DE3811193A1 - NEW PEPTIDES, METHOD FOR THE PRODUCTION THEREOF AND PHARMACEUTICAL COMPOSITIONS CONTAINING THESE PEPTIDES - Google Patents
NEW PEPTIDES, METHOD FOR THE PRODUCTION THEREOF AND PHARMACEUTICAL COMPOSITIONS CONTAINING THESE PEPTIDESInfo
- Publication number
- DE3811193A1 DE3811193A1 DE19883811193 DE3811193A DE3811193A1 DE 3811193 A1 DE3811193 A1 DE 3811193A1 DE 19883811193 DE19883811193 DE 19883811193 DE 3811193 A DE3811193 A DE 3811193A DE 3811193 A1 DE3811193 A1 DE 3811193A1
- Authority
- DE
- Germany
- Prior art keywords
- tyr
- arg
- ile
- lys
- pro
- 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.)
- Withdrawn
Links
- 108090000765 processed proteins & peptides Proteins 0.000 title claims abstract description 30
- 239000008194 pharmaceutical composition Substances 0.000 title claims description 3
- 238000004519 manufacturing process Methods 0.000 title claims 2
- 102000004196 processed proteins & peptides Human genes 0.000 title abstract description 13
- 238000000034 method Methods 0.000 title description 7
- 150000001413 amino acids Chemical class 0.000 claims description 43
- 150000001875 compounds Chemical class 0.000 claims description 40
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 claims description 27
- -1 aliphatic amino acid Chemical class 0.000 claims description 21
- 239000002253 acid Substances 0.000 claims description 7
- 210000004899 c-terminal region Anatomy 0.000 claims description 7
- 150000003839 salts Chemical class 0.000 claims description 6
- DTERQYGMUDWYAZ-UHFFFAOYSA-N N-acetyl-N-thioacetyl-Lysine Natural products CC(=O)NCCCCC(N)C(O)=O DTERQYGMUDWYAZ-UHFFFAOYSA-N 0.000 claims description 5
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 5
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 5
- 239000000203 mixture Substances 0.000 claims description 5
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 claims description 5
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 4
- 229910002091 carbon monoxide Inorganic materials 0.000 claims description 4
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 4
- 125000003277 amino group Chemical group 0.000 claims description 3
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 claims description 3
- IYKLZBIWFXPUCS-VIFPVBQESA-N (2s)-2-(naphthalen-1-ylamino)propanoic acid Chemical compound C1=CC=C2C(N[C@@H](C)C(O)=O)=CC=CC2=C1 IYKLZBIWFXPUCS-VIFPVBQESA-N 0.000 claims description 2
- OABOXRPGTFRBFZ-IMJSIDKUSA-N Cys-Cys Chemical compound SC[C@H](N)C(=O)N[C@@H](CS)C(O)=O OABOXRPGTFRBFZ-IMJSIDKUSA-N 0.000 claims description 2
- 229960002684 aminocaproic acid Drugs 0.000 claims description 2
- 238000009833 condensation Methods 0.000 claims description 2
- 230000005494 condensation Effects 0.000 claims description 2
- 108010004073 cysteinylcysteine Proteins 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 2
- 150000002993 phenylalanine derivatives Chemical class 0.000 claims description 2
- TUCNEACPLKLKNU-UHFFFAOYSA-N acetyl Chemical compound C[C]=O TUCNEACPLKLKNU-UHFFFAOYSA-N 0.000 claims 1
- 150000002148 esters Chemical class 0.000 claims 1
- 208000024172 Cardiovascular disease Diseases 0.000 abstract description 2
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- 206010047163 Vasospasm Diseases 0.000 abstract description 2
- 230000002490 cerebral effect Effects 0.000 abstract description 2
- 235000020824 obesity Nutrition 0.000 abstract description 2
- 238000002560 therapeutic procedure Methods 0.000 abstract description 2
- 235000001014 amino acid Nutrition 0.000 description 33
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 32
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 16
- 238000003786 synthesis reaction Methods 0.000 description 16
- 238000004458 analytical method Methods 0.000 description 14
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- URPYMXQQVHTUDU-OFGSCBOVSA-N nucleopeptide y Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(N)=O)NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](C)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)CNC(=O)[C@H]1N(CCC1)C(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CCCCN)NC(=O)[C@H](CO)NC(=O)[C@H]1N(CCC1)C(=O)[C@@H](N)CC=1C=CC(O)=CC=1)C1=CC=C(O)C=C1 URPYMXQQVHTUDU-OFGSCBOVSA-N 0.000 description 12
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 11
- 239000011347 resin Substances 0.000 description 10
- 229920005989 resin Polymers 0.000 description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 9
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 9
- 238000005859 coupling reaction Methods 0.000 description 9
- 125000006239 protecting group Chemical group 0.000 description 9
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 9
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 description 8
- 230000008878 coupling Effects 0.000 description 8
- 238000010168 coupling process Methods 0.000 description 8
- 239000000126 substance Substances 0.000 description 8
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 7
- 238000003776 cleavage reaction Methods 0.000 description 7
- 230000007017 scission Effects 0.000 description 7
- 239000000243 solution Substances 0.000 description 7
- 238000012360 testing method Methods 0.000 description 7
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 6
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 5
- 230000036772 blood pressure Effects 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 239000003153 chemical reaction reagent Substances 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 238000000746 purification Methods 0.000 description 4
- 230000006340 racemization Effects 0.000 description 4
- 150000003254 radicals Chemical class 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical group CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 102400000345 Angiotensin-2 Human genes 0.000 description 3
- 101800000733 Angiotensin-2 Proteins 0.000 description 3
- 102000005572 Cathepsin A Human genes 0.000 description 3
- 108010059081 Cathepsin A Proteins 0.000 description 3
- QMMFVYPAHWMCMS-UHFFFAOYSA-N Dimethyl sulfide Chemical compound CSC QMMFVYPAHWMCMS-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- CZGUSIXMZVURDU-JZXHSEFVSA-N Ile(5)-angiotensin II Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC=1C=CC=CC=1)C([O-])=O)NC(=O)[C@@H](NC(=O)[C@H](CCCNC(N)=[NH2+])NC(=O)[C@@H]([NH3+])CC([O-])=O)C(C)C)C1=CC=C(O)C=C1 CZGUSIXMZVURDU-JZXHSEFVSA-N 0.000 description 3
- 229920005654 Sephadex Polymers 0.000 description 3
- 239000012507 Sephadex™ Substances 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- GXBMIBRIOWHPDT-UHFFFAOYSA-N Vasopressin Natural products N1C(=O)C(CC=2C=C(O)C=CC=2)NC(=O)C(N)CSSCC(C(=O)N2C(CCC2)C(=O)NC(CCCN=C(N)N)C(=O)NCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(CCC(N)=O)NC(=O)C1CC1=CC=CC=C1 GXBMIBRIOWHPDT-UHFFFAOYSA-N 0.000 description 3
- 102000002852 Vasopressins Human genes 0.000 description 3
- 108010004977 Vasopressins Proteins 0.000 description 3
- 229950006323 angiotensin ii Drugs 0.000 description 3
- KBZOIRJILGZLEJ-LGYYRGKSSA-N argipressin Chemical compound C([C@H]1C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CSSC[C@@H](C(N[C@@H](CC=2C=CC(O)=CC=2)C(=O)N1)=O)N)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCN=C(N)N)C(=O)NCC(N)=O)C1=CC=CC=C1 KBZOIRJILGZLEJ-LGYYRGKSSA-N 0.000 description 3
- 210000004556 brain Anatomy 0.000 description 3
- 238000004992 fast atom bombardment mass spectroscopy Methods 0.000 description 3
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- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 3
- 238000012163 sequencing technique Methods 0.000 description 3
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 3
- 230000002792 vascular Effects 0.000 description 3
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- 239000008215 water for injection Substances 0.000 description 3
- SFLSHLFXELFNJZ-QMMMGPOBSA-N (-)-norepinephrine Chemical compound NC[C@H](O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-QMMMGPOBSA-N 0.000 description 2
- JAUKCFULLJFBFN-VWLOTQADSA-N (2s)-2-(9h-fluoren-9-ylmethoxycarbonylamino)-3-[4-[(2-methylpropan-2-yl)oxy]phenyl]propanoic acid Chemical compound C1=CC(OC(C)(C)C)=CC=C1C[C@@H](C(O)=O)NC(=O)OCC1C2=CC=CC=C2C2=CC=CC=C21 JAUKCFULLJFBFN-VWLOTQADSA-N 0.000 description 2
- YUGBZNJSGOBFOV-INIZCTEOSA-N (2s)-4-amino-2-(9h-fluoren-9-ylmethoxycarbonylamino)-4-oxobutanoic acid Chemical compound C1=CC=C2C(COC(=O)N[C@@H](CC(=O)N)C(O)=O)C3=CC=CC=C3C2=C1 YUGBZNJSGOBFOV-INIZCTEOSA-N 0.000 description 2
- DVBUCBXGDWWXNY-SFHVURJKSA-N (2s)-5-(diaminomethylideneamino)-2-(9h-fluoren-9-ylmethoxycarbonylamino)pentanoic acid Chemical compound C1=CC=C2C(COC(=O)N[C@@H](CCCN=C(N)N)C(O)=O)C3=CC=CC=C3C2=C1 DVBUCBXGDWWXNY-SFHVURJKSA-N 0.000 description 2
- BDNKZNFMNDZQMI-UHFFFAOYSA-N 1,3-diisopropylcarbodiimide Chemical compound CC(C)N=C=NC(C)C BDNKZNFMNDZQMI-UHFFFAOYSA-N 0.000 description 2
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- 241001465754 Metazoa Species 0.000 description 2
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- SFPCGPWJDDRSRL-UHFFFAOYSA-N 1-(4,5-dihydroimidazol-1-yl)ethanone Chemical compound CC(=O)N1CCN=C1 SFPCGPWJDDRSRL-UHFFFAOYSA-N 0.000 description 1
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 1
- QSVZJVOANHUCEB-UHFFFAOYSA-N 2,3-dimethoxy-2-phenoxypentanoic acid Chemical compound COC(C(C(=O)O)(OC1=CC=CC=C1)OC)CC QSVZJVOANHUCEB-UHFFFAOYSA-N 0.000 description 1
- NHJVRSWLHSJWIN-UHFFFAOYSA-N 2,4,6-trinitrobenzenesulfonic acid Chemical compound OS(=O)(=O)C1=C([N+]([O-])=O)C=C([N+]([O-])=O)C=C1[N+]([O-])=O NHJVRSWLHSJWIN-UHFFFAOYSA-N 0.000 description 1
- 125000001917 2,4-dinitrophenyl group Chemical group [H]C1=C([H])C(=C([H])C(=C1*)[N+]([O-])=O)[N+]([O-])=O 0.000 description 1
- LXUNZSDDXMPKLP-UHFFFAOYSA-N 2-Methylbenzenethiol Chemical compound CC1=CC=CC=C1S LXUNZSDDXMPKLP-UHFFFAOYSA-N 0.000 description 1
- QTWJRLJHJPIABL-UHFFFAOYSA-N 2-methylphenol;3-methylphenol;4-methylphenol Chemical compound CC1=CC=C(O)C=C1.CC1=CC=CC(O)=C1.CC1=CC=CC=C1O QTWJRLJHJPIABL-UHFFFAOYSA-N 0.000 description 1
- YLZOPXRUQYQQID-UHFFFAOYSA-N 3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)-1-[4-[2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidin-5-yl]piperazin-1-yl]propan-1-one Chemical compound N1N=NC=2CN(CCC=21)CCC(=O)N1CCN(CC1)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F YLZOPXRUQYQQID-UHFFFAOYSA-N 0.000 description 1
- HJBLUNHMOKFZQX-UHFFFAOYSA-N 3-hydroxy-1,2,3-benzotriazin-4-one Chemical compound C1=CC=C2C(=O)N(O)N=NC2=C1 HJBLUNHMOKFZQX-UHFFFAOYSA-N 0.000 description 1
- 125000006181 4-methyl benzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])C([H])([H])* 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical class [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- BWGNESOTFCXPMA-UHFFFAOYSA-N Dihydrogen disulfide Chemical compound SS BWGNESOTFCXPMA-UHFFFAOYSA-N 0.000 description 1
- 238000012286 ELISA Assay Methods 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
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Polymers OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- QUOGESRFPZDMMT-UHFFFAOYSA-N L-Homoarginine Natural products OC(=O)C(N)CCCCNC(N)=N QUOGESRFPZDMMT-UHFFFAOYSA-N 0.000 description 1
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- KAFHLONDOVSENM-HNNXBMFYSA-N O-Benzyl-L-tyrosine Chemical compound C1=CC(C[C@H](N)C(O)=O)=CC=C1OCC1=CC=CC=C1 KAFHLONDOVSENM-HNNXBMFYSA-N 0.000 description 1
- 229920000954 Polyglycolide Polymers 0.000 description 1
- 241000282887 Suidae Species 0.000 description 1
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- JAWMENYCRQKKJY-UHFFFAOYSA-N [3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-ylmethyl)-1-oxa-2,8-diazaspiro[4.5]dec-2-en-8-yl]-[2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidin-5-yl]methanone Chemical compound N1N=NC=2CN(CCC=21)CC1=NOC2(C1)CCN(CC2)C(=O)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F JAWMENYCRQKKJY-UHFFFAOYSA-N 0.000 description 1
- PQLVXDKIJBQVDF-UHFFFAOYSA-N acetic acid;hydrate Chemical compound O.CC(O)=O PQLVXDKIJBQVDF-UHFFFAOYSA-N 0.000 description 1
- PBCJIPOGFJYBJE-UHFFFAOYSA-N acetonitrile;hydrate Chemical compound O.CC#N PBCJIPOGFJYBJE-UHFFFAOYSA-N 0.000 description 1
- 230000000397 acetylating effect Effects 0.000 description 1
- 230000021736 acetylation Effects 0.000 description 1
- 238000006640 acetylation reaction Methods 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 230000010933 acylation Effects 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- 238000001042 affinity chromatography Methods 0.000 description 1
- 235000004279 alanine Nutrition 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 150000003862 amino acid derivatives Chemical class 0.000 description 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 239000012964 benzotriazole Substances 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 230000017531 blood circulation Effects 0.000 description 1
- 150000001718 carbodiimides Chemical class 0.000 description 1
- 238000001460 carbon-13 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 1
- 238000001311 chemical methods and process Methods 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 238000004140 cleaning Methods 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 229930003836 cresol Natural products 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- MGHPNCMVUAKAIE-UHFFFAOYSA-N diphenylmethanamine Chemical compound C=1C=CC=CC=1C(N)C1=CC=CC=C1 MGHPNCMVUAKAIE-UHFFFAOYSA-N 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 230000037406 food intake Effects 0.000 description 1
- 235000012631 food intake Nutrition 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 125000002795 guanidino group Chemical group C(N)(=N)N* 0.000 description 1
- 239000005555 hypertensive agent Substances 0.000 description 1
- 230000001631 hypertensive effect Effects 0.000 description 1
- 239000007943 implant Substances 0.000 description 1
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 1
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
- 150000002668 lysine derivatives Chemical class 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 description 1
- IOPLHGOSNCJOOO-UHFFFAOYSA-N methyl 3,4-diaminobenzoate Chemical compound COC(=O)C1=CC=C(N)C(N)=C1 IOPLHGOSNCJOOO-UHFFFAOYSA-N 0.000 description 1
- RMAHPRNLQIRHIJ-UHFFFAOYSA-N methyl carbamimidate Chemical compound COC(N)=N RMAHPRNLQIRHIJ-UHFFFAOYSA-N 0.000 description 1
- 239000004292 methyl p-hydroxybenzoate Substances 0.000 description 1
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 1
- 229960002216 methylparaben Drugs 0.000 description 1
- 230000030564 negative regulation of blood pressure Effects 0.000 description 1
- 210000005036 nerve Anatomy 0.000 description 1
- 210000001640 nerve ending Anatomy 0.000 description 1
- 239000002658 neuropeptide Y receptor agonist Substances 0.000 description 1
- BPGXUIVWLQTVLZ-OFGSCBOVSA-N neuropeptide y(npy) Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCN=C(N)N)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCN=C(N)N)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(O)=O)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](C)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)CNC(=O)[C@H]1N(CCC1)C(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CCCCN)NC(=O)[C@H](CO)NC(=O)[C@H]1N(CCC1)C(=O)[C@@H](N)CC=1C=CC(O)=CC=1)C1=CC=C(O)C=C1 BPGXUIVWLQTVLZ-OFGSCBOVSA-N 0.000 description 1
- 239000002858 neurotransmitter agent Substances 0.000 description 1
- 229960002748 norepinephrine Drugs 0.000 description 1
- SFLSHLFXELFNJZ-UHFFFAOYSA-N norepinephrine Natural products NCC(O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-UHFFFAOYSA-N 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 125000000636 p-nitrophenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)[N+]([O-])=O 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 238000010647 peptide synthesis reaction Methods 0.000 description 1
- 230000036581 peripheral resistance Effects 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 229920000747 poly(lactic acid) Polymers 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- ULWHHBHJGPPBCO-UHFFFAOYSA-N propane-1,1-diol Chemical compound CCC(O)O ULWHHBHJGPPBCO-UHFFFAOYSA-N 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 239000002516 radical scavenger Substances 0.000 description 1
- 230000029865 regulation of blood pressure Effects 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- UQDJGEHQDNVPGU-UHFFFAOYSA-N serine phosphoethanolamine Chemical compound [NH3+]CCOP([O-])(=O)OCC([NH3+])C([O-])=O UQDJGEHQDNVPGU-UHFFFAOYSA-N 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- ZERULLAPCVRMCO-UHFFFAOYSA-N sulfure de di n-propyle Natural products CCCSCCC ZERULLAPCVRMCO-UHFFFAOYSA-N 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 210000002820 sympathetic nervous system Anatomy 0.000 description 1
- 125000003698 tetramethyl group Chemical group [H]C([H])([H])* 0.000 description 1
- HNKJADCVZUBCPG-UHFFFAOYSA-N thioanisole Chemical compound CSC1=CC=CC=C1 HNKJADCVZUBCPG-UHFFFAOYSA-N 0.000 description 1
- 230000001960 triggered effect Effects 0.000 description 1
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 125000001493 tyrosinyl group Chemical group [H]OC1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])(N([H])[H])C(*)=O 0.000 description 1
- 125000005500 uronium group Chemical group 0.000 description 1
- 239000005526 vasoconstrictor agent Substances 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 235000014692 zinc oxide Nutrition 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
- C07K14/57545—Neuropeptide Y
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biophysics (AREA)
- Gastroenterology & Hepatology (AREA)
- Zoology (AREA)
- Biochemistry (AREA)
- Toxicology (AREA)
- General Health & Medical Sciences (AREA)
- Genetics & Genomics (AREA)
- Medicinal Chemistry (AREA)
- Molecular Biology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Endocrinology (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Peptides Or Proteins (AREA)
Abstract
Description
Gegenstand der Erfindung sind Verbindungen der allgemeinen Formel IThe invention relates to compounds of general formula I
R₁-U-X-Y-Z-Ile-Asn-Leu-Ile-Thr-X-W-X-Z-NH₂ (I)R₁-U-X-Y-Z-Ile-Asn-Leu-Ile-Thr-X-W-X-Z-NH₂ (I)
deren pharmazeutisch annehmbaren Salze, Verfahren zu ihrer Herstellung und diese Verbindungen enthaltende pharmazeutische Zusammensetzungen.their pharmaceutically acceptable salts, processes their preparation and containing these compounds pharmaceutical compositions.
In Formel I stehtIn formula I stands
R₁ für R₂-CO oder für einen peptidisch gebundenen
Di-, Tri-, Tetra- oder Pentapeptid-Rest der
Zusammensetzung H-Z-Pro-S-X-V-, H-Z-Pro-S-V-,
H-Z-Pro-V-, H-Z-V- oder Acetyl-Z-Pro-S-X-V-,
S für Ser, Glu, Cys oder eine Bindung,
U für eine aliphatische Aminosäure wie Leu, Ile,
Val, Ala oder eine Bindung,
X für eine basische Aminosäure wie Arg, Lys, Orn
und Homo-Arg oder für eine basische Aminosäure,
bei der die Aminogruppe der Seitenkette
acetyliert ist (z. B. Lys(Ac), Orn(Ac)), oder
eine Bindung,
Y für eine Aminosäure wie His, Trp, Phe und Tyr
oder eine Bindung,
Z für eine Aminosäure wie Tyr, Phe, His, Trp oder
eine unnatürliche Aminosäure wie z. B.
Naphthylalanin oder substituierte
Phenylalanin-Derivate oder wenn Z nicht
C-terminal steht auch für Cys,
W für eine Aminosäure wie Gln, Asn, Glu, Asp,
V für einen ω-Aminoalkansäure-Rest wie
ε-Aminocapronsäure-Rest oder einen Rest der
allgemeinen Formel NH-(CH₂) n -CO oder
NH-(CH₂) n -CONH-(CH₂) n CO mit n=2 bis 15
oder eine Aminosäuresequenz mit Turn-Struktur
wie z. B. Pro-Gly-T, Asn-Ser-T und Cys-Cys bzw.
Homo-Cys-Homo-Cys, die jeweils über ihre
Seitenketten disulfidisch miteinander
ringgeschlossen sein können,
T für eine der natürlichen Aminosäuren,
R₂ für C₁- bis C₇-Alkyl oder Benzyl.R₁ for R₂-CO or for a peptide-bound di-, tri-, tetra- or pentapeptide radical of the composition HZ-Pro-SXV, HZ-Pro-SV, HZ-Pro-V, HZV or acetyl Z-Pro-SXV-,
S for Ser, Glu, Cys or a bond,
U is an aliphatic amino acid such as Leu, Ile, Val, Ala or a bond,
X represents a basic amino acid such as Arg, Lys, Orn and Homo-Arg or a basic amino acid in which the amino group of the side chain is acetylated (eg Lys (Ac), Orn (Ac)), or a bond,
Y is an amino acid such as His, Trp, Phe and Tyr or a bond,
Z for an amino acid such as Tyr, Phe, His, Trp or an unnatural amino acid such. As naphthylalanine or substituted phenylalanine derivatives or if Z is not C-terminal for Cys,
W for an amino acid such as Gln, Asn, Glu, Asp,
V for a ω-aminoalkanoic acid radical such as ε-aminocaproic acid radical or a radical of the formula NH- (CH₂) n -CO or NH- (CH₂) n -CONH- (CH₂) n CO with n = 2 to 15, or an amino acid sequence with turn structure such. Pro-Gly-T, Asn-Ser-T and Cys-Cys or Homo-Cys-Homo-Cys, which may each be disulphidically ring-closed with each other via their side chains,
T for one of the natural amino acids,
R₂ is C₁ to C₇ alkyl or benzyl.
Wenn S für Glu und das nicht C-terminale Z für Tyr steht, kann die Seitenkette-Carboxylgruppe mit der phenolischen OH-Gruppe des Tyrosins esterartig verknüpft sein.If S for Glu and the non-C-terminal Z for Tyr stands, the side chain carboxyl group with the phenolic OH group of tyrosine ester-like be linked.
Falls S für Cys und das nicht C-terminale Z für Cys stehen, können die Seitenketten dieser Aminosäuren disulfidisch miteinander verknüpft sein.If S for Cys and the non-C-terminal Z for Cys can stand, the side chains of these amino acids be linked disulfide with each other.
In dem Sequenzteil U-X-Y-Z sind Aminosäuren bevorzugt, die in Verbindung mit dem Pentapeptid Ile-Asn-Leu-Ile-Thr alphahelikale Konformationen begünstigen.In the sequence part U-X-Y-Z, amino acids are preferred, that in conjunction with the pentapeptide Ile-Asn-Leu-Ile-Thr alphahelical conformations favor.
Bevorzugt sind Verbindungen, worin die Symbole der Formel I folgende Bedeutungen haben:Preference is given to compounds in which the symbols of the Formula I have the following meanings:
R₁: R₂-CO, H-Z-Pro-S-X-V-, H-Z-Pro-S-V-,
H-Z-Pro-V-, H-Z-V- oder Acetyl-Z-Pro-S-X-V-,
S: Ser oder Glu,
U: Leu oder eine Bindung,
X: Arg, Lys, Orn oder Homo-Arg,
Y: His oder Trp,
Z: Tyr oder Phe,
W: Gln oder Asn,
V: ω-Aminoalkansäure-Rest wie HN-(CH₂) n -CO
und NH-(CH₂) n -CONH-(CH₂) n -CO mit n=2 bis
10,
R₂: für C₁- bis C₇-Alkyl oder Benzyl.R₁: R₂-CO, HZ-Pro-SXV, HZ-Pro-SV, HZ-Pro-V, HZV or acetyl-Z-Pro-SXV-,
S: Ser or Glu,
U: Leu or a bond,
X: Arg, Lys, Orn or Homo-Arg,
Y: His or Trp,
Z: Tyr or Phe,
W: Gln or Asn,
V: ω- aminoalkanoic acid radical such as HN- (CH₂) n -CO and NH- (CH₂) n -CONH- (CH₂) n -CO with n = 2 to 10,
R₂: for C₁ to C₇-alkyl or benzyl.
Verbindungen der allgemeinen Formel I besitzen Säuregruppen, hauptsächlich Carboxylgruppen, oder phenolische Hydroxygruppen und/oder basische Gruppen wie z. B. Guanidino- oder Aminofunktionen. Verbindungen der allgemeinen Formel I können deshalb entweder als innere Salze, als Salze mit pharmazeutisch verwendbaren Säuren wie Salzsäure, Schwefelsäure, Phosphorsäure, Sulfonsäure oder organische Säuren oder als Salze mit pharmazeutisch verwendbaren Basen wie Alkali- oder Erdalkalimetallhydroxiden oder Carbonaten, Zink- oder Ammoniumhydroxiden oder organischen Aminen wie z. B. Diethylamin, Triethylamin, Triethanolamin u. a. vorliegen.Possess compounds of general formula I. Acid groups, mainly carboxyl groups, or phenolic hydroxy groups and / or basic groups such as B. guanidino or amino functions. links of the general formula I can therefore either as internal salts, as salts with pharmaceutically acceptable Acids such as hydrochloric acid, sulfuric acid, phosphoric acid, Sulfonic acid or organic acids or as salts with pharmaceutically usable bases such as alkali or Alkaline earth metal hydroxides or carbonates, zinc or Ammonium hydroxides or organic amines such. B. Diethylamine, triethylamine, triethanolamine u. a. available.
Verbindungen der allgemeinen Formel I enthalten Aminosäuren, welche entweder in ihrer L-Form oder D-Form vorliegen können. Verbindungen der Formel I können deshalb entweder aus Aminosäure-Resten mit L-Konfiguration aufgebaut sein, oder einzelne oder mehrere der Aminosäure-Reste der Verbindungen liegen in der D-Konfiguration vor. Compounds of general formula I included Amino acids, either in their L-form or D-form can be present. Compounds of the formula I can therefore either from amino acid residues with L configuration can be constructed, or single or several of the amino acid residues of the compounds are in the D configuration.
Bevorzugte erfindungsgemäße Verbindungen sindPreferred compounds of the invention are
1) H-Tyr-Pro-Ser-Lys-NH-(CH₂)₅-CO-Arg-His-Tyr-Ile-
Asn-Leu-Ile-Thr-Arg-Gln-Arg-Tyr-NH₂,
2) H-Tyr-Pro-Ser-Lys-NH-(CH₂)₅-CO-Leu-Arg-His-Tyr-
Ile-Asn-Leu-Ile-Thr-Arg-Gln-Arg-Tyr-NH₂,
3) H-Tyr-Pro-Ser-NH-(CH₂)₇-CO-Arg-His-Tyr-Ile-Asn-
Leu-Ile-Thr-Arg-Gln-Arg-Tyr-NH₂,
4) Ac-Tyr-Pro-Ser-Lys-NH-(CH₂)₅-CO-Arg-His-Tyr-Ile-
Asn-Leu-Ile-Thr-Arg-Gln-Arg-Tyr-NH₂,
5) H-Tyr-Pro-NH-(CH₂)₁₀-CO-Arg-His-Tyr-Ile-Asn-Leu-
Ile-Thr-Arg-Gln-Arg-Tyr-NH₂,
6) H-Tyr-Pro-NH-(CH₂)₁₀-CO-Tyr-Ile-Asn-Leu-Ile-Thr-
Arg-Gln-Arg-Tyr-NH₂,
7) H-Tyr-NH-(CH₂)₁₀-CO-Tyr-Ile-Asn-Leu-Ile-Thr-Arg-
Gln-Arg-Gln-Arg-Tyr-NH₂,
8) H-Tyr-Pro-Ser-NH-(CH₂)₅-CO-Tyr-Ile-Asn-Leu-Ile-
Thr-Arg-Gln-Arg-Tyr-NH₂,
9) H-Phe-Pro-Ser-Lys-NH-(CH₂)₅-CO-Arg-His-Tyr-Ile-
Asn-Leu-Ile-Thr-Arg-Gln-Arg-Tyr-NH₂,
10) H-Tyr-Pro-Ser-Lys-NH-(CH₂)₇-CO-Arg-His-Tyr-Ile-
Asn-Leu-Ile-Thr-Arg-Gln-Arg-Tyr-NH₂,
11) H-Tyr-Pro-Ser-NH-(CH₂)₁₀-CO-Arg-His-Tyr-Ile-Asn-
Leu-Ile-Thr-Arg-Gln-Arg-Tyr-NH₂,
12) H-Tyr-NH-(CH₂)₁₂-CO-Arg-His-Tyr-Ile-Asn-Leu-Ile-
Thr-Arg-Gln-Arg-Tyr-NH₂,
13) H-Tyr-Pro-Ser-Lys-NH-(CH₂)₅-CO-Lys-His-Tyr-Ile-
Asn-Leu-Ile-Thr-Arg-Gln-Arg-Tyr-NH₂,
14) H-Tyr-Pro-Ser-Lys-NH-(CH₂)₅-CO-Lys-His-Tyr-Ile-
Asn-Leu-Ile-Thr-Lys-Gln-Arg-Tyr-NH₂,
15) H-Tyr-Pro-Ser-Lys-NH-(CH₂)₅-CO-Lys-His-Tyr-Ile-
Asn-Leu-Ile-Thr-Lys-Gln-Lys-Tyr-NH₂,
16) H-Tyr-Pro-Ser-Lys-NH-(CH₂)₅-CO-Arg-Trp-Tyr-Ile-
Asn-Leu-Ile-Thr-Arg-Gln-Arg-Tyr-NH₂,
17) H-Tyr-Pro-Ser-Lys-NH-(CH₂)₇-CO-Arg-His-Tyr-Ile-
Asn-Leu-Ile-Thr-Arg-Gln-Arg-Tyr-NH₂,
18) H-Tyr-Pro-Ser-Lys-NH-(CH₂)₅-CO-Arg-His-Phe-Ile-
Asn-Leu-Ile-Thr-Arg-Gln-Arg-Tyr-NH₂,
19) CH₃-CO-Arg-His-Tyr-Ile-Asn-Leu-Ile-Thr-Arg-Gln-Arg-
Tyr-NH₂,
20) CH₃-CO-Lys-His-Tyr-Ile-Asn-Leu-Ile-Thr-Arg-Gln-Arg-
Tyr-NH₂,
21) CH₃-CO-Lys-His-Tyr-Ile-Asn-Leu-Ile-Thr-Lys-Gln-Arg-
Tyr-NH₂,
22) CH₃-CO-Lys-His-Tyr-Ile-Asn-Leu-Ile-Thr-Lys-Gln-Lys-
Tyr-NH₂,
23) CH₃-CO-Lys(Ac)-His-Tyr-Ile-Asn-Leu-Ile-Thr-Lys(Ac)-
Gln-Lys(Ac)-Tyr-NH₂,
24) CH₃-CO-Orn-His-Tyr-Ile-Asn-Leu-Ile-Thr-Orn-Gln-Orn-
Tyr-NH₂.1) H-Tyr-Pro-Ser-Lys-NH- (CH₂) ₅-CO-Arg-His-Tyr-Ile-Asn-Leu-Ile-Thr-Arg-Gln-Arg-Tyr-NH₂,
2) H-Tyr-Pro-Ser-Lys-NH- (CH₂) ₅-CO-Leu-Arg-His-Tyr-Ile-Asn-Leu-Ile-Thr-Arg-Gln-Arg-Tyr-NH₂,
3) H-Tyr-Pro-Ser-NH- (CH₂) ₇-CO-Arg-His-Tyr-Ile-Asn-Leu-Ile-Thr-Arg-Gln-Arg-Tyr-NH₂,
4) Ac-Tyr-Pro-Ser-Lys-NH- (CH₂) ₅-CO-Arg-His-Tyr-Ile-Asn-Leu-Ile-Thr-Arg-Gln-Arg-Tyr-NH₂,
5) H-Tyr-Pro-NH- (CH₂) ₁₀-CO-Arg-His-Tyr-Ile-Asn-Leu-Ile-Thr-Arg-Gln-Arg-Tyr-NH₂,
6) H-Tyr-Pro-NH- (CH₂) ₁₀-CO-Tyr-Ile-Asn-Leu-Ile-Thr-Arg-Gln-Arg-Tyr-NH₂,
7) H-Tyr-NH- (CH₂) ₁₀-CO-Tyr-Ile-Asn-Leu-Ile-Thr-Arg-Gln-Arg-Gln-Arg-Tyr-NH₂,
8) H-Tyr-Pro-Ser-NH- (CH₂) ₅-CO-Tyr-Ile-Asn-Leu-Ile-Thr-Arg-Gln-Arg-Tyr-NH₂,
9) H-Phe-Pro-Ser-Lys-NH- (CH₂) ₅-CO-Arg-His-Tyr-Ile-Asn-Leu-Ile-Thr-Arg-Gln-Arg-Tyr-NH₂,
10) H-Tyr-Pro-Ser-Lys-NH- (CH₂) ₇-CO-Arg-His-Tyr-Ile-Asn-Leu-Ile-Thr-Arg-Gln-Arg-Tyr-NH₂,
11) H-Tyr-Pro-Ser-NH- (CH₂) ₁₀-CO-Arg-His-Tyr-Ile-Asn-Leu-Ile-Thr-Arg-Gln-Arg-Tyr-NH₂,
12) H-Tyr-NH- (CH₂) ₁₂-CO-Arg-His-Tyr-Ile-Asn-Leu-Ile-Thr-Arg-Gln-Arg-Tyr-NH₂,
13) H-Tyr-Pro-Ser-Lys-NH- (CH₂) ₅-CO-Lys-His-Tyr-Ile-Asn-Leu-Ile-Thr-Arg-Gln-Arg-Tyr-NH₂,
14) H-Tyr-Pro-Ser-Lys-NH- (CH₂) ₅-CO-Lys-His-Tyr-Ile-Asn-Leu-Ile-Thr-Lys-Gln-Arg-Tyr-NH₂,
15) H-Tyr-Pro-Ser-Lys-NH- (CH₂) ₅-CO-Lys-His-Tyr-Ile-Asn-Leu-Ile-Thr-Lys-Gln-Lys-Tyr-NH₂,
16) H-Tyr-Pro-Ser-Lys-NH- (CH₂) ₅-CO-Arg-Trp-Tyr-Ile-Asn-Leu-Ile-Thr-Arg-Gln-Arg-Tyr-NH₂,
17) H-Tyr-Pro-Ser-Lys-NH- (CH₂) ₇-CO-Arg-His-Tyr-Ile-Asn-Leu-Ile-Thr-Arg-Gln-Arg-Tyr-NH₂,
18) H-Tyr-Pro-Ser-Lys-NH- (CH₂) ₅-CO-Arg-His-Phe-Ile-Asn-Leu-Ile-Thr-Arg-Gln-Arg-Tyr-NH₂,
19) CH₃-CO-Arg-His-Tyr-Ile-Asn-Leu-Ile-Thr-Arg-Gln-Arg-Tyr-NH₂,
20) CH₃-CO-Lys-His-Tyr-Ile-Asn-Leu-Ile-Thr-Arg-Gln-Arg-Tyr-NH₂,
21) CH₃-CO-Lys-His-Tyr-Ile-Asn-Leu-Ile-Thr-Lys-Gln-Arg-Tyr-NH₂,
22) CH₃-CO-Lys-His-Tyr-Ile-Asn-Leu-Ile-Thr-Lys-Gln-Lys-Tyr-NH₂,
23) CH₃-CO-Lys (Ac) -His-Tyr-Ile-Asn-Leu-Ile-Thr-Lys (Ac) - Gln-Lys (Ac) -Tyr-NH₂,
24) CH₃-CO-Orn-His-Tyr-Ile-Asn-Leu-Ile-Thr-Orn-Gln-Orn-Tyr-NH₂.
Die Verbindungen der allgemeinen Formel I stellen Segmente, diskontinuierliche miteinander verknüpfte Segmente und Analoge des Neuropeptid Y dar.The compounds of general formula I provide Segments, discontinuous interlinked Segments and analogues of the neuropeptide Y represent.
Neuropeptid Y (NPY) ist ein aus 36 Aminosäuren bestehendes Peptid, das erstmals 1982 im Gehirn von Schweinen nachgewiesen wurde (K. Tatemoto u. a., Nature 296, 659 [1982]). Inzwischen wurde NPY in allen bisher untersuchten Tierspezies und auch beim Menschen nachgewiesen (J. M. Lundberg u. a., Neurosci. Lett., 42, 167 [1983]). Es kommt im Organismus nahezu ubiquitär vor, besonders hohe Konzentrationen werden im Gehirn und in Organen, die vom sympathischen Nervensystem innerviert werden (Herz, Nieren, Nebennieren, Gefäßsystem), nachgewiesen (T. L. O'Donohue u. a., Peptides, 6, 755 [1985]). Vielfach ist NPY zusammen mit Noradrenalin (NA) in den Nervenendigungen lokalisiert und wird auf Nervenimpuls hin freigesetzt (J. M. Lundberg u. a., Regulatory Peptides, 13, 41 [1985]). Hervorstechende Eigenschaft von exogen in die Körperperipherie zugeführtem NPY ist eine markante Blutdrucksteigerung. Zusammen mit NA, Vasopressin (VP) und Angiotensin II (AII) zählt NPY zu den stärksten bekannten körpereigenen gefäßkontrahierenden, d. h. blutdrucksteigernden Substanzen (P. C. Emson u. a., TINS, 1984, 31). Lokale Injektion von NPY in das Gehirn verursacht Blutdrucksenkung (ähnlich Adrenalin und NA) sowie eine drastische Steigerung der Nahrungsaufnahme (T. S. Gray u. a., Life Sci., 38, 389 [1986]). Neuropeptide Y (NPY) is one of 36 amino acids existing peptide, first in the brain of 1982 Pigs has been detected (K. Tatemoto et al., Nature 296, 659 [1982]). Meanwhile, NPY has been in all so far studied animal species and also in humans (M.M. Lundberg et al., Neurosci. Lett., 42, 167 [1983]). It is almost ubiquitous in the organism Before, particularly high concentrations are in the brain and in organs that are of the sympathetic nervous system innervated (heart, kidneys, adrenals, Vascular system), proven (T.L. O'Donohue et al., Peptides, 6, 755 [1985]). In many cases NPY is together with Norepinephrine (NA) located in the nerve endings and is released upon nerve impulse (J.M. Lundberg u. a., Regulatory Peptides, 13, 41 [1985]). Salient feature of exogenous in the Body periphery supplied NPY is a striking Increase in blood pressure. Together with NA, vasopressin (VP) and angiotensin II (AII) is one of the strongest NPY known autologous vascular contractors, d. H. hypertensive substances (P.C. Emson et al., TINS, 1984, 31). Local injection of NPY into the brain causes lower blood pressure (similar to adrenaline and NA) as well as a drastic increase in food intake (T.S. Gray et al., Life Sci., 38, 389 [1986]).
Hauptangriffsorte von NPY in der Peripherie sind das Herz (starke Koronarkonstriktion), die Nieren (Minderdurchblutung) und das arterielle Gefäßsystem (Erhöhung des peripheren Widerstandes). Zusätzlich zu seiner gefäßkontrahierenden Eigenwirkung potenziert NPY auch die Wirkung der obengenannten Neurotransmitter (NA, VP, AII) sowie anderer körpereigener vasopressorischer Substanzen (L. Edvinsson u. a., Br. J. Pharacol., 83, 519 [1984]).The main attack of NPY in the periphery is that Heart (strong coronary constriction), kidneys (reduced blood flow) and the arterial vascular system (increase of peripheral resistance). In addition to his NPY also potentiates vasoconstrictor self-efficacy the effect of the above neurotransmitters (NA, VP, AII) as well as other body's own vasopressoric substances (L. Edvinsson et al., Br. Pharacol., 83, 519 [1984]).
Aus diesen Wirkungen sowie dem gehäuften Vorkommen von NPY in den Geweben, die für den Blutdruck relevant sind, kann geschlossen werden, daß NPY bei der Blutdruckregulation involviert ist.From these effects as well as the accumulated occurrence of NPY in tissues relevant to blood pressure can be concluded that NPY at the Blood pressure regulation is involved.
Überraschenderweise besitzen die erfindungsgemäßen Verbindungen NPY-agonistische, besonders aber auch NPY-antagonistische Wirksamkeit.Surprisingly, the inventive Compounds NPY-agonistic, but especially NPY antagonist activity.
Eine NPY-agonistische, d. h. blutdrucksteigernde Wirkung wurde an narkotisierten, despinalisierten Ratten nachgewiesen. Nach intravenöser Applikation verschiedener Dosen der jeweiligen Testsubstanz wurde der Blutdruckanstieg registriert und ED₂₀-Werte ermittelt. Der ED₂₀-Wert bezeichnet hier die Dosis der Testsubstanz, die den Blutdruck um 20 mm Hg steigert. An NPY agonist, d. H. hypertensive effect was given to anesthetized, despinalized rats demonstrated. After intravenous administration different doses of the respective test substance was the blood pressure increase registered and ED₂₀ values determined. The ED₂₀ value here denotes the dose the test substance which raises the blood pressure by 20 mm Hg increases.
Es ergaben sich folgende ED₂₀-Werte:There were the following ED₂₀ values:
Die NPY-antagonistische Wirkung wurde an narkotisierten Ratten ermittelt. Registriert wurde die Hemmung der durch eine definierte Dosis NPY ausgelöste Blutdrucksteigerung nach Vorbehandlung mit der Testsubstanz gegenüber den Kontrollwerten von nicht vorbehandelten Tieren.The NPY antagonist effect was anesthetized Rats determined. Was registered the inhibition of Blood pressure increase triggered by a defined dose of NPY after pretreatment with the test substance compared to the control values of non-pretreated Animals.
Es ergaben sich bei einer Dosierung von 1 bis 2×10-6 M/kg Testsubstanz folgende Hemmwerte:The following inhibition values were obtained at a dosage of 1 to 2 × 10 -6 M / kg test substance:
Verbindung Beispiel 1 83%,
Verbindung Beispiel 2 84%,
Verbindung Beispiel 19 94%,
Verbindung Beispiel 20 62%.Compound Example 1 83%,
Compound Example 2 84%,
Compound Example 19 94%,
Compound Example 20 62%.
Wegen der oben geschilderten Wirksamkeit können Verbindungen der allgemeinen Formel I zur Therapie cardiovasculärer Erkrankungen wie Hypertension, koronarer, cerebraler und renaler Vasospasmen sowie Obesitas verwendet werden. Darüber hinaus können diese Verbindungen als wertvolle Hilfsmittel zur Erzeugung und Reinigung (Affinitätschromatographie) von Antikörpern und in RIA- oder ELISA-Assays Anwendung finden. Because of the above-mentioned effectiveness can Compounds of the general formula I for therapy cardiovascular diseases such as hypertension, coronary, cerebral and renal vasospasm as well Obesity can be used. In addition, these can Compounds as valuable tools for generation and purification (affinity chromatography) of Antibodies and in RIA or ELISA assays Find.
Die Erfindung betrifft daher auch die Verwendung der erfindungsgemäßen Verbindungen als Heilmittel und pharmazeutische Zubereitungen, die diese Verbindungen enthalten. Bevorzugt ist die Anwendung am Menschen. Zur parenteralen Applikation werden die Verbindungen der Formel I oder deren physiologisch verträglichen Salze, eventuell mit den dafür üblichen Substanzen wie Lösungsvermittler, Emulgatoren oder weitere Hilfsstoffe in Lösung, Suspension oder Emulsion gebracht. Als Lösungsmittel kommen z. B. in Frage: Wasser, physiologische Kochsalzlösungen oder Alkohole, z. B. Ethanol, Propandiol oder Glycerin, Zuckerlösungen wie Glucose- oder Mannit-Lösungen oder auch eine Mischung aus verschiedenen Lösungsmitteln.The invention therefore also relates to the use of Compounds of the invention as a remedy and pharmaceutical preparations containing these compounds contain. The application on humans is preferred. to parenteral administration, the compounds of the Formula I or its physiologically acceptable salts, possibly with the usual substances such as Solubilizers, emulsifiers or other auxiliaries brought in solution, suspension or emulsion. When Solvents come z. B. in question: water, physiological saline solutions or alcohols, eg. B. Ethanol, propanediol or glycerine, sugar solutions like Glucose or mannitol solutions or else a mixture from different solvents.
Außerdem können die Verbindungen durch Implantate, z. B. aus Polylactid, Polyglycolid oder Polyhydroxybuttersäure bzw. intranasale Zubereitungen appliziert werden.In addition, the compounds by implants, z. B. from polylactide, polyglycolide or Polyhydroxybutyric acid or intranasal preparations be applied.
Die oben angegebenen Verbindungen können nach allgemein bekannten Methoden der Peptidchemie, wie z. B. in Houben-Weyl, Methoden der organischen Chemie, Bd. 15/2, beschrieben oder bevorzugt nach der Festphasenpeptidsynthese (z. B. B. Barany, R. B. Merrifield in The Peptides, Analysis, Synthesis, Biology, Vol. 2, 2-284 [1980], Academic Press, New York, oder R. C. Sheppard, Int. J. Pept. Prot. Res., 21, 118 [1983]) oder gleichwertigen bekannten Methoden hergestellt werden. Als Aminoschutzgruppen werden die in Houben-Weyl, Methoden der organischen Chemie, Bd. 15/1, beschriebenen verwendet, bevorzugt werden Urethanschutzgruppen wie z. B. die Fluorenylmethoxycarbonyl- oder die tert-Butyloxycarbonylschutzgruppe angewendet. Zur Verhinderung von Nebenreaktionen sind in der Regel eventuell vorhandene funktionelle Gruppen in den Seitenketten der Aminosäuren durch geeignete Schutzgruppen (siehe z. B. T. W. Greene, Protective Groups in Organic Synthesis) zusätzlich geschützt. Bevorzugt verwendet werden dabei Arg(NO₂), Arg(Mtr), Arg(di-Z), Arg(Pmc), Tyr(t-Bu), Tyr(Bzl), Tyr(Br-Z), Ser(t-Bu), Ser(Bzl), Glu(t-Bu), Glu(Bzl), Lys(BOC), Lys(Z), His(Trt), His(Bum), His(Dnp), His(Z), Thr(t-Bu), Thr(Bzl), Cys(Acm), Cys(4-Me-Bzl), Cys(t-Bu), Asp(t-Bu), Asp(Bzl), Orn(BOC), Orn(Z).The above-mentioned compounds may be general known methods of peptide chemistry, such as. In Houben-Weyl, Methods of Organic Chemistry, Vol. 15/2, described or preferred according to the Solid Phase Peptide Synthesis (e.g., B. Barany, R. B. Merrifield in The Peptides, Analysis, Synthesis, Biology, Vol. 2, 2-284 [1980], Academic Press, New York, or R.C. Sheppard, Int. J. Pept. Prot. Res., 21, 118 [1983]) or equivalent known methods getting produced. As amino protecting groups, the in Houben-Weyl, Methods of Organic Chemistry, Vol. 15/1, used, are preferred Urethane protective groups such. B. the Fluorenylmethoxycarbonyl or the tert-butyloxycarbonyl protecting group applied. To prevent Side reactions are usually present functional groups in the side chains of the Amino acids by suitable protecting groups (see eg. T.W. Greene, Protective Groups in Organic Synthesis) additionally protected. Preferably be used Arg (NO₂), Arg (Mtr), Arg (di-Z), Arg (Pmc), Tyr (t-Bu), Tyr (Bzl), Tyr (Br-Z), Ser (t-Bu), Ser (Bzl), Glu (t-Bu), Glu (Bzl), Lys (BOC), Lys (Z), His (Trt), His (Bum), His (Dnp), His (Z), Thr (t-Bu), Thr (Bzl), Cys (Acm), Cys (4-Me-Bzl), Cys (t-Bu), Asp (t-Bu), Asp (Bzl), Orn (BOC), Orn (Z).
Zur Synthese der Verbindungen der allgemeinen Formel I
nach der Festphasensynthese sind als Ankergruppen alle
diejenigen geeignet, die bei der Abspaltung des Peptids
vom polymeren Träger Peptidamide liefern. In
Kombination mit der BOC-Aminoschutzgruppe werden
bevorzugt die Benzhydrylamino-Ankergruppe (P. G. Pietta
u. a., J. Org. Chem., 39, 44 [1974]) und die
4-Methylbenzhydrylaminankergruppe (G. R. Matsueda u. a.,
Peptides, 2, 45 [1981]) verwendet. In Kombination mit
der Fmoc-Schutzgruppe sind verschiedene Ankergruppen
anwendbar:
p-Aminomethyl-phenoxymethyl-Gruppe (P. Pietta u. a., J.
Org. Chem., 40, 2995 [1975]),
Bis- und Trialkoxybenzylamin-Linker (F. Albericio, G.
Barany, Int. J. Pept. Prot. Res., 30, 206 [1987])
Benzhydrylalkohol-Linker (G. Breipohl u. a., Tetrah.
Lett., 28, 5651 [1987]).For the synthesis of the compounds of the general formula I according to the solid-phase synthesis are suitable as anchor groups all those which provide Peptidamide in the cleavage of the peptide from the polymeric carrier. In combination with the BOC-amino protecting group, preference is given to the benzhydrylamino anchor group (PG Pietta et al., J. Org. Chem., 39, 44 [1974]) and the 4-methylbenzhydrylamine anchor group (GR Matsueda et al., Peptides, 2, 45 [1981] ) used. In combination with the Fmoc protecting group different anchor groups are applicable:
p-aminomethyl-phenoxymethyl group (P. Pietta et al., J. Org. Chem., 40, 2995 [1975]),
Bis- and trialkoxybenzylamine linkers (F. Albericio, G. Barany, Int J. Pept. Prot. Res., 30, 206 [1987]) Benzhydryl alcohol linkers (G. Breipohl et al., Tetrah. Lett., 28, 5651 [1987]).
Besonders der Dimethoxyphenoxyvaleriansäure-Anker, der an mit Alanin beladenes Benzhydrylamin-Polystyrol über die Carboxygruppe geknüpft wurde, bewährt sich. Nach Kupplung der C-terminalen Fmoc-geschützten Aminosäure mit Standardmethoden, z. B. DCCI oder DIC/HOBt bei Raumtemperatur über Nacht. Especially the dimethoxyphenoxyvaleric acid anchor, the on alanine-loaded benzhydrylamine polystyrene over the carboxy group has been attached, has proven itself. To Coupling of the C-terminal Fmoc-protected amino acid with standard methods, e.g. DCCI or DIC / HOBt Room temperature overnight.
Nach Abspaltung der Aminoschutzgruppe der an das Harz gekuppelten Aminosäure mit einem geeigneten Reagenz, z. B. Trifluoressigsäure in Dichlormethan im Falle der BOC-Gruppe oder einer 20-50%igen Lösung von Piperidin in DMF im Falle der Fmoc-Gruppe, werden die geeignet geschützten Aminosäuren angekuppelt. Dieser Cyclus wird nacheinander so oft durchlaufen bis das gewünschte Harz-gebundene Peptid entstanden ist.After cleavage of the amino protecting group of the resin coupled amino acid with a suitable reagent, z. B. trifluoroacetic acid in dichloromethane in the case of BOC group or a 20-50% solution of piperidine in DMF in the case of the Fmoc group, which are suitable coupled with protected amino acids. This cycle will Run through one after the other as often as you want Resin-bound peptide has emerged.
Zur Kupplung können die in der Peptidchemie bekannten Methoden (s. Houben-Weyl, Methoden der organischen Chemie, Bd. 15/2) angewendet werden. Bevorzugt verwendet werden Carbodiimide, wie z. B. Dicyclohexylcarbodiimid, Diisopropylcarbodiimid oder Ethyl-(3-dimethylaminopropyl)- carbodiimid oder O-Benzotriazol-tetramethyl-uroniumhexafluorophosphat oder Benzotriazol-1-yl-oxy- tris-(dimethylamino)-phosphoniumhexafluorophosphat. Durch Zusatz von 1-Hydroxybenzotriazol (HOBt) oder 3-Hydroxy-4-oxo-3,4-dihydrobenzotriazin (HOObt) kann gegebenenfalls die Racemisierung unterdrückt bzw. die Reaktionsgeschwindigkeit gesteigert werden. Die Aminosäuren Asn und Gln werden bevorzugt in Form ihrer N-geschützten p-Nitrophenylester gekuppelt. Die Kupplungen werden normalerweise mit einem 2- bis 5fachen Überschuß an N-geschützter Aminosäure und Kupplungsreagenz in Lösungsmitteln wie Dichlormethan, Dimethylformamid, N-Methylpyrrolidon (NMP) oder Gemischen aus diesen durchgeführt. Der Verlauf der Kupplungsreaktion wird durch den Kaiser-Test (E. Kaiser u. a., Anal. Biochem., 34, 595 [1970]) oder durch den TNBS-Test verfolgt. Falls eine unvollständige Acylierung festgestellt wird, wird die Kupplung bis zur Vollständigkeit wiederholt. Die Festphasensynthese kann sowohl manuell als auch automatisch mit Hilfe eines Peptidsynthesizers erfolgen. For coupling, those known in peptide chemistry Methods (see Houben-Weyl, Methods of Organic Chemie, Vol. 15/2). Preferably used carbodiimides, such as. Dicyclohexylcarbodiimide, Diisopropylcarbodiimide or ethyl (3-dimethylaminopropyl) - carbodiimide or O-benzotriazole tetramethyl uronium hexafluorophosphate or benzotriazol-1-yl-oxy- tris- (dimethylamino) phosphonium hexafluorophosphate. By addition of 1-hydroxybenzotriazole (HOBt) or 3-hydroxy-4-oxo-3,4-dihydrobenzotriazine (HOObt) optionally suppresses the racemization or the Reaction rate can be increased. The Amino acids Asn and Gln are preferred in the form of their N-protected p-nitrophenyl ester coupled. The Clutches are usually equipped with a 2- to 5-fold excess of N-protected amino acid and Coupling reagent in solvents such as dichloromethane, Dimethylformamide, N-methylpyrrolidone (NMP) or Mixtures of these are performed. The course of the Coupling reaction is confirmed by the Kaiser test (E. Kaiser u. a., anal. Biochem., 34, 595 [1970]) or by the TNBS test tracked. If an incomplete Acylation is detected, the coupling is up to Completeness repeated. The solid phase synthesis can both manually and automatically with the help of a Peptidsynthesizers done.
Bevorzugt werden Festphasensynthesen unter Verwendung des Dimethoxyvaleriansäure-Linkers, Fmoc-Aminoschutzgruppen und des automatischen Synthesizers von ABI mit selbst entwickelten Syntheseprogrammen. Es werden Doppelkupplungen durchgeführt; die erste mit DCC/HOBt in DMF, die zweite mit symmetrischen Anhydriden in N-Methylpyrrolidon. Nach der ersten Kupplung wird ein Waschschritt mit E-Ethylmorpholin in NMP zwischengeschaltet. Nach der zweiten Kupplung erfolgt Capping mit Acetanhydrid und N-Ethylmorpholin. Gewaschen wird das Harz nach jedem Kupplungsschritt mit DMF, NMP und Isopropanol.Preferred are solid phase syntheses using of the dimethoxyvaleric acid linker, Fmoc-amino protecting groups and the automatic synthesizer from ABI self-developed synthesis programs. It will Double clutches carried out; the first with DCC / HOBt in DMF, the second with symmetrical anhydrides in N-methylpyrrolidone. After the first clutch is a Washing step with E-ethylmorpholine in NMP interposed. After the second clutch takes place Capping with acetic anhydride and N-ethylmorpholine. The resin is washed with each coupling step DMF, NMP and isopropanol.
Die zum Teil bei den Sequenzen der vorliegenden Erfindung auftretende N-terminale Acetylgruppe wird durch Acetylierung des Peptids am Harz mit Acetanhydrid oder Acetylimidazol in DMF oder NMP mit eventuellem Zusatz von Pyridin als Base eingeführt.The part in the sequences of the present Invention occurring N-terminal acetyl group is by acetylating the peptide on the resin with acetic anhydride or acetylimidazole in DMF or NMP with eventual Addition of pyridine introduced as a base.
Nach Aufbau der Peptide am Harz kann das Peptid mit geeigneten Reagenzien wie flüssigem Fluorwasserstoff im Falle der nach der BOC-Strategie aufgebauten Peptide oder Trifluoressigsäure im Falle der nach der Fmoc-Strategie aufgebauten Peptide vom polymeren Träger abgespalten werden. Bei Verwendung der oben angeführten Ankergruppen erhält man direkt die entsprechenden Peptidamide. Mit diesen Reagenzien werden in der Regel und bei Verwendung der entsprechenden Seitenkettenschutzgruppen auch die funktionellen, während der Synthese geschützten Gruppen des Peptids freigesetzt.After construction of the peptides on the resin, the peptide with suitable reagents such as liquid hydrogen fluoride in Case of the built-up by the BOC strategy peptides or trifluoroacetic acid in the case of after Fmoc strategy constructed peptides from the polymeric carrier be split off. When using the above Anchor groups you get directly the corresponding Peptide amides. With these reagents are usually and using the appropriate side chain protecting groups also the functional, during the Synthesis protected groups of the peptide released.
Üblicherweise werden bei der Abspaltung des Peptids vom Harz als Kationenfänger Substanzen wie Phenol, Kresol, Anisol, Thiokresol, Thioanisol, Indol, Dimethylsulfid oder Ethylmethylsulfid oder eine Mischung dieser Substanzen dem Fluorwasserstoff bzw. der Trifluoressigsäure zugesetzt. Usually, in the cleavage of the peptide of the resin as cation scavenger substances such as phenol, Cresol, anisole, thiocresol, thioanisole, indole, Dimethyl sulfide or ethyl methyl sulfide or a Mixture of these substances to the hydrogen fluoride or added to the trifluoroacetic acid.
Der Aufbau der Disulfidbrücke erfolgt nach Abspaltung der Peptide vom Harz nach üblichen Methoden, z. B. Houben-Weyl, Bd. 15/1, oder B. Kamber u. a., Helv. Chim. Acta, 61, Fasc 4, 899 (1980), bevorzugt mit Luftsauerstoff oder Jod in Methanol oder Essigsäure.The structure of the disulfide bridge occurs after cleavage the peptides from the resin by conventional methods, for. B. Houben-Weyl, Vol. 15/1, or B. Kamber u. a., Helv. Chim. Acta, 61, Fasc 4, 899 (1980), preferably with atmospheric oxygen or iodine in methanol or acetic acid.
Die beschriebenen Homoarginin enthaltenden Peptide werden durch Umsatz der entsprechenden Lysin-Derivate mit O-Methylisoharnstoff hergestellt oder durch direkten Einsatz geeignet geschützter Homoarginin-Derivate.The described homoarginine containing peptides are due to sales of the corresponding lysine derivatives made with O-methylisourea or by direct use suitably protected Homoarginine derivatives.
Die Reinigung der erhaltenen Rohprodukte erfolgt mittels Gelchromatographie z. B. an Sephadex G25 (MR<1400) oder G15 (MR<1400) mit 1%iger oder 5%iger Essigsäure. Falls erforderlich erfolgt die weitere Aufreinigung mittels präparativer RP-HPLC mit Methanol- oder Acetonitril-Wasser-Gradienten unter Zusatz von 1 bis 2% Trifluoressigsäure. Zur Reinigung können auch Kationenaustauscher auf Sephadex- oder Polystyrol-Basis angewendet werden.The purification of the crude products obtained takes place by gel chromatography z. To Sephadex G25 (MR <1400) or G15 (MR <1400) with 1% or 5% Acetic acid. If necessary, the others Purification by preparative RP-HPLC with methanol or acetonitrile-water gradient with the addition of 1 to 2% trifluoroacetic acid. For cleaning can also Sephadex or polystyrene based cation exchangers be applied.
Die Verbindungen der allgemeinen Formel I können mittels RP-HPLC auf Reinheit geprüft werden. Es wird jeweils eine Aminosäureanalyse am Ionenaustauscher (LKB) und am Gaschromatographen an chiraler Säule zur zusätzlichen Racemisierungskontrolle durchgeführt. Darüber hinaus werden 13C-NMR-Spektren (Bruker 400 MHz) sowie FAB-Massenspektren (MAT711, Varian) aufgenommen. Die Prüfung auf Peptidamide erfolgt mittels Resistenzermittlung gegenüber Carboxypeptidase Y.The compounds of general formula I can be checked for purity by RP-HPLC. There is an amino acid analysis on each Ion exchanger (LKB) and on the gas chromatograph Chiral column for additional racemization control carried out. In addition, 13C NMR spectra (Bruker 400 MHz) and FAB mass spectra (MAT711, Varian). Testing for peptide amides takes place by means of resistance determination Carboxypeptidase Y.
Die Sequenzbestimmung erfolgt mittels Gasphasensequenzierung. The sequence determination is carried out by means of Gas-phase sequencing.
Die für die Aminosäuren verwendeten Abkürzungen entsprechen dem üblichen Dreibuchstabencode wie er z. B. in Europ. J. Biochem., 138, 9 (1984), beschrieben ist. Die übrigen Abkürzungen werden nachfolgend erklärt.The abbreviations used for the amino acids correspond to the usual three-letter code as z. B. in Europ. J. Biochem., 138, 9 (1984). The remaining abbreviations are explained below.
Die Synthese erfolgte mit einem Peptidsynthesizer Modell 430A der Fa. Applied Biosystems unter Anwendung der Fmoc-Strategie unter Verwendung der Dimethoxyvalerianoyloxybenzylamid-Ankergruppe (Beladung ca. 0,5 mmol/g Harz), beginnend mit der Ankondensation von Fmoc-Tyr(t-Bu)-OH an das Harz mittels DIC/HOBt in DMF (Doppelkupplung von jeweils 2 Moläquivalenten). Die Synthese wurde über ein modifiziertes Steuerungsprogramm durchgeführt. Folgende Aminosäure-Derivate wurden verwendet: Fmoc-Arg(Mtr)-OH, Fmoc-Gln-OpNP, Fmoc-Thr(t-Bu)-OH, Fmoc-Ile-OH, Fmoc-Leu-OH, Fmoc-Asn-OH, Fmoc-His(Trt)-OH, Fmoc-NH-(CH₂)₅-COOH, Fmoc-Lys(BOC)-OH, Fmoc-Ser(t-Bu)-OH, Fmoc-Pro-OH und BOC-Tyr(t-Bu)-OH.The synthesis was carried out with a peptide synthesizer Model 430A from Applied Biosystems under application the Fmoc strategy using the Dimethoxyvalerianoyloxybenzylamide anchor group (loading about 0.5 mmol / g resin), starting with the condensation of Fmoc-Tyr (t-Bu) -OH to the resin via DIC / HOBt in DMF (double clutch of 2 molar equivalents each). The Synthesis was via a modified control program carried out. Following amino acid derivatives were used: Fmoc-Arg (Mtr) -OH, Fmoc-Gln-OpNP, Fmoc-Thr (t-Bu) -OH, Fmoc-Ile-OH, Fmoc-Leu-OH, Fmoc-Asn-OH, Fmoc-His (Trt) -OH, Fmoc-NH- (CH₂) ₅-COOH, Fmoc-Lys (BOC) -OH, Fmoc-Ser (t-Bu) -OH, Fmoc-Pro-OH and BOC-Tyr (t-Bu) -OH.
Die Abspaltung der Fmoc-Schutzgruppe wurde mit 25%iger Piperidin-Lösung in DMF durchgeführt (2×10 min), anschließende Waschschritte mit DMF. Die erste Kupplung erfolgte jeweils mit Fmoc-Aminosäure/DIC/HOBt mit jeweils 2 Moläquivalenten (30 min Voraktivierung), die Kupplungszeit 60 oder 90 min. Die Voraktivierungszeit bei Fmoc-Gln-OH/pNP-OH und Fmoc-Asn-OH wurde auf 10 min reduziert. Lösungsmittel war DMF, im Fall von Fmoc-Gln-OpNP NMP. Danach wurde mit DMF, NMP, Isopropanol und N-Ethylmorpholin in NMP gewaschen; die zweite Kupplung mit den symmetrischen Anhydriden der Fmoc-Aminosäuren erfolgte in NMP. Dann wurde mit DMF, NMP und Isopropanol gewaschen und der Cyclus mit der nächsten Aminosäure angeschlossen. Die Abspaltung des Peptids vom polymeren Träger geschah mit Trifluoressigsäure (4h). Der vollständigen Abspaltung der Mtr-Schutzgruppe diente die 30minütige Behandlung des Rohpeptids mit Trifluoressigsäure bei 50°C. Die Reinigung wurde mittels Gelchromatographie an Sephadex G15 mit 1%iger Essigsäure durchgeführt. Das saubere Peptid wurde lyophilisiert. The cleavage of the Fmoc protecting group was 25% Piperidine solution in DMF (2 × 10 min), subsequent washes with DMF. The first clutch each with Fmoc-amino acid / DIC / HOBt with 2 molar equivalents (30 min pre-activation), the Coupling time 60 or 90 min. The pre-activation time for Fmoc-Gln-OH / pNP-OH and Fmoc-Asn-OH was for 10 min reduced. Solvent was DMF, in the case of Fmoc-Gln-OpNP NMP. Thereafter, with DMF, NMP, Isopropanol and N-ethylmorpholine in NMP; the second coupling with the symmetrical anhydrides of Fmoc-amino acids were made in NMP. Then with DMF, Washed NMP and isopropanol and the cycle with the connected to the next amino acid. The splitting off of Peptides from the polymeric carrier were involved Trifluoroacetic acid (4h). The complete separation the Mtr-Schutzgruppe served the 30-minute treatment of the crude peptide with trifluoroacetic acid at 50 ° C. The Purification was by gel chromatography on Sephadex G15 carried out with 1% acetic acid. The clean Peptide was lyophilized.
HPLC an Nucleosil C18,5 u, 4,6×250 mm; Detektion bei
220 nm Gradient: 15% B auf 60% B in 30 min, linear
(A=Wasser/Trifluoressigsäure 100 : 0,1,
B = Acetonitril/Trifluoressigsäure 100 : 0,1) Fluß 1 ml/min;
Retentionszeit 22,3 min;
Aminosäureanalyse: gemessen (theoretisch)
Arg 3.00(3), Asn 1.07(1), Thr 1.04(1), Gln 0.99(1), Leu
0.93(1), Ile 1.91(2), His 1.03(1), Tyr 2.77(3),
Pro 0.82(1), Ser 0.86(1), Lys 0.85(1);
Racemisierung <3,5%;
kein Verdau mit Carboxypeptidase Y;
Gasphasensequenzierung: Tyr-Pro-Ser-Lys-Ende des Edman-
Abbaus.HPLC on Nucleosil C18.5 u, 4.6 x 250 mm; Detection at 220 nm gradient: 15% B to 60% B in 30 min, linear (A = water / trifluoroacetic acid 100: 0.1, B = acetonitrile / trifluoroacetic acid 100: 0.1) flow 1 ml / min;
Retention time 22.3 min;
Amino acid analysis: measured (theoretically)
Arg 3.00 (3), Asn 1.07 (1), Thr 1.04 (1), Gln 0.99 (1), Leu 0.93 (1), Ile 1.91 (2), His 1.03 (1), Tyr 2.77 (3), Pro 0.82 (1), Ser 0.86 (1), Lys 0.85 (1);
Racemization <3.5%;
no digestion with carboxypeptidase Y;
Gas phase sequencing: Tyr-Pro-Ser-Lys end of Edman degradation.
Wie unter Beispiel 1 beschrieben, wurde die Synthese durchgeführt.As described in Example 1, the synthesis was carried out.
HPLC: Retentionszeit 24,6 min;
Aminosäureanalyse:
Arg 3.00(3), Asn 1.02(1), Thr 1.05(1), Gln 1.02(1),
Leu 2.11(2), Ile 2.04(2), His 0.94(1), Tyr 2.71(3),
Pro 0.95(1), Ser 1.05(1), Lys 0.97(1);
Racemisierung <3,4%;
kein Verdau mit Carboxypeptidase Y;
Gasphasensequenzierung: Tyr-Pro-Ser-Lys-Ende des Edman-
Abbaus.
HPLC: retention time 24.6 min;
Amino acid analysis:
Arg 3.00 (3), Asn 1.02 (1), Thr 1.05 (1), Gln 1.02 (1), Leu 2.11 (2), Ile 2.04 (2), His 0.94 (1), Tyr 2.71 (3), Pro 0.95 (1), Ser 1.05 (1), Lys 0.97 (1);
Racemization <3.4%;
no digestion with carboxypeptidase Y;
Gas phase sequencing: Tyr-Pro-Ser-Lys end of Edman degradation.
Wie unter Beispiel 1 beschrieben, wurde die Synthese durchgeführt. Abweichungen: Die Kupplung des N-terminalen Tyrosins wurde als Fmoc-Tyr(t-Bu)-OH mit anschließender Fmoc-Abspaltung und Acetylierung mit Acetylimidazol in DMF (5 Moläquivalente, 30 min) durchgeführt.As described in Example 1, the synthesis was carried out. Deviations: The coupling of the N-terminal tyrosine was reported as Fmoc-Tyr (t-Bu) -OH subsequent Fmoc cleavage and acetylation with Acetylimidazole in DMF (5 molar equivalents, 30 min) carried out.
HPLC: Retentionszeit 18,5 min;
Aminosäureanalyse:
Tyr 2,71(3), Pro 0.96(1), Ser 0.86(1), Lys 1.00(1),
His 1.09(1), Ile 1.90(2), Leu 1.04(1), Asn 0.97(1),
Thr 1.00(1), Gln 0.95(1), Arg 3.23(3).HPLC: retention time 18.5 min;
Amino acid analysis:
Tyr 2.71 (3), Pro 0.96 (1), Ser 0.86 (1), Lys 1.00 (1), His 1.09 (1), Ile 1.90 (2), Leu 1.04 (1), Asn 0.97 (1), Thr 1.00 (1), Gln 0.95 (1), Arg 3.23 (3).
Die Synthese erfolgte wie unter Beispiel 1 beschrieben.The synthesis was carried out as described in Example 1.
HPLC: Retentionszeit 23,4 min;
Aminosäureanalyse:
Tyr 2.53(3), Pro 0.93(1), Ile 1.96(2), Leu 1.00(1),
Asn 0.99(1), Thr 1.00(1), Gln 1.02(1), Arg 2.09(2).HPLC: retention time 23.4 min;
Amino acid analysis:
Tyr 2.53 (3), Pro 0.93 (1), Ile 1.96 (2), Leu 1.00 (1), Asn 0.99 (1), Thr 1.00 (1), Gln 1.02 (1), Arg 2.09 (2).
Die Synthese erfolgte wie unter Beispiel 1 beschrieben.The synthesis was carried out as described in Example 1.
HPLC: Retentionszeit 24,9 min;
Aminosäureanalyse:
Tyr 3.26(3), Ile 1.97(2), Leu 1.05(1), Asn 0.98(1),
Thr 1.00(1), Gln 1.09(1), Arg 2.17(2).
HPLC: retention time 24.9 min;
Amino acid analysis:
Tyr 3.26 (3), Ile 1.97 (2), Leu 1.05 (1), Asn 0.98 (1), Thr 1.00 (1), Gln 1.09 (1), Arg 2.17 (2).
Die Synthese erfolgte wie unter Beispiel 1 beschrieben.The synthesis was carried out as described in Example 1.
HPLC: Retentionszeit;
Aminosäureanalyse:
Tyr 2.61(3), Pro 1.10(1), Ser 0.93(1), Ile 1.90(2),
Leu 1.00(1), Asn 1.04(1), Thr 1.00(1), Gln 1.00(1),
Arg 2.07(2).HPLC: retention time;
Amino acid analysis:
Tyr 2.61 (3), Pro 1.10 (1), Ser 0.93 (1), Ile 1.90 (2), Leu 1.00 (1), Asn 1.04 (1), Thr 1.00 (1), Gln 1.00 (1), Arg 2.07 (2).
Die Synthese erfolgte wie unter Beispiel 1 beschrieben.The synthesis was carried out as described in Example 1.
HPLC: Retentionszeit 19,3 min;
Aminosäureanalyse:
Tyr 2.97(3), Pro 0.90(1), Ser 0.83(1), Lys 0.94(1),
His 1.10(1), Ile 1.92(2), Leu 1.08(1), Asn 0.97(1),
Thr 1.00(1), Gln 1.03(1), Arg 3.03(3).HPLC: retention time 19.3 min;
Amino acid analysis:
Tyr 2.97 (3), Pro 0.90 (1), Ser 0.83 (1), Lys 0.94 (1), His 1.10 (1), Ile 1.92 (2), Leu 1.08 (1), Asn 0.97 (1), Thr 1.00 (1), Gln 1.03 (1), Arg 3.03 (3).
Die Synthese erfolgte wie unter Beispiel 1 beschrieben.The synthesis was carried out as described in Example 1.
HPLC: Retentionszeit;
Aminosäureanalyse:
Tyr 2.70(3), Pro 0.90(1), Ser 0.90(1), His 1.05(1),
Ile 2.00(2), Leu 1.04(1), Asn 0.99(1), Thr 1.00(1),
Gln 1.04(1), Arg 3.15(3).
HPLC: retention time;
Amino acid analysis:
Tyr 2.70 (3), Pro 0.90 (1), Ser 0.90 (1), His 1.05 (1), Ile 2.00 (2), Leu 1.04 (1), Asn 0.99 (1), Thr 1.00 (1), Gln 1.04 (1), Arg 3.15 (3).
Die Synthese erfolgte analog zu der in Beispiel 4 beschriebenen Weise.The synthesis was carried out analogously to that in Example 4 described way.
HPLC: Retentionszeit 25,6 min;
Aminosäureanalyse:
Thr 0.98(1), Ile 1.82(2), Leu 1.00(1), Gln 1.09(1),
Tyr 1.86(2), Arg 2.73(3), Asn 1.00(1), His 1.01(1);
FAB-MS: M+H 1673.HPLC: retention time 25.6 min;
Amino acid analysis:
Thr 0.98 (1), Ile 1.82 (2), Leu 1.00 (1), Gln 1.09 (1), Tyr 1.86 (2), Arg 2.73 (3), Asn 1.00 (1), His 1.01 (1);
FAB-MS: M + H 1673.
Die Verbindung wurde analog der in Beispiel 4 beschriebenen Weise hergestellt.The compound was analogous to that in Example 4 produced manner described.
HPLC: Retentionszeit 22,3 min;
Aminosäureanalyse:
Arg 2.00(2), Tyr 2.06(2), Gln 1.03(1), Thr 1.07(1),
Ile 1.80(2), Leu 0.99(1), Asn 1.00(1), His 0.98(1),
Lys 0.97(1).HPLC: retention time 22.3 min;
Amino acid analysis:
Arg 2.00 (2), Tyr 2.06 (2), Gln 1.03 (1), Thr 1.07 (1), Ile 1.80 (2), Leu 0.99 (1), Asn 1.00 (1), His 0.98 (1), Lys 0.97 (1).
Die Verbindung wurde analog der in Beispiel 4 beschriebenen Weise erhalten.The compound was analogous to that in Example 4 received described manner.
HPLC: Retentionszeit 24,1 min;
Aminosäureanalyse:
Thr 0.95(1), Ile 2.07(2), Leu 1.01(1), Gln 0.99(1),
Tyr 2.06(2), Lys 3.03(3), His 0.95(1);
FAB-MS: M+H 1589.
HPLC: retention time 24.1 min;
Amino acid analysis:
Thr 0.95 (1), Ile 2.07 (2), Leu 1.01 (1), Gln 0.99 (1), Tyr 2.06 (2), Lys 3.03 (3), His 0.95 (1);
FAB-MS: M + H 1589.
Die Verbindung wurde analog der in Beispiel 4 angegebenen Art synthetisiert. Nach Abspaltung des Peptids vom Harz wurden die ε-Seitenkettenaminogruppen mit Acetylimidazolin in DMF acetyliert.The compound was synthesized analogously to the manner indicated in Example 4. After cleavage of the peptide from the resin, the ε- side chain amino groups were acetylated with acetylimidazoline in DMF.
HPLC: Retentionszeit 27,8 min;
FAB-MS: m+H 1589.HPLC: retention time 27.8 min;
FAB-MS: m + H 1589.
Die Verbindung wurde analog der in Beispiel 4 angegebenen Weise erhalten.The compound was analogous to that in Example 4 received manner.
HPLC: Retentionszeit 24,1 min;
Aminosäureanalyse:
Thr 0.95(1), Ile 1.93(2), Leu 1.05(1), Gln 0.99(1),
Tyr 2.00(2), Orn 3.12(3), Asn 1.00(1), His 0.93(1).HPLC: retention time 24.1 min;
Amino acid analysis:
Thr 0.95 (1), Ile 1.93 (2), Leu 1.05 (1), Gln 0.99 (1), Tyr 2.00 (2), Orn 3.12 (3), Asn 1.00 (1), His 0.93 (1).
Die übrigen obengenannten Verbindungen (Verbindungen 3, 5, 9, 12-18 und 21) werden analog hergestellt.The other compounds mentioned above (compounds 3, 5, 9, 12-18 and 21) are prepared analogously.
Die Verbindung, die Konservierungsstoffe und Natriumchlorid werden in 3 l Wasser für die Injektion gelöst und auf 5 l mit Wasser für die Injektion aufgefüllt. Die Lösung wird steril gefiltert und aseptisch in vorsterilisierte Flaschen gefüllt, die mit sterilisierten Gummikappen verschlossen werden. Jede Flasche enthält 5 ml Lösung.The compound, the preservatives and Sodium chloride is added to 3 liters of water for injection dissolved and to 5 l with water for injection refilled. The solution is sterile filtered and Aseptically filled in pre-sterilized bottles with sterilized rubber caps are sealed. each Bottle contains 5 ml of solution.
Claims (9)
R₁ für R₂-CO oder für einen peptidisch gebundenen Di-, Tri-, Tetra- oder Pentapeptid-Rest der Zusammensetzung H-Z-Pro-S-X-V-, H-Z-Pro-S-V-, H-Z-Pro-V-, H-Z-V- oder Acetyl-Z-Pro-S-X-V-,
S für Ser, Glu, Cys oder eine Bindung,
U für eine aliphatische Aminosäure wie Leu, Ile, Val, Ala oder eine Bindung,
X für eine basische Aminosäure wie Arg, Lys, Orn und Homo-Arg oder für eine basische Aminosäure, bei der die Aminogruppe der Seitenkette acetyliert ist (z. B. Lys(Ac), Orn(Ac)), oder eine Bindung,
Y für eine Aminosäure wie His, Trp, Phe und Tyr oder eine Bindung,
Z für eine Aminosäure wie Tyr, Phe, His, Trp oder eine unnatürliche Aminosäure wie z. B. Naphthylalanin oder substituierte Phenylalanin-Derivate oder wenn Z nicht C-terminal steht auch für Cys,
W für eine Aminosäure wie Gln, Asn, Glu, Asp,
V für einen ω-Aminoalkansäure-Rest wie ε-Aminocapronsäure-Rest oder einen Rest der allgemeinen Formel NH-(CH₂) n -CO oder NH-(CH₂) n -CONH-(CH₂) n CO mit n=2 bis 15 oder eine Aminosäuresequenz mit Turn-Struktur wie z. B. Pro-Gly-T, Asn-Ser-T und Cys-Cys bzw. Homo-Cys-Homo-Cys, die jeweils über ihre Seitenketten disulfidisch miteinander ringgeschlossen sein können,
T für eine der natürlichen Aminosäuren,
R₂ für C₁- bis C₇-Alkyl oder Benzyl
steht und worin ferner
wenn S für Glu und das nicht C-terminale Z für Tyr steht, die Seitenkette-Carboxylgruppe mit der phenolischen OH-Gruppe des Tyrosins esterartig verknüpft sein kann und
falls S für Cys und das nicht C-terminale Z für Cys stehen, die Seitenketten dieser Aminosäuren disulfidisch miteinander verknüpft sein können.A compound of general formula I R₁-UXYZ-Ile-Asn-Leu-Ile-Thr-XWXZ-NH₂ (I) and its pharmaceutically acceptable salts, wherein
R₁ for R₂-CO or for a peptide-bound di-, tri-, tetra- or pentapeptide radical of the composition HZ-Pro-SXV, HZ-Pro-SV, HZ-Pro-V, HZV or acetyl Z-Pro-SXV-,
S for Ser, Glu, Cys or a bond,
U is an aliphatic amino acid such as Leu, Ile, Val, Ala or a bond,
X represents a basic amino acid such as Arg, Lys, Orn and Homo-Arg or a basic amino acid in which the amino group of the side chain is acetylated (eg Lys (Ac), Orn (Ac)), or a bond,
Y is an amino acid such as His, Trp, Phe and Tyr or a bond,
Z for an amino acid such as Tyr, Phe, His, Trp or an unnatural amino acid such. As naphthylalanine or substituted phenylalanine derivatives or if Z is not C-terminal for Cys,
W for an amino acid such as Gln, Asn, Glu, Asp,
V for a ω-aminoalkanoic acid radical such as ε-aminocaproic acid radical or a radical of the formula NH- (CH₂) n -CO or NH- (CH₂) n -CONH- (CH₂) n CO with n = 2 to 15, or an amino acid sequence with turn structure such. Pro-Gly-T, Asn-Ser-T and Cys-Cys or Homo-Cys-Homo-Cys, which may each be disulphidically ring-closed with each other via their side chains,
T for one of the natural amino acids,
R₂ is C₁ to C₇ alkyl or benzyl
and wherein further
when S is Glu and the non-C-terminal Z is Tyr, the side-chain carboxyl group may be ester-linked to the phenolic OH group of tyrosine, and
if S stands for Cys and the non-C-terminal Z stands for Cys, the side chains of these amino acids can be linked disulfidically to one another.
R₁: R₂-CO, H-Z-Pro-S-X-V-, H-Z-Pro-S-V-, H-Z-Pro-V-, H-Z-V- oder Acetyl-Z-Pro-S-X-V-,
S: Ser oder Glu,
U: Leu oder eine Bindung,
X: Arg, Lys, Orn oder Homo-Arg,
Y: His oder Trp,
Z: Tyr oder Phe,
W: Gln oder Asn,
V: ω-Aminoalkansäure-Rest wie HN-(CH₂) n -CO und NH-(CH₂) n -CONH-(CH₂) n -CO mit n=2 bis 10,
R₂: für C₁- bis C₇-Alkyl oder Benzyl.2. A compound according to claim 1, wherein the symbols of the formula I have the following meanings:
R₁: R₂-CO, HZ-Pro-SXV, HZ-Pro-SV, HZ-Pro-V, HZV or acetyl-Z-Pro-SXV-,
S: Ser or Glu,
U: Leu or a bond,
X: Arg, Lys, Orn or Homo-Arg,
Y: His or Trp,
Z: Tyr or Phe,
W: Gln or Asn,
V: ω- aminoalkanoic acid radical such as HN- (CH₂) n -CO and NH- (CH₂) n -CONH- (CH₂) n -CO with n = 2 to 10,
R₂: for C₁ to C₇-alkyl or benzyl.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19883811193 DE3811193A1 (en) | 1988-04-01 | 1988-04-01 | NEW PEPTIDES, METHOD FOR THE PRODUCTION THEREOF AND PHARMACEUTICAL COMPOSITIONS CONTAINING THESE PEPTIDES |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19883811193 DE3811193A1 (en) | 1988-04-01 | 1988-04-01 | NEW PEPTIDES, METHOD FOR THE PRODUCTION THEREOF AND PHARMACEUTICAL COMPOSITIONS CONTAINING THESE PEPTIDES |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| DE3811193A1 true DE3811193A1 (en) | 1989-10-19 |
Family
ID=6351270
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DE19883811193 Withdrawn DE3811193A1 (en) | 1988-04-01 | 1988-04-01 | NEW PEPTIDES, METHOD FOR THE PRODUCTION THEREOF AND PHARMACEUTICAL COMPOSITIONS CONTAINING THESE PEPTIDES |
Country Status (1)
| Country | Link |
|---|---|
| DE (1) | DE3811193A1 (en) |
Cited By (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1991008223A1 (en) * | 1989-12-01 | 1991-06-13 | Basf Aktiengesellschaft | Novel peptides derived from neuropeptide y |
| EP0439174A3 (en) * | 1990-01-25 | 1991-11-06 | Merrell Dow Pharmaceuticals Inc. | Inhibition of gut endothelium ion-secretion by peptide derivatives |
| EP0355793A3 (en) * | 1988-08-26 | 1992-04-22 | Merrell Pharmaceuticals Inc. | Neuropeptide y agonists and partial agonists |
| WO1993012139A1 (en) * | 1991-12-19 | 1993-06-24 | Garvan Institute Of Medical Research | A novel molecule which inhibits neuropeptide tyrosine biological function |
| US5395823A (en) * | 1988-08-26 | 1995-03-07 | Merrell Dow Pharmaceuticals Inc. | Neuropeptide Y agonists and partial agonists |
| US5670482A (en) * | 1992-06-20 | 1997-09-23 | Glaxo Wellcome Inc. | Neuropeptide Y antagonists |
| US5696093A (en) * | 1994-10-28 | 1997-12-09 | Crc For Biopharmaceutical Research Pty Limited | Method of treating nasal congestion using neuropeptide Y Y2 agonist peptides |
| WO1997046579A1 (en) * | 1996-06-05 | 1997-12-11 | Peptech Limited | Neuropeptide y agonists |
| EP0838217A2 (en) | 1996-10-23 | 1998-04-29 | Sanofi | Cosmetic composition containing neuropeptide Y receptor antagonist |
| US6696409B1 (en) | 1996-06-05 | 2004-02-24 | Prince Of Wales Medical Research Institute Limited (Powmr Ltd.) | Neuropeptide Y agonists |
| AU772915B2 (en) * | 1996-06-05 | 2004-05-13 | Prince Of Wales Medical Research Institute Limited | Neuropeptide Y agonists |
| US7544662B2 (en) * | 1993-06-17 | 2009-06-09 | Carle Development Foundation | Polypeptides useful for appetite suppression |
| WO2009110510A1 (en) | 2008-03-06 | 2009-09-11 | 萬有製薬株式会社 | Alkylaminopyridine derivative |
-
1988
- 1988-04-01 DE DE19883811193 patent/DE3811193A1/en not_active Withdrawn
Cited By (14)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0355793A3 (en) * | 1988-08-26 | 1992-04-22 | Merrell Pharmaceuticals Inc. | Neuropeptide y agonists and partial agonists |
| US5395823A (en) * | 1988-08-26 | 1995-03-07 | Merrell Dow Pharmaceuticals Inc. | Neuropeptide Y agonists and partial agonists |
| WO1991008223A1 (en) * | 1989-12-01 | 1991-06-13 | Basf Aktiengesellschaft | Novel peptides derived from neuropeptide y |
| EP0439174A3 (en) * | 1990-01-25 | 1991-11-06 | Merrell Dow Pharmaceuticals Inc. | Inhibition of gut endothelium ion-secretion by peptide derivatives |
| WO1993012139A1 (en) * | 1991-12-19 | 1993-06-24 | Garvan Institute Of Medical Research | A novel molecule which inhibits neuropeptide tyrosine biological function |
| US5670482A (en) * | 1992-06-20 | 1997-09-23 | Glaxo Wellcome Inc. | Neuropeptide Y antagonists |
| US7544662B2 (en) * | 1993-06-17 | 2009-06-09 | Carle Development Foundation | Polypeptides useful for appetite suppression |
| US5696093A (en) * | 1994-10-28 | 1997-12-09 | Crc For Biopharmaceutical Research Pty Limited | Method of treating nasal congestion using neuropeptide Y Y2 agonist peptides |
| US6696409B1 (en) | 1996-06-05 | 2004-02-24 | Prince Of Wales Medical Research Institute Limited (Powmr Ltd.) | Neuropeptide Y agonists |
| AU772915B2 (en) * | 1996-06-05 | 2004-05-13 | Prince Of Wales Medical Research Institute Limited | Neuropeptide Y agonists |
| WO1997046579A1 (en) * | 1996-06-05 | 1997-12-11 | Peptech Limited | Neuropeptide y agonists |
| EP0838217A2 (en) | 1996-10-23 | 1998-04-29 | Sanofi | Cosmetic composition containing neuropeptide Y receptor antagonist |
| EP1922078A4 (en) * | 2005-08-05 | 2011-01-26 | Carle Foundation | Polypeptides useful for appetite suppression |
| WO2009110510A1 (en) | 2008-03-06 | 2009-09-11 | 萬有製薬株式会社 | Alkylaminopyridine derivative |
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