EP0000053B1 - Somatostatin analogs, process for their preparation and pharmaceutical compositions containing them - Google Patents
Somatostatin analogs, process for their preparation and pharmaceutical compositions containing them Download PDFInfo
- Publication number
- EP0000053B1 EP0000053B1 EP78100095A EP78100095A EP0000053B1 EP 0000053 B1 EP0000053 B1 EP 0000053B1 EP 78100095 A EP78100095 A EP 78100095A EP 78100095 A EP78100095 A EP 78100095A EP 0000053 B1 EP0000053 B1 EP 0000053B1
- Authority
- EP
- European Patent Office
- Prior art keywords
- phe
- tyr
- thr
- peptide
- resin
- 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
Links
- NHXLMOGPVYXJNR-ATOGVRKGSA-N somatostatin Chemical class C([C@H]1C(=O)N[C@H](C(N[C@@H](CO)C(=O)N[C@@H](CSSC[C@@H](C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@@H](CC=2C3=CC=CC=C3NC=2)C(=O)N[C@@H](CCCCN)C(=O)N[C@H](C(=O)N1)[C@@H](C)O)NC(=O)CNC(=O)[C@H](C)N)C(O)=O)=O)[C@H](O)C)C1=CC=CC=C1 NHXLMOGPVYXJNR-ATOGVRKGSA-N 0.000 title description 28
- 238000000034 method Methods 0.000 title description 17
- 238000002360 preparation method Methods 0.000 title description 8
- 239000008194 pharmaceutical composition Substances 0.000 title 1
- 108090000765 processed proteins & peptides Proteins 0.000 claims description 39
- 239000011347 resin Substances 0.000 claims description 33
- 229920005989 resin Polymers 0.000 claims description 33
- 239000002253 acid Substances 0.000 claims description 10
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 claims description 9
- 125000003277 amino group Chemical group 0.000 claims description 9
- 102000001189 Cyclic Peptides Human genes 0.000 claims description 7
- 108010069514 Cyclic Peptides Proteins 0.000 claims description 7
- 150000001540 azides Chemical class 0.000 claims description 7
- 102000004196 processed proteins & peptides Human genes 0.000 claims description 7
- 239000000203 mixture Substances 0.000 claims description 6
- 150000003839 salts Chemical class 0.000 claims description 6
- 239000007790 solid phase Substances 0.000 claims description 6
- 231100000252 nontoxic Toxicity 0.000 claims description 5
- 230000003000 nontoxic effect Effects 0.000 claims description 5
- 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 5
- 150000001875 compounds Chemical class 0.000 claims description 4
- OWFXIOWLTKNBAP-UHFFFAOYSA-N isoamyl nitrite Chemical compound CC(C)CCON=O OWFXIOWLTKNBAP-UHFFFAOYSA-N 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 230000000903 blocking effect Effects 0.000 claims description 2
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
- 238000007865 diluting Methods 0.000 claims 1
- 230000003472 neutralizing effect Effects 0.000 claims 1
- 150000001413 amino acids Chemical class 0.000 description 23
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 15
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 15
- -1 t-butyl carbonium ions Chemical class 0.000 description 12
- 102000005157 Somatostatin Human genes 0.000 description 11
- 108010056088 Somatostatin Proteins 0.000 description 11
- 229960000553 somatostatin Drugs 0.000 description 11
- 239000000243 solution Substances 0.000 description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- 239000007787 solid Substances 0.000 description 8
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 description 7
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 7
- 238000005859 coupling reaction Methods 0.000 description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 5
- 230000008878 coupling Effects 0.000 description 5
- 238000010168 coupling process Methods 0.000 description 5
- 125000006239 protecting group Chemical group 0.000 description 5
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 4
- IQHUITKNHOKGFC-MIMYLULJSA-N Thr-Phe Chemical compound C[C@@H](O)[C@H](N)C(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 IQHUITKNHOKGFC-MIMYLULJSA-N 0.000 description 4
- RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical compound COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 description 4
- 125000004429 atom Chemical group 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 4
- 230000002401 inhibitory effect Effects 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
- 239000000047 product Substances 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- 102000004400 Aminopeptidases Human genes 0.000 description 3
- 108090000915 Aminopeptidases Proteins 0.000 description 3
- 102000005367 Carboxypeptidases Human genes 0.000 description 3
- 108010006303 Carboxypeptidases Proteins 0.000 description 3
- 230000004071 biological effect Effects 0.000 description 3
- 230000037396 body weight Effects 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 150000002148 esters Chemical class 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 230000002496 gastric effect Effects 0.000 description 3
- 238000001727 in vivo Methods 0.000 description 3
- 150000007530 organic bases Chemical class 0.000 description 3
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 3
- 238000010254 subcutaneous injection Methods 0.000 description 3
- 239000007929 subcutaneous injection Substances 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 229920003002 synthetic resin Polymers 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- MYRTYDVEIRVNKP-UHFFFAOYSA-N 1,2-Divinylbenzene Chemical compound C=CC1=CC=CC=C1C=C MYRTYDVEIRVNKP-UHFFFAOYSA-N 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- 125000006847 BOC protecting group Chemical group 0.000 description 2
- 125000001433 C-terminal amino-acid group Chemical group 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- 229920002261 Corn starch Polymers 0.000 description 2
- QIVBCDIJIAJPQS-SECBINFHSA-N D-tryptophane Chemical compound C1=CC=C2C(C[C@@H](N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-SECBINFHSA-N 0.000 description 2
- KRHYYFGTRYWZRS-UHFFFAOYSA-N Fluorane Chemical compound F KRHYYFGTRYWZRS-UHFFFAOYSA-N 0.000 description 2
- 238000005727 Friedel-Crafts reaction Methods 0.000 description 2
- 102000051325 Glucagon Human genes 0.000 description 2
- 108060003199 Glucagon Proteins 0.000 description 2
- 102000018997 Growth Hormone Human genes 0.000 description 2
- 108010051696 Growth Hormone Proteins 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 102000004877 Insulin Human genes 0.000 description 2
- 108090001061 Insulin Proteins 0.000 description 2
- LEVWYRKDKASIDU-IMJSIDKUSA-N L-cystine Chemical compound [O-]C(=O)[C@@H]([NH3+])CSSC[C@H]([NH3+])C([O-])=O LEVWYRKDKASIDU-IMJSIDKUSA-N 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- 229920005654 Sephadex Polymers 0.000 description 2
- 239000012507 Sephadex™ Substances 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- PPBRXRYQALVLMV-UHFFFAOYSA-N Styrene Chemical compound C=CC1=CC=CC=C1 PPBRXRYQALVLMV-UHFFFAOYSA-N 0.000 description 2
- KCXMKQUNVWSEMD-UHFFFAOYSA-N benzyl chloride Chemical compound ClCC1=CC=CC=C1 KCXMKQUNVWSEMD-UHFFFAOYSA-N 0.000 description 2
- 229940073608 benzyl chloride Drugs 0.000 description 2
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 2
- 210000004899 c-terminal region Anatomy 0.000 description 2
- 150000001733 carboxylic acid esters Chemical class 0.000 description 2
- 239000000969 carrier Substances 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 238000003776 cleavage reaction Methods 0.000 description 2
- 239000008120 corn starch Substances 0.000 description 2
- 239000007822 coupling agent Substances 0.000 description 2
- 229960003067 cystine Drugs 0.000 description 2
- 206010012601 diabetes mellitus Diseases 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- MASNOZXLGMXCHN-ZLPAWPGGSA-N glucagon Chemical compound C([C@@H](C(=O)N[C@H](C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O)C(C)C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](C)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC=1NC=NC=1)[C@@H](C)O)[C@@H](C)O)C1=CC=CC=C1 MASNOZXLGMXCHN-ZLPAWPGGSA-N 0.000 description 2
- 229960004666 glucagon Drugs 0.000 description 2
- 239000000122 growth hormone Substances 0.000 description 2
- 229910000040 hydrogen fluoride Inorganic materials 0.000 description 2
- 229940125396 insulin Drugs 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 description 2
- 239000012299 nitrogen atmosphere Substances 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
- 239000002952 polymeric resin Substances 0.000 description 2
- 230000007017 scission Effects 0.000 description 2
- 230000028327 secretion Effects 0.000 description 2
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- PJUPKRYGDFTMTM-UHFFFAOYSA-N 1-hydroxybenzotriazole;hydrate Chemical compound O.C1=CC=C2N(O)N=NC2=C1 PJUPKRYGDFTMTM-UHFFFAOYSA-N 0.000 description 1
- HBAHZZVIEFRTEY-UHFFFAOYSA-N 2-heptylcyclohex-2-en-1-one Chemical compound CCCCCCCC1=CCCCC1=O HBAHZZVIEFRTEY-UHFFFAOYSA-N 0.000 description 1
- XDOLZJYETYVRKV-UHFFFAOYSA-N 7-Aminoheptanoic acid Chemical compound NCCCCCCC(O)=O XDOLZJYETYVRKV-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 206010000599 Acromegaly Diseases 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 241000416162 Astragalus gummifer Species 0.000 description 1
- FGUUSXIOTUKUDN-IBGZPJMESA-N C1(=CC=CC=C1)N1C2=C(NC([C@H](C1)NC=1OC(=NN=1)C1=CC=CC=C1)=O)C=CC=C2 Chemical compound C1(=CC=CC=C1)N1C2=C(NC([C@H](C1)NC=1OC(=NN=1)C1=CC=CC=C1)=O)C=CC=C2 FGUUSXIOTUKUDN-IBGZPJMESA-N 0.000 description 1
- 0 CCCN**CC Chemical compound CCCN**CC 0.000 description 1
- XJUZRXYOEPSWMB-UHFFFAOYSA-N Chloromethyl methyl ether Chemical compound COCCl XJUZRXYOEPSWMB-UHFFFAOYSA-N 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- 235000019739 Dicalciumphosphate Nutrition 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- JOYRKODLDBILNP-UHFFFAOYSA-N Ethyl urethane Chemical compound CCOC(N)=O JOYRKODLDBILNP-UHFFFAOYSA-N 0.000 description 1
- 235000007297 Gaultheria procumbens Nutrition 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 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 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- 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 1
- 241000124008 Mammalia Species 0.000 description 1
- 229920001367 Merrifield resin Polymers 0.000 description 1
- 125000001429 N-terminal alpha-amino-acid group Chemical group 0.000 description 1
- 229910017849 NH2—NH2 Inorganic materials 0.000 description 1
- IOVCWXUNBOPUCH-UHFFFAOYSA-N Nitrous acid Chemical compound ON=O IOVCWXUNBOPUCH-UHFFFAOYSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 241000333569 Pyrola minor Species 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- 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 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 229910021627 Tin(IV) chloride Inorganic materials 0.000 description 1
- 229920001615 Tragacanth Polymers 0.000 description 1
- AZFNGPAYDKGCRB-XCPIVNJJSA-M [(1s,2s)-2-amino-1,2-diphenylethyl]-(4-methylphenyl)sulfonylazanide;chlororuthenium(1+);1-methyl-4-propan-2-ylbenzene Chemical compound [Ru+]Cl.CC(C)C1=CC=C(C)C=C1.C1=CC(C)=CC=C1S(=O)(=O)[N-][C@@H](C=1C=CC=CC=1)[C@@H](N)C1=CC=CC=C1 AZFNGPAYDKGCRB-XCPIVNJJSA-M 0.000 description 1
- 239000003929 acidic solution Substances 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 239000000783 alginic acid Substances 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 229960001126 alginic acid Drugs 0.000 description 1
- 150000004781 alginic acids Chemical class 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000003125 aqueous solvent Substances 0.000 description 1
- 229940072107 ascorbate Drugs 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 239000011324 bead Substances 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- RBHJBMIOOPYDBQ-UHFFFAOYSA-N carbon dioxide;propan-2-one Chemical compound O=C=O.CC(C)=O RBHJBMIOOPYDBQ-UHFFFAOYSA-N 0.000 description 1
- 125000004218 chloromethyl group Chemical group [H]C([H])(Cl)* 0.000 description 1
- 229940061627 chloromethyl methyl ether Drugs 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 238000007334 copolymerization reaction Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 238000012217 deletion Methods 0.000 description 1
- 230000037430 deletion Effects 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- NEFBYIFKOOEVPA-UHFFFAOYSA-K dicalcium phosphate Chemical compound [Ca+2].[Ca+2].[O-]P([O-])([O-])=O NEFBYIFKOOEVPA-UHFFFAOYSA-K 0.000 description 1
- 229940038472 dicalcium phosphate Drugs 0.000 description 1
- 229910000390 dicalcium phosphate Inorganic materials 0.000 description 1
- 125000002228 disulfide group Chemical group 0.000 description 1
- 230000007515 enzymatic degradation Effects 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- XZBIXDPGRMLSTC-UHFFFAOYSA-N formohydrazide Chemical compound NNC=O XZBIXDPGRMLSTC-UHFFFAOYSA-N 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 125000005842 heteroatom Chemical group 0.000 description 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 1
- 239000000413 hydrolysate Substances 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 230000002779 inactivation Effects 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 229940049920 malate Drugs 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N malic acid Chemical compound OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- OSWPMRLSEDHDFF-UHFFFAOYSA-N methyl salicylate Chemical compound COC(=O)C1=CC=CC=C1O OSWPMRLSEDHDFF-UHFFFAOYSA-N 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 229920001184 polypeptide Polymers 0.000 description 1
- 229920003053 polystyrene-divinylbenzene Polymers 0.000 description 1
- 239000004304 potassium nitrite Substances 0.000 description 1
- 235000010289 potassium nitrite Nutrition 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 238000006894 reductive elimination reaction Methods 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 235000010288 sodium nitrite Nutrition 0.000 description 1
- 238000003746 solid phase reaction Methods 0.000 description 1
- 239000008223 sterile water Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 239000000057 synthetic resin Substances 0.000 description 1
- IOGXOCVLYRDXLW-UHFFFAOYSA-N tert-butyl nitrite Chemical compound CC(C)(C)ON=O IOGXOCVLYRDXLW-UHFFFAOYSA-N 0.000 description 1
- HPGGPRDJHPYFRM-UHFFFAOYSA-J tin(iv) chloride Chemical compound Cl[Sn](Cl)(Cl)Cl HPGGPRDJHPYFRM-UHFFFAOYSA-J 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
- 238000005406 washing Methods 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
- C07K14/655—Somatostatins
- C07K14/6555—Somatostatins at least 1 amino acid in D-form
-
- 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
- A61P3/02—Nutrients, e.g. vitamins, minerals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
-
- 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
- Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
- Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10S930/00—Peptide or protein sequence
- Y10S930/01—Peptide or protein sequence
- Y10S930/16—Somatostatin; related peptides
Definitions
- Somatostatin is a tetradecapeptide having the structure: and has the properties of inhibiting the release of growth hormone, inhibiting the release of insulin and glucagon and reducing gastric secretion. This lack of specificity of the biological activity of somatostatin has led to an intensive search for analogs which exhibit a more specific biological activity. Somatostatin itself has a short duration of action because it is inactivated, inter alia, by aminopeptidases and carboxypeptidases present in vivo. This problem of the short duration of action has been partially solved in the prior art by preparing derivatives of somatostatin which have low solubility, thus attaining a slow release on subcutaneous injection.
- the derivatives are no more stable to inactivation by aminopeptidases and carboxypeptidases than somatostatin itself.
- the present invention provides somatostatin analogs having no material affect on gastric secretion and a longer duration of action and a novel method for preparing said analogs.
- the present invention further provides somatostatin analogs which are easier to prepare because they contain only 26 atoms in the peptide backbone.
- This invention is concerned with novel somatostatin analogs having a more specific biological activity and duration of activity than naturally occurring somatostatin and which are easier to prepare because of the smaller ring size and having the structural formula: wherein
- the preferred somatostatin analogs of the present invention are illustrated by the following structural formula: and the pharmaceutically acceptable non-toxic acid addition salts thereof.
- acid addition salts are hydrochloride, hydrobromide, sulfate, phosphate, maleate, acetate, citrate, benzoate, succinate, malate, ascorbate and the like.
- the somatostatin analogs of the present invention differ from somatostatin by virtue of the fact that they lack an N-terminal amino group and a C-terminal carboxyl group thus eliminating the groups involved in enzymic cleavage of the molecule by aminopeptidases and carboxypeptidases. Furthermore, the deletion of the adjacent heteroatoms of the disulfide bridge of somatostatin increases the stability of the analogs in vivo by preventing enzymatic degradation by reductive cleavage. Therefore, the analogs of the present invention are more resistent to cleavage in vivo than somatostatin and thus have a prolonged duration of action.
- Somatostatin is a tetradecapeptide having the structure: The portion of somatostatin extending from amino acid Cys 3 to Cys' 4 forms a dodecapeptide of the following structure: The peptide backbone and the disulfide bridge consist of a continuous 38 atom ring.
- the present invention provides somatostatin analogs wherein the Ala'-Gly 2 , Lys 4 -Asn 5 , Thr 12- Ser 13 and the amino groups of Cys 3 and carboxyl group of Cys 14 are deleted.
- the disulfide atoms of the cystine, -S-S- have been replaced by the dicarba group, ⁇ CH 2 ⁇ CH 2 .
- the present invention provides somatostatin analogs wherein amino acids 6 and 11 are bridged by 7-aminoheptanoic acid.
- the resulting ring contains 26 atoms.
- the somatostatin analogs of the present invention include those wherein Phe 6 is replaced by Tyr or O-Me-Tyr; Phe 7 is replaced by Tyr; Trp 8 is replaced by D-Trp and Thr'° is replaced by Val.
- the novel somatostatin analogs are prepared by cyclizing corresponding linear peptides.
- the linear peptides are prepared by using the solid phase sequencial synthesis technique.
- the process for preparing the somatostatin analogs of the present invention comprises a) preparing a corresponding blocked linear peptide attached to a solid phase resin; b) selectively deblocking the N-terminal amine group;.c) removing the linear peptide from the resin; d) treating the linear peptide with a cyclizing agent to obtain the cyclic peptide; and e) removing the remaining blocking groups.
- linear peptide When the linear peptide is prepared on the resin, it is not critical which amino acid is selected to be at the C-terminal position provided only that the sequence of amino acids in the linear peptide corresponds to that in the desired somatostatin analog. Once a linear peptide has been cyclized one can no longer determine which amino acid was at the C-terminus of the linear peptide. As an example to illustrate this, either of the two following linear peptides, when cyclized, will give the identical somatostatin analog: or
- the synthesis of the linear peptides by the solid phase technique is conducted in a stepwise manner on chloromethylated resin.
- the resin is composed of fine beads (20-70 microns in diameter) of a synthetic resin prepared by copolymerization of styrene with 1 to 2 percent divinylbenzene.
- the benzene rings in the resin are chloromethylated in a Friedel-Crafts reaction with chloromethyl methyl ether and stannic chloride. The Friedel-Crafts reaction is continued until the resin contains 0.5 to 5 mmoles of chlorine per gram of resin.
- the amino acid selected to be the C-terminal amino acid of the linear peptide is converted to its amino protected derivative.
- the carboxyl group of the selected C-terminal amino acid is bound covalently to the insoluble polymeric resin support, as for example, as the carboxylic ester of the resin-bonded benzyl chloride present in chloromethyl-substituted polystyrene-divinylbenzene resin.
- the amino protected derivative of the next amino acid in the sequence is added along with a coupling agent, such as dicyclohexylcarbodiimide.
- the amino acid reactant may be employed in the form of a carboxyl-activated amino acid such as the ONp ester, an amino acid azide, and the like. Deprotection and addition of successive amino acids is performed until the desired linear peptide is formed.
- protecting groups are, in part, dictated by particular coupling conditions, in part by the amino acid and peptide components involved in the reaction.
- Amino-protecting groups ordinarily employed include those which are well known in the art, for example, urethane protecting substituents such as benzyloxycarbonyl (carbobenzoxy), p-methoxy- carbobenzoxy, p-nitrocarbobenzoxy, t-butyloxycarbonyl, and the like. It is preferred to utilize t-butyloxycarbonyl (BOC) for protecting the a-amino group in the amino acids undergoing reaction at the carboxyl end of said amino acid.
- BOC t-butyloxycarbonyl
- the BOC protecting group is readily removed following such coupling reaction and prior to the subsequent step by the relatively mild action of acids (i.e., trifluoro acetic acid, or hydrogen chloride in ethyl acetate).
- the -OH group of Thr can be protected by the Bzl group and the E -amino group of Lys can be protected by the INOC group or the 2-chlorobenzyloxycarbonyl (2-Cl-CBZ) group.
- the E -amino group with 2-Cl-CBZ group it is preferred to protect the E -amino group with 2-Cl-CBZ group as this group is removed simultaneously with the Bzl groups by treatment with HF after the linear peptide has been cyclized.
- the INOC group is not removed by HF and requires an additional treatment with Zn. Neither group is affected by TFA, used for removing BOC protecting groups.
- the linear peptide may be removed from the resin by a variety of methods which are well known in the art.
- the peptide may be cleaved from the resin with hydrazine and thus directly form the peptide hydrazide which may be subsequently cyclized via the azide to the desired cyclic peptide.
- the hydrazide is converted to the corresponding azide by reaction with a reagent which furnishes nitrous acid in situ.
- Suitable reagents for this purpose include a lower alkyl nitrite (e.g.
- t-butyl nitrite, isoamyl nitrite) or an alkali metal nitrite salt e.g., sodium nitrite, potassium nitrite
- a strong acid such as hydrochloric, phosphoric, sulfonic, etc.
- This reaction is carried out in the presence of either water and/or a non-aqueous solvent such as dimethylformamide, tetrahydrofuran, dioxane, chloroform, methylene chloride, etc., at a temperature between about -40°C and +20°C.
- the peptide may be removed from the resin by treatment with a lower alcohol such as methanol in the presence of an organic base such as triethylamine, thus resulting in the formation of the corresponding lower alcohol ester of the linear hexapeptide.
- a lower alcohol such as methanol
- an organic base such as triethylamine
- the resulting compound may be converted to the azide via the hydrazide which may then be cyclized to the desired cyclic peptide.
- the preferred method in the present invention is the use of hydrazine.
- one preferred overall procedure for preparing the desired cyclic peptides of the present invention involves the stepwise synthesis of the linear peptide on a solid phase resin. More specifically, in the process for preparing cyc/o(Aha-Phe-Phe-D-Trp-Lys-Thr-Phe), the carboxyl end of the N-blocked amino acid phenylalanine is bound covalently to an insoluble polymeric resin support as the carboxylic acid ester of the resin-bonded benzyl chloride. The amino group of Phe is protected by the BOC group. After the attachment of the Phe is completed on the resin, the protecting group BOC is removed by treatment with TFA in CH 2 CL 2 .
- the subsequent amino acids are attached, in the form of BOC-amino acid, using DCCI as the condensing agent or an active ester such as ONp.
- DCCI condensing agent
- an active ester such as ONp.
- the N-terminal amino group is selectively deblocked and the peptide is removed from the resin by treatment with hydrazine.
- the resulting linear peptide hydrazide with the N-terminal amino group deblocked having the amino acid sequence: D-Trp-( ⁇ -2-CI-CBZ)Lys-(O-Bzl)Thr-Phe-Aha-Phe-Phe-NH ⁇ NH 2 is treated with isoamyl nitrite in acid pH to form the corresponding azide.
- the azide solution is diluted with solvent and neutralized with an organic base.
- the linear peptide cyclizes to form cyclo[Aha-Phe-Phe-D-Trp-( ⁇ -2-Cl-CBZ)Lys-(O-Bzl)Thr-Phe].
- the "pH” is checked and maintained at neutral by the addition of organic base.
- the "pH” in organic solvent is determined by the application of an aliquot of the solution to narrow range pH paper.
- Step a) Preparation of D-Trp-( ⁇ -2-Cl-CBZ)Lys-(O-Bzl)Thr-Phe Aha-Phe-Phe-O-CH 2 - ⁇ -Resin
- Chloromethyl resin (2% cross-linked Merrifield resin), 862.0 g. (2.37 moles), having 2.75 meq. chlorine/g., and 607.0 g. (2.37 moles, 1 equivalent) of BOC-Phe were added to 4320 ml. of peroxide- free tetrahydrofuran. The mixture was stirred in an oil bath at 80°C. bath temperature for 45 minutes. Triethylamine, 310.0 ml., was added and the reaction mixture stirred at 80°C. bath temperature for 70 hours, cooled to 25°C. and transferred to a stirred solid phase reaction column with 2000 ml. of tetrahydrofuran.
- BOC-Phe-O-CH 2 - ⁇ -resin (2.84 g.; 2.0 mmole) was carried through the procedures in Tables III and IV using 2 deblockings (2 minutes and 25 minutes) with 25% TFA in methylene chloride, and 2.5 equivalents of BOC-amino acid in the required sequence until the desired BOC-octapeptide-O-CH2- ⁇ - resin was obtained.
- DCCI was used as the coupling agent in every step except the coupling of BOC-Phe-to Aha-Phe-Phe-O-CH 2 - ⁇ -resin in which case the coupling was carried out in the presence of DCCI and 1-hydroxybenzotriazole monohydrate (HBT. H 2 0).
- the coupling reactions were carried out in methylene chloride, freshly degassed DMF or a mixture of these two solvents.
- the N-terminal amino group was blocked with a BOC group in each case; the hydroxy group of Thr was blocked with Bzl and the e-amino group of Lys with 2-Cl-CBZ.
- Step b) ⁇ Preparation of D-Trp-( ⁇ -2-Cl ⁇ CBZ)-Lys-(O-Bz)Thr-Phe Aha-Phe-Phe-NH-NH 2
- Step cJ Preparation of D-Trp-( ⁇ -2-Cl-CBZ-)Lys-(O-Bzl)Thr-Phe-Aha-Phe-Phe-N 3
- Step d) Preparation of Cyclo[Aha-Phe-Phe-D-Trp-( ⁇ -2-Cl-CBZ)Lys-(O-Bzl)Thr-Phe)
- Step f) Purification of Cyclo(Aha-Phe-Phe-D-Trp-Lys-Thr-Phe)
- the somatostatin analogs of the present invention and the non-toxic pharmaceutically acceptable salts thereof are useful in humans and animals for inhibiting growth hormone release as in the treatment of acromegaly, inhibiting the release of glucagon and alone or in conjunction with insulin, for lowering blood glucose as in the treatment of diabetes with reduced gastrointestinal side effects.
- the number and size of daily doses and the time of administration are determined by an individual study of each subject. The method of determining these factors is known to those skilled in the art.
- the somatostatin analogs described herein may be administered to warm blooded animals, including humans, either intravenously, subcutaneously, intramuscularly or orally.
- the contemplated dose range for oral administration in tablet or capsule form to large mammals is about 0.001 mg. to about 7 mg./kg. of body weight per day.
- These somatostatin analogs are preferably administered by injection.
- a therapeutically effective amount of an analog is ordinarily supplied at a dosage level of from about 0.001 mg. to about 2 mg./kg. of body weight.
- the range is from about 0.00142 mg. to about 0.428 mg./kg. of body weight administered by intravenous infusion or by subcutaneous injection.
- the required dosage will vary with the particular condition being treated, the severity of the condition and the duration of treatment.
- the tablet may contain: a binder such as gum tragacanth, corn starch, gelatin, an excipient such as dicalcium phosphate; a disintegrating agent such as corn starch, and alginic acid; a lubricant such as magnesium stearate; and a sweetening and/or flavoring agent such as sucrose, lactose and wintergreen.
- a binder such as gum tragacanth, corn starch, gelatin, an excipient such as dicalcium phosphate
- a disintegrating agent such as corn starch, and alginic acid
- a lubricant such as magnesium stearate
- a sweetening and/or flavoring agent such as sucrose, lactose and wintergreen.
- suitable liquid carriers for intravenous administration include sterile water, isotonic saline and phosphate buffer solutions or other pharmaceutically acceptable injectable carriers.
Description
- Somatostatin is a tetradecapeptide having the structure:
- The present invention further provides somatostatin analogs which are easier to prepare because they contain only 26 atoms in the peptide backbone.
-
- A is Phe, Tyr, O-Me-Tyr,
- B is Phe, Tyr,
- C is Thr, Val,
-
- Illustrative of acid addition salts are hydrochloride, hydrobromide, sulfate, phosphate, maleate, acetate, citrate, benzoate, succinate, malate, ascorbate and the like.
- The somatostatin analogs of the present invention differ from somatostatin by virtue of the fact that they lack an N-terminal amino group and a C-terminal carboxyl group thus eliminating the groups involved in enzymic cleavage of the molecule by aminopeptidases and carboxypeptidases. Furthermore, the deletion of the adjacent heteroatoms of the disulfide bridge of somatostatin increases the stability of the analogs in vivo by preventing enzymatic degradation by reductive cleavage. Therefore, the analogs of the present invention are more resistent to cleavage in vivo than somatostatin and thus have a prolonged duration of action.
-
- The present invention provides somatostatin analogs wherein the Ala'-Gly2, Lys4-Asn5, Thr12- Ser13 and the amino groups of Cys3 and carboxyl group of Cys14 are deleted.
- Furthermore, the disulfide atoms of the cystine, -S-S-, have been replaced by the dicarba group, ―CH2―CH2. Whereas, in somatostatin the amino acids 4 and 13 are bridged by cystine, the present invention provides somatostatin analogs wherein amino acids 6 and 11 are bridged by 7-aminoheptanoic acid. The resulting ring contains 26 atoms. Furthermore, the somatostatin analogs of the present invention include those wherein Phe6 is replaced by Tyr or O-Me-Tyr; Phe7 is replaced by Tyr; Trp8 is replaced by D-Trp and Thr'° is replaced by Val.
-
- In accordance with the present invention, the novel somatostatin analogs are prepared by cyclizing corresponding linear peptides. The linear peptides are prepared by using the solid phase sequencial synthesis technique. Accordingly, the process for preparing the somatostatin analogs of the present invention comprises a) preparing a corresponding blocked linear peptide attached to a solid phase resin; b) selectively deblocking the N-terminal amine group;.c) removing the linear peptide from the resin; d) treating the linear peptide with a cyclizing agent to obtain the cyclic peptide; and e) removing the remaining blocking groups.
- When the linear peptide is prepared on the resin, it is not critical which amino acid is selected to be at the C-terminal position provided only that the sequence of amino acids in the linear peptide corresponds to that in the desired somatostatin analog. Once a linear peptide has been cyclized one can no longer determine which amino acid was at the C-terminus of the linear peptide. As an example to illustrate this, either of the two following linear peptides, when cyclized, will give the identical somatostatin analog:
- It is evident that since the linear peptide is going to be cyclized, it does not matter which amino acid is used to start the chain. Starting with Phe at the carboxyl end, as illustrated in the first of the two examples above, has an advantage over the second example. In the first example, D-Trp, which reacts with t-butyl carbonium ions formed when BOC groups are removed, is the N-terminal amino acid and thus will be added last and hence will be subjected to the least number of exposures to t-butyl carbonium ion.
- The synthesis of the linear peptides by the solid phase technique is conducted in a stepwise manner on chloromethylated resin. The resin is composed of fine beads (20-70 microns in diameter) of a synthetic resin prepared by copolymerization of styrene with 1 to 2 percent divinylbenzene. The benzene rings in the resin are chloromethylated in a Friedel-Crafts reaction with chloromethyl methyl ether and stannic chloride. The Friedel-Crafts reaction is continued until the resin contains 0.5 to 5 mmoles of chlorine per gram of resin.
- The amino acid selected to be the C-terminal amino acid of the linear peptide is converted to its amino protected derivative. The carboxyl group of the selected C-terminal amino acid is bound covalently to the insoluble polymeric resin support, as for example, as the carboxylic ester of the resin-bonded benzyl chloride present in chloromethyl-substituted polystyrene-divinylbenzene resin. After the amino protecting group is removed, the amino protected derivative of the next amino acid in the sequence is added along with a coupling agent, such as dicyclohexylcarbodiimide. The amino acid reactant may be employed in the form of a carboxyl-activated amino acid such as the ONp ester, an amino acid azide, and the like. Deprotection and addition of successive amino acids is performed until the desired linear peptide is formed.
- The selection of protecting groups is, in part, dictated by particular coupling conditions, in part by the amino acid and peptide components involved in the reaction.
- Amino-protecting groups ordinarily employed include those which are well known in the art, for example, urethane protecting substituents such as benzyloxycarbonyl (carbobenzoxy), p-methoxy- carbobenzoxy, p-nitrocarbobenzoxy, t-butyloxycarbonyl, and the like. It is preferred to utilize t-butyloxycarbonyl (BOC) for protecting the a-amino group in the amino acids undergoing reaction at the carboxyl end of said amino acid. The BOC protecting group is readily removed following such coupling reaction and prior to the subsequent step by the relatively mild action of acids (i.e., trifluoro acetic acid, or hydrogen chloride in ethyl acetate).
- The -OH group of Thr can be protected by the Bzl group and the E-amino group of Lys can be protected by the INOC group or the 2-chlorobenzyloxycarbonyl (2-Cl-CBZ) group. In the case of Lys, it is preferred to protect the E-amino group with 2-Cl-CBZ group as this group is removed simultaneously with the Bzl groups by treatment with HF after the linear peptide has been cyclized.
- The INOC group is not removed by HF and requires an additional treatment with Zn. Neither group is affected by TFA, used for removing BOC protecting groups.
- After the linear peptide has been formed on the solid phase resin, it may be removed from the resin by a variety of methods which are well known in the art. For example, the peptide may be cleaved from the resin with hydrazine and thus directly form the peptide hydrazide which may be subsequently cyclized via the azide to the desired cyclic peptide. The hydrazide is converted to the corresponding azide by reaction with a reagent which furnishes nitrous acid in situ. Suitable reagents for this purpose include a lower alkyl nitrite (e.g. t-butyl nitrite, isoamyl nitrite) or an alkali metal nitrite salt (e.g., sodium nitrite, potassium nitrite) in the presence of a strong acid such as hydrochloric, phosphoric, sulfonic, etc. This reaction is carried out in the presence of either water and/or a non-aqueous solvent such as dimethylformamide, tetrahydrofuran, dioxane, chloroform, methylene chloride, etc., at a temperature between about -40°C and +20°C. Alternatively, the peptide may be removed from the resin by treatment with a lower alcohol such as methanol in the presence of an organic base such as triethylamine, thus resulting in the formation of the corresponding lower alcohol ester of the linear hexapeptide. In the case wherein the ester is the methyl ester, the resulting compound may be converted to the azide via the hydrazide which may then be cyclized to the desired cyclic peptide. The preferred method in the present invention is the use of hydrazine.
-
- As reference to Table II will show, one preferred overall procedure for preparing the desired cyclic peptides of the present invention involves the stepwise synthesis of the linear peptide on a solid phase resin. More specifically, in the process for preparing cyc/o(Aha-Phe-Phe-D-Trp-Lys-Thr-Phe), the carboxyl end of the N-blocked amino acid phenylalanine is bound covalently to an insoluble polymeric resin support as the carboxylic acid ester of the resin-bonded benzyl chloride. The amino group of Phe is protected by the BOC group. After the attachment of the Phe is completed on the resin, the protecting group BOC is removed by treatment with TFA in CH2CL2. The subsequent amino acids are attached, in the form of BOC-amino acid, using DCCI as the condensing agent or an active ester such as ONp. After the desired linear peptide has been prepared, the N-terminal amino group is selectively deblocked and the peptide is removed from the resin by treatment with hydrazine. The resulting linear peptide hydrazide with the N-terminal amino group deblocked having the amino acid sequence: D-Trp-(ε-2-CI-CBZ)Lys-(O-Bzl)Thr-Phe-Aha-Phe-Phe-NH―NH2 is treated with isoamyl nitrite in acid pH to form the corresponding azide. The azide solution is diluted with solvent and neutralized with an organic base. The linear peptide cyclizes to form cyclo[Aha-Phe-Phe-D-Trp-(ε-2-Cl-CBZ)Lys-(O-Bzl)Thr-Phe]. During the cyclization the "pH" is checked and maintained at neutral by the addition of organic base. The "pH" in organic solvent is determined by the application of an aliquot of the solution to narrow range pH paper.
- After the linear peptide is cyclized, the remaining protective groups, 2-Cl-CBZ and Bzl, are removed in one step by treatment with HF in the presence of anisole. The crude cyclic peptides obtained by the processes of Table II are purified by chromatography, preferably on "Sephadex" (a registered trademark in the United Kingdom) eluted with 50% aqueous acetic acid.
- The following Examples illustrate methods of carrying out the present invention, but is to be understood that these Examples are given for purposes of illustration and not of limitation. It is to be understood that by changing the amino acid sequence of the polypeptide in accordance with the instructions provided by this disclosure, affords each of the compounds embraced by the description presented herein and embraced by the claims of this application.
- Chloromethyl resin (2% cross-linked Merrifield resin), 862.0 g. (2.37 moles), having 2.75 meq. chlorine/g., and 607.0 g. (2.37 moles, 1 equivalent) of BOC-Phe were added to 4320 ml. of peroxide- free tetrahydrofuran. The mixture was stirred in an oil bath at 80°C. bath temperature for 45 minutes. Triethylamine, 310.0 ml., was added and the reaction mixture stirred at 80°C. bath temperature for 70 hours, cooled to 25°C. and transferred to a stirred solid phase reaction column with 2000 ml. of tetrahydrofuran. After removal of the solvent, the resin was washed using the stirred column with:
- BOC-Phe-O-CH2-Ø-resin (2.84 g.; 2.0 mmole) was carried through the procedures in Tables III and IV using 2 deblockings (2 minutes and 25 minutes) with 25% TFA in methylene chloride, and 2.5 equivalents of BOC-amino acid in the required sequence until the desired BOC-octapeptide-O-CH2-Ø- resin was obtained.
- DCCI was used as the coupling agent in every step except the coupling of BOC-Phe-to Aha-Phe-Phe-O-CH2-Ø-resin in which case the coupling was carried out in the presence of DCCI and 1-hydroxybenzotriazole monohydrate (HBT. H20).
- The coupling- of each amino acid proceeded smoothly. Best yields were obtained when the coupling was repeated in each step. When the coupling was repeated, the initial two chloroform washes, the deblocking step and the succeeding three chloroform washes were all omitted and replaced by a single chloroform wash.
- The coupling reactions were carried out in methylene chloride, freshly degassed DMF or a mixture of these two solvents. The N-terminal amino group was blocked with a BOC group in each case; the hydroxy group of Thr was blocked with Bzl and the e-amino group of Lys with 2-Cl-CBZ.
-
- After the sequence of Tables III, IV and V were completed, the blocked heptapeptide-O-CH2-Ø- resin was filtered, washed with MeOH 3 x 40 ml. (3 minutes per wash) and dried overnight in vacuo. It weighed 3.41 g.
- To a mixture of 3.20 g. D-Trp-(ε-2-Cl-CBZ)Lys-(O-Bzl)Thr-Phe-Aha-Phe-Phe-O-CH2-Ø-resin in 33 ml. freshly degassed DMF was added 3.3 ml. NH2―NH2. The mixture was magnetically stirred at room temperature for 1 hour. The mixture was filtered to remove the resin. The resin was washed with 4 x 10 ml. DMF. The filtrate and washings were concentrated in vacuo to near dryness. The semi-solid residue was triturated with ether to obtain a solid. The solid was collected by filtration and dried in vacuo for 45 min. to yield 3.14 g, crude product. The solid was slurried with 4 x 20 mi. water to remove all traces of formyl hydrazide and dried in vacuo overnight to give 1.81 g. of product.
- D-Trp-(ε-2-Cl-CBZ)Lys-(O-Bzl)Thr-Phe-Aha-Phe-Phe-NH-NH2 (1.75 g., 1.39 mmole), prepared by the process set forth in Step b), was suspended in 20 mi. freshly degassed DMF. The turbid solution was stirred magnetically at -40°C. under a nitrogen atmosphere. To the suspension was added 1.94 ml., 5.07N HCI in THF (8.34 mmole), 6.0 equivalents). The resulting clear acidic solution, "pH" 1.0 to 1.5, was warmed to -25°C. and 0.215 ml. isoamyl nitrite (1.39 mmole, 1.0 equivalents) was added and stirring continued for 30 minutes. This solution of D-Trp-(ε-2-Cl-CBZ)Lys-(O-Bzl)-Thr-Phe-Aha-Phe-Phe-N3 was used immediately in step d).
- The solution of D-Trp-(E-2-CI-CBZ)Lys-(0-Bzl)Thr-Phe-Aha-Phe-Phe-N3 in DMF, obtained by the process set forth in Step c), was diluted in 1200 ml. freshly degassed DMF, precooled to -40°C. The solution was maintained under a nitrogen atmosphere and allowed to warm to -20°C. during which time the "pH" was maintained at 7.2 to 7.6 by the addition of 1.62 ml. N,N-diisopropylethylamine. The solution was maintained at -16°C. for 24 hours and then kept at 5°C. for an additional 24 hours. During this period 1.95 ml. of N,N-diisopropylethylamine was added to maintain a "pH" of 7.2 to 7.6.
- The solution was concentrated in vacuo to a thick oil, washed twice with ether and once with ethyl acetate and triturated with water to give a solid. The solid was collected by filtration and dried in vacuo overnight to give 1.17 g. of product.
- Cyclo[Aha-Phe-Phe-D-Trp-(ε-2-Cl-CBZ)Lys-(O-Bzl)-Thr-Phe], 1.15 g., obtained by the process set forth in Step d), was dissolved in 2 mi. anisole and 20 ml. hydrogen fluoride at dry ice-acetone bath temperature. The solution was stirred magnetically at ice-bath temperature for 1 1/2 hours. The excess hydrogen fluoride was removed in vacuo at ice-bath temperature. The resulting oily residue was maintained in vacuo for an additional 3/4 hour at ice-bath temperature and triturated with ethyl acetate to give a solid. The solid was collected by filtration and dried in vacuo to give 674 mg. of product.
- The cyc/o(Aha-Phe-Phe-D-Trp-Lys-Thr-Phe), 654 mg., obtained by the process set forth in step e), was dissolved in 12 ml. 50% aqueous acetic acid and charged to a column of Sephadex G-50, (5 cm. x 115 cm., 2260 ml.) packed in 50% aqueous acetic acid. The column was eluted with 50% aqueous acetic acid at the rate of 21 ml./10 min./fraction. The effluent was monitored at 280 nm.
- Fractions 83 to 91 were combined, concentrated to dryness in vacuo and the residue lyophilized from 20 ml. 10% aqueous acetic acid to give 369 mg. of substantially pure product. A 20 hour acid hydrolysate showed the following amino acid analysis:
-
- The somatostatin analogs of the present invention and the non-toxic pharmaceutically acceptable salts thereof, are useful in humans and animals for inhibiting growth hormone release as in the treatment of acromegaly, inhibiting the release of glucagon and alone or in conjunction with insulin, for lowering blood glucose as in the treatment of diabetes with reduced gastrointestinal side effects. In the treatment of diabetes, the number and size of daily doses and the time of administration are determined by an individual study of each subject. The method of determining these factors is known to those skilled in the art.
- The somatostatin analogs described herein may be administered to warm blooded animals, including humans, either intravenously, subcutaneously, intramuscularly or orally. The contemplated dose range for oral administration in tablet or capsule form to large mammals is about 0.001 mg. to about 7 mg./kg. of body weight per day. These somatostatin analogs are preferably administered by injection. A therapeutically effective amount of an analog is ordinarily supplied at a dosage level of from about 0.001 mg. to about 2 mg./kg. of body weight. Preferably the range is from about 0.00142 mg. to about 0.428 mg./kg. of body weight administered by intravenous infusion or by subcutaneous injection. The required dosage will vary with the particular condition being treated, the severity of the condition and the duration of treatment.
- If the active ingredient is administered in tablet form, the tablet may contain: a binder such as gum tragacanth, corn starch, gelatin, an excipient such as dicalcium phosphate; a disintegrating agent such as corn starch, and alginic acid; a lubricant such as magnesium stearate; and a sweetening and/or flavoring agent such as sucrose, lactose and wintergreen. Suitable liquid carriers for intravenous administration include sterile water, isotonic saline and phosphate buffer solutions or other pharmaceutically acceptable injectable carriers.
- The following example is included to illustrate the preparation of a representative dose of cyc/o(Aha-Phe-Phe-D-Trp-Lys-Thr-Phe) suitable for subcutaneous injection.
-
- 1 ml. sterile saline;
- 1 mg. cyclo(Aha-Phe-Phe-D-Trp-Lys-Thr-P"he).
wherein the ring formed by the peptide backbone contains 26 atoms and pharmaceutically acceptable non-toxic acid addition salts thereof.
Claims (4)
which comprises:
wherein the ring formed by the peptide backbone contains 26 atoms and pharmaceutically acceptable non-toxic acid addition salts thereof in a pharmaceutically acceptable excipient.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US80467877A | 1977-06-08 | 1977-06-08 | |
US804678 | 1977-06-08 |
Publications (2)
Publication Number | Publication Date |
---|---|
EP0000053A1 EP0000053A1 (en) | 1978-12-20 |
EP0000053B1 true EP0000053B1 (en) | 1981-05-27 |
Family
ID=25189555
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP78100095A Expired EP0000053B1 (en) | 1977-06-08 | 1978-06-06 | Somatostatin analogs, process for their preparation and pharmaceutical compositions containing them |
Country Status (7)
Country | Link |
---|---|
US (1) | US4146612A (en) |
EP (1) | EP0000053B1 (en) |
JP (1) | JPS543085A (en) |
DE (1) | DE2860734D1 (en) |
DK (1) | DK252778A (en) |
IE (1) | IE47421B1 (en) |
IT (1) | IT1105131B (en) |
Families Citing this family (28)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
LU78191A1 (en) * | 1977-09-28 | 1979-05-25 | Ciba Geigy Ag | METHOD FOR PRODUCING NEW CYCLOPEPTIDES |
US4190648A (en) * | 1979-03-13 | 1980-02-26 | Merck & Co., Inc. | Peptides having somatostatin activity |
NZ195303A (en) * | 1979-10-31 | 1984-10-19 | Merck & Co Inc | Cyclic hexapeptide somatostatin analogues,and pharmaceutical compositions |
US4358439A (en) * | 1979-12-21 | 1982-11-09 | Ciba-Geigy Corporation | Cyclooctapeptides |
US4508711A (en) * | 1983-04-18 | 1985-04-02 | American Cyanamid Company | Cyclic pentapeptide displaying somatostatin antagonism and method of treatment of mammals therewith |
DE3845000C2 (en) * | 1987-07-10 | 1998-11-19 | Novartis Ag | Compsn. contg. somatostatin analogues for treating breast cancer |
ZW11290A1 (en) * | 1989-07-14 | 1990-10-31 | Smithkline Beecham Corp | Hemoregulatory peptides |
JPH0745517B1 (en) * | 1989-11-08 | 1995-05-17 | Daicel Chem | |
US5700905A (en) * | 1992-09-01 | 1997-12-23 | The Trustees Of The University Of Pennsylvania | Synthetic somatostatin mimics |
US6001960A (en) * | 1992-09-01 | 1999-12-14 | The Trustees Of The University Of Pennsylvania | Synthetic somatostatin mimics |
US5965694A (en) * | 1992-09-01 | 1999-10-12 | The Trustees Of The University Of Pennsylvania | Somatostatin mimics and synthetic methods therefor |
US5504069A (en) * | 1993-02-11 | 1996-04-02 | Biomeasure, Inc. | Inhibition of trauma-induced tumor growth |
DE4342907A1 (en) * | 1993-12-16 | 1995-06-22 | Bayer Ag | New cyclic depsipeptides with 18 ring atoms and their use for the control of endoparasites |
WO1996014810A2 (en) * | 1994-11-03 | 1996-05-23 | The Saunders Group, Inc. | Portable traction device |
US5597894A (en) * | 1995-06-05 | 1997-01-28 | The Louisiana State University Medical Center Foundation | Multi-tyrosinated somatostatin analogs |
US6004928A (en) * | 1997-05-13 | 1999-12-21 | Biomeasure, Incorporated | Method of treating hyperlipidemia |
CA2290592A1 (en) * | 1997-05-13 | 1998-11-19 | Michael Anthony Cawthorne | Somatostatin and somatostatin agonists for decreasing body weight |
WO1998051330A1 (en) * | 1997-05-13 | 1998-11-19 | Societe De Conseils De Recherches Et D'applications Scientifiques S.A. (S.C.R.A.S.) | Method and compositions for treating hyperlipidemia and other conditions |
ES2216290T3 (en) * | 1997-05-13 | 2004-10-16 | Societe De Conseils De Recherches Et D'applications Scientifiques S.A.S. | SOMATOSTATIN AND AGOMISTS OF SOMATOSTATIN FOR THE TREATMENT OF INSENSITIVITY TO INSULIN AND SYNDROME X. |
US5968903A (en) * | 1998-05-07 | 1999-10-19 | Biomeasure, Incorporated | Inhibition of H. pylori proliferation |
US6171273B1 (en) | 1999-08-06 | 2001-01-09 | The Saunders Group, Inc. | Self-seating occiput wedge system for applying a therapeutic traction force |
RU2277539C2 (en) | 2001-06-08 | 2006-06-10 | Сосьете Де Консей Де Решерш Э Д`Аппликасьон Сьентифик С.А.С. | Chimeric analogs of somatostatin-dopamine |
US7189214B1 (en) | 2002-01-22 | 2007-03-13 | The Saunders Group, Inc. | Multi-axis cervical and lumbar traction table |
US20040145462A1 (en) * | 2003-01-29 | 2004-07-29 | Honda Giken Kogyo Kabushiki Kaisha | Variable electronic display apparatus for a vehicle, and method of using same |
EP2161037A3 (en) | 2003-04-22 | 2010-05-26 | Ipsen Pharma | Camptothecin-Somatostatin conjugates |
WO2009150469A2 (en) | 2008-06-12 | 2009-12-17 | Syntaxin Limited | Suppression of neuroendocrine diseases |
JP5799397B2 (en) | 2008-06-12 | 2015-10-28 | イプセン・バイオイノベーション・リミテッドIpsen Bioinnovation Limited | Cancer suppression |
GB0820970D0 (en) | 2008-11-17 | 2008-12-24 | Syntaxin Ltd | Suppression of cancer |
Family Cites Families (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US781610A (en) * | 1904-01-11 | 1905-01-31 | Winfield S Livengood | Wagon-brake. |
US3904594A (en) * | 1973-07-02 | 1975-09-09 | Salk Inst For Biological Studi | Somatostatin and acylated des-(ala' 1', gly' 2') derivatives thereof |
US3882098A (en) * | 1974-01-03 | 1975-05-06 | American Home Prod | Synthesis of des-Ala{hu 1{b , Gly{hu 2{b , Asn{hu 5{b -SRIF and intermediates |
DE2460469A1 (en) * | 1974-12-20 | 1976-07-01 | Hoechst Ag | Cyclic peptides inhibiting hormone release - prepd by cyclisation of linear undecapeptides contg a terminal omega- amino acid gp |
US3933784A (en) * | 1975-01-27 | 1976-01-20 | American Home Products Corporation | Des-(ser13)-srif and intermediates |
US4011182A (en) * | 1975-03-21 | 1977-03-08 | American Home Products Corporation | Cyclic undecapeptide analogs of somatostatin and intermediates |
CA1083143A (en) * | 1976-01-02 | 1980-08-05 | Nedumparambil A. Abraham | Carba derivatives of somatostatin and process therefor |
-
1978
- 1978-06-06 DE DE7878100095T patent/DE2860734D1/en not_active Expired
- 1978-06-06 IE IE1151/78A patent/IE47421B1/en unknown
- 1978-06-06 EP EP78100095A patent/EP0000053B1/en not_active Expired
- 1978-06-06 IT IT49736/78A patent/IT1105131B/en active
- 1978-06-07 DK DK252778A patent/DK252778A/en unknown
- 1978-06-07 JP JP6872378A patent/JPS543085A/en active Pending
- 1978-06-29 US US05/920,529 patent/US4146612A/en not_active Expired - Lifetime
Also Published As
Publication number | Publication date |
---|---|
DK252778A (en) | 1978-12-09 |
IT1105131B (en) | 1985-10-28 |
IT7849736A0 (en) | 1978-06-06 |
IE47421B1 (en) | 1984-03-07 |
DE2860734D1 (en) | 1981-09-03 |
EP0000053A1 (en) | 1978-12-20 |
IE781151L (en) | 1978-12-08 |
JPS543085A (en) | 1979-01-11 |
US4146612A (en) | 1979-03-27 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
EP0000053B1 (en) | Somatostatin analogs, process for their preparation and pharmaceutical compositions containing them | |
US4310518A (en) | Cyclic hexapeptide somatostatin analogs | |
Cai et al. | Synthesis and biological activity of highly potent octapeptide analogs of somatostatin. | |
EP0017746B1 (en) | Peptides having somatostatin activity, compositions comprising them and process for making the peptides | |
US4191754A (en) | Bicyclic somatostatin analogs | |
EP0143307B1 (en) | Cyclic hexapeptide somatostatin analogs; process for their preparation and pharmaceutical compositions containing them | |
EP0063308B1 (en) | Modified d-retro cyclic hexapeptide somatostatin analogs, process for their preparation and pharmaceutical compositions containing them | |
US4238481A (en) | Novel cyclopeptides | |
JPH0161120B2 (en) | ||
US4486415A (en) | Cyclic hexapeptide somatostatin analogs | |
US4162248A (en) | Somatostatin analogs | |
US4703034A (en) | Novel cyclic tetrapeptide | |
EP0206118B1 (en) | Cyclic hexapeptide somatostatin analogs, process for their preparation and pharmaceutical compositions containing them | |
EP0000919B1 (en) | Somatostatin analogs, process for their preparation and their use in pharmaceuticals. | |
EP0190946A2 (en) | Novel cyclic hexapeptide LHRH antagonists | |
EP0002264B1 (en) | Somatostatin analogs, process for their preparation and pharmaceutical composition thereof | |
EP0029310B1 (en) | Cyclic hexapeptide somatostatin analogs, process for their preparation and pharmaceutical compositions containing them | |
EP0002262B1 (en) | Somatostatin analogs and process for their preparation | |
EP0104348A2 (en) | Fluorinated cyclic hexapeptide somatostatin analogs, process for their preparation, intermediate products for their preparation and pharmaceutical compositions containing them | |
EP0113029B1 (en) | Dicyclic hexapeptides, processes for their preparation and pharmaceutical compositions containing them | |
US4159263A (en) | (D-Ala5)-somatostatin and analogues thereof | |
IE46462B1 (en) | Somatostatin peptide analogues | |
KR810000692B1 (en) | Process for preparing somatostain analogs | |
JPS636560B2 (en) | ||
IE47454B1 (en) | Somatostatin analogs |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PUAI | Public reference made under article 153(3) epc to a published international application that has entered the european phase |
Free format text: ORIGINAL CODE: 0009012 |
|
AK | Designated contracting states |
Kind code of ref document: A1 Designated state(s): BE CH DE FR GB LU NL SE |
|
17P | Request for examination filed | ||
GRAA | (expected) grant |
Free format text: ORIGINAL CODE: 0009210 |
|
AK | Designated contracting states |
Kind code of ref document: B1 Designated state(s): BE CH DE FR GB LU NL SE |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: LU Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 19810630 |
|
REF | Corresponds to: |
Ref document number: 2860734 Country of ref document: DE Date of ref document: 19810903 |
|
PGFP | Annual fee paid to national office [announced via postgrant information from national office to epo] |
Ref country code: FR Payment date: 19820322 Year of fee payment: 5 |
|
PGFP | Annual fee paid to national office [announced via postgrant information from national office to epo] |
Ref country code: BE Payment date: 19820331 Year of fee payment: 5 |
|
PGFP | Annual fee paid to national office [announced via postgrant information from national office to epo] |
Ref country code: LU Payment date: 19820525 Year of fee payment: 5 |
|
PGFP | Annual fee paid to national office [announced via postgrant information from national office to epo] |
Ref country code: SE Payment date: 19820630 Year of fee payment: 5 Ref country code: NL Payment date: 19820630 Year of fee payment: 5 Ref country code: DE Payment date: 19820630 Year of fee payment: 5 |
|
PGFP | Annual fee paid to national office [announced via postgrant information from national office to epo] |
Ref country code: CH Payment date: 19830301 Year of fee payment: 6 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: BE Effective date: 19830606 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: SE Effective date: 19830607 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: NL Effective date: 19840101 |
|
GBPC | Gb: european patent ceased through non-payment of renewal fee | ||
NLV4 | Nl: lapsed or anulled due to non-payment of the annual fee | ||
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: FR Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 19840229 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: DE Effective date: 19840301 |
|
REG | Reference to a national code |
Ref country code: FR Ref legal event code: ST |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: CH Effective date: 19840630 |
|
REG | Reference to a national code |
Ref country code: CH Ref legal event code: PL |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: GB Effective date: 19881117 |
|
EUG | Se: european patent has lapsed |
Ref document number: 78100095.5 Effective date: 19850610 |
|
PLBE | No opposition filed within time limit |
Free format text: ORIGINAL CODE: 0009261 |
|
STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: NO OPPOSITION FILED WITHIN TIME LIMIT |