFFFAOYSA-N 0.000 description 1
- AVBJHQDHVYGQLS-UHFFFAOYSA-N 2-(dodecanoylamino)pentanedioic acid Chemical compound CCCCCCCCCCCC(=O)NC(C(O)=O)CCC(O)=O AVBJHQDHVYGQLS-UHFFFAOYSA-N 0.000 description 1
- TWJNQYPJQDRXPH-UHFFFAOYSA-N 2-cyanobenzohydrazide Chemical compound NNC(=O)C1=CC=CC=C1C#N TWJNQYPJQDRXPH-UHFFFAOYSA-N 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- 101100505161 Caenorhabditis elegans mel-32 gene Proteins 0.000 description 1
- PJWWRFATQTVXHA-UHFFFAOYSA-N Cyclohexylaminopropanesulfonic acid Chemical compound OS(=O)(=O)CCCNC1CCCCC1 PJWWRFATQTVXHA-UHFFFAOYSA-N 0.000 description 1
- BWGNESOTFCXPMA-UHFFFAOYSA-N Dihydrogen disulfide Chemical compound SS BWGNESOTFCXPMA-UHFFFAOYSA-N 0.000 description 1
- 235000021360 Myristic acid Nutrition 0.000 description 1
- JWGGSJFIGIGFSQ-UHFFFAOYSA-N N-dodecanoylglycine Chemical compound CCCCCCCCCCCC(=O)NCC(O)=O JWGGSJFIGIGFSQ-UHFFFAOYSA-N 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 150000008065 acid anhydrides Chemical class 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 125000003630 glycyl group Chemical group [H]N([H])C([H])([H])C(*)=O 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 238000007689 inspection Methods 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
- 125000002960 margaryl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 238000010979 pH adjustment Methods 0.000 description 1
- 238000001139 pH measurement Methods 0.000 description 1
- 125000002958 pentadecyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000010647 peptide synthesis reaction Methods 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- 230000017854 proteolysis Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000004007 reversed phase HPLC Methods 0.000 description 1
- 239000007790 solid phase Substances 0.000 description 1
- 239000011877 solvent mixture Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000000108 ultra-filtration Methods 0.000 description 1
- 230000000007 visual effect Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/575—Hormones
- C07K14/62—Insulins
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
- C07K1/107—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length by chemical modification of precursor peptides
- C07K1/1072—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length by chemical modification of precursor peptides by covalent attachment of residues or functional groups
- C07K1/1077—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length by chemical modification of precursor peptides by covalent attachment of residues or functional groups by covalent attachment of residues other than amino acids or peptide residues, e.g. sugars, polyols, fatty acids
Landscapes
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Molecular Biology (AREA)
- Biochemistry (AREA)
- Biophysics (AREA)
- General Health & Medical Sciences (AREA)
- Genetics & Genomics (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Analytical Chemistry (AREA)
- Diabetes (AREA)
- Endocrinology (AREA)
- Toxicology (AREA)
- Zoology (AREA)
- Gastroenterology & Hepatology (AREA)
- Peptides Or Proteins (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US08/341,231 US5646242A (en) | 1994-11-17 | 1994-11-17 | Selective acylation of epsilon-amino groups |
| US341231 | 1994-11-17 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| ES2264124T3 true ES2264124T3 (es) | 2006-12-16 |
Family
ID=23336740
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| ES95308167T Expired - Lifetime ES2264124T3 (es) | 1994-11-17 | 1995-11-14 | Acilacion selectiva de grupos epsilon-amino de insulina. |
Country Status (27)
| Country | Link |
|---|---|
| US (2) | US5646242A (OSRAM) |
| EP (2) | EP1227107A1 (OSRAM) |
| JP (1) | JP4312828B2 (OSRAM) |
| CN (1) | CN1171742A (OSRAM) |
| AR (1) | AR003915A1 (OSRAM) |
| AT (1) | ATE328902T1 (OSRAM) |
| AU (2) | AU691066B2 (OSRAM) |
| BR (1) | BR9509652A (OSRAM) |
| CA (1) | CA2205061A1 (OSRAM) |
| CO (1) | CO4520285A1 (OSRAM) |
| CZ (1) | CZ287731B6 (OSRAM) |
| DE (1) | DE69535031T2 (OSRAM) |
| DK (1) | DK0712862T3 (OSRAM) |
| ES (1) | ES2264124T3 (OSRAM) |
| HU (2) | HU9903007D0 (OSRAM) |
| IL (1) | IL115972A (OSRAM) |
| IN (1) | IN179820B (OSRAM) |
| NO (1) | NO972185D0 (OSRAM) |
| NZ (1) | NZ297256A (OSRAM) |
| PL (1) | PL320556A1 (OSRAM) |
| PT (1) | PT712862E (OSRAM) |
| RU (1) | RU2155773C2 (OSRAM) |
| SI (1) | SI0712862T1 (OSRAM) |
| TR (1) | TR199501421A2 (OSRAM) |
| WO (1) | WO1996015803A1 (OSRAM) |
| YU (1) | YU71495A (OSRAM) |
| ZA (1) | ZA959680B (OSRAM) |
Families Citing this family (76)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB9316895D0 (en) | 1993-08-13 | 1993-09-29 | Guy S And St Thomas Hospitals | Hepatoselective insulin analogues |
| US6869930B1 (en) | 1993-09-17 | 2005-03-22 | Novo Nordisk A/S | Acylated insulin |
| US5951974A (en) * | 1993-11-10 | 1999-09-14 | Enzon, Inc. | Interferon polymer conjugates |
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1994
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1995
- 1995-11-14 AR ARP950100165A patent/AR003915A1/es not_active Application Discontinuation
- 1995-11-14 CO CO95053590A patent/CO4520285A1/es unknown
- 1995-11-14 AT AT95308167T patent/ATE328902T1/de active
- 1995-11-14 TR TR95/01421A patent/TR199501421A2/xx unknown
- 1995-11-14 DE DE69535031T patent/DE69535031T2/de not_active Expired - Lifetime
- 1995-11-14 ZA ZA959680A patent/ZA959680B/xx unknown
- 1995-11-14 CA CA002205061A patent/CA2205061A1/en not_active Abandoned
- 1995-11-14 HU HU9903007A patent/HU9903007D0/hu unknown
- 1995-11-14 JP JP51696396A patent/JP4312828B2/ja not_active Expired - Lifetime
- 1995-11-14 IN IN1452CA1995 patent/IN179820B/en unknown
- 1995-11-14 DK DK95308167T patent/DK0712862T3/da active
- 1995-11-14 EP EP02000258A patent/EP1227107A1/en not_active Ceased
- 1995-11-14 HU HU9800566A patent/HU217585B/hu not_active IP Right Cessation
- 1995-11-14 WO PCT/US1995/014872 patent/WO1996015803A1/en not_active Ceased
- 1995-11-14 PT PT95308167T patent/PT712862E/pt unknown
- 1995-11-14 PL PL95320556A patent/PL320556A1/xx unknown
- 1995-11-14 AU AU42372/96A patent/AU691066B2/en not_active Revoked
- 1995-11-14 BR BR9509652A patent/BR9509652A/pt not_active Application Discontinuation
- 1995-11-14 SI SI9530727T patent/SI0712862T1/sl unknown
- 1995-11-14 NZ NZ297256A patent/NZ297256A/xx active IP Right Revival
- 1995-11-14 RU RU97110075/04A patent/RU2155773C2/ru active
- 1995-11-14 IL IL11597295A patent/IL115972A/xx unknown
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- 1995-11-14 CZ CZ19971456A patent/CZ287731B6/cs not_active IP Right Cessation
- 1995-11-14 CN CN95197224A patent/CN1171742A/zh active Pending
- 1995-11-14 ES ES95308167T patent/ES2264124T3/es not_active Expired - Lifetime
- 1995-11-14 EP EP95308167A patent/EP0712862B1/en not_active Expired - Lifetime
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