NO342380B1 - Nye triazolderivater som ghrelinanalogligander av veksthormonutskillende reseptorer, anvendelse derav og farmasøytiske sammensetninger som inneholder slike - Google Patents
Nye triazolderivater som ghrelinanalogligander av veksthormonutskillende reseptorer, anvendelse derav og farmasøytiske sammensetninger som inneholder slike Download PDFInfo
- Publication number
- NO342380B1 NO342380B1 NO20081248A NO20081248A NO342380B1 NO 342380 B1 NO342380 B1 NO 342380B1 NO 20081248 A NO20081248 A NO 20081248A NO 20081248 A NO20081248 A NO 20081248A NO 342380 B1 NO342380 B1 NO 342380B1
- Authority
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- Norway
- Prior art keywords
- indol
- ethyl
- compound
- triazol
- phenethyl
- Prior art date
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- GNKDKYIHGQKHHM-RJKLHVOGSA-N ghrelin Chemical class C([C@H](NC(=O)[C@@H](NC(=O)[C@H](CO)NC(=O)CN)COC(=O)CCCCCCC)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1N=CNC=1)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N1[C@@H](CCC1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O)C1=CC=CC=C1 GNKDKYIHGQKHHM-RJKLHVOGSA-N 0.000 title claims abstract description 73
- 239000008194 pharmaceutical composition Substances 0.000 title claims description 10
- 239000003446 ligand Substances 0.000 title abstract description 23
- 102000018997 Growth Hormone Human genes 0.000 title abstract description 19
- 108010051696 Growth Hormone Proteins 0.000 title abstract description 19
- 239000000122 growth hormone Substances 0.000 title abstract description 18
- 230000003248 secreting effect Effects 0.000 title abstract description 11
- 229940042055 systemic antimycotics triazole derivative Drugs 0.000 title abstract description 6
- 238000011282 treatment Methods 0.000 claims abstract description 72
- 101800001586 Ghrelin Proteins 0.000 claims abstract description 60
- 229940044551 receptor antagonist Drugs 0.000 claims abstract description 28
- 239000002464 receptor antagonist Substances 0.000 claims abstract description 28
- 230000000638 stimulation Effects 0.000 claims abstract description 26
- 230000004963 pathophysiological condition Effects 0.000 claims abstract description 25
- 230000004962 physiological condition Effects 0.000 claims abstract description 25
- 230000037396 body weight Effects 0.000 claims abstract description 21
- 230000037406 food intake Effects 0.000 claims abstract description 19
- 235000012631 food intake Nutrition 0.000 claims abstract description 19
- 206010006895 Cachexia Diseases 0.000 claims abstract description 15
- 238000011321 prophylaxis Methods 0.000 claims abstract description 15
- 230000009467 reduction Effects 0.000 claims abstract description 15
- 230000005764 inhibitory process Effects 0.000 claims abstract description 14
- 230000001404 mediated effect Effects 0.000 claims abstract description 14
- 206010054048 Postoperative ileus Diseases 0.000 claims abstract description 13
- 230000009063 long-term regulation Effects 0.000 claims abstract description 13
- 241000124008 Mammalia Species 0.000 claims abstract description 12
- 206010053759 Growth retardation Diseases 0.000 claims abstract description 11
- 231100000001 growth retardation Toxicity 0.000 claims abstract description 11
- 230000002496 gastric effect Effects 0.000 claims abstract description 10
- 230000011759 adipose tissue development Effects 0.000 claims abstract description 9
- 238000013110 gastrectomy Methods 0.000 claims abstract description 9
- 206010061218 Inflammation Diseases 0.000 claims abstract description 8
- 230000004054 inflammatory process Effects 0.000 claims abstract description 8
- 238000009256 replacement therapy Methods 0.000 claims abstract description 7
- 230000002757 inflammatory effect Effects 0.000 claims abstract description 6
- 102000012004 Ghrelin Human genes 0.000 claims abstract 2
- 150000001875 compounds Chemical class 0.000 claims description 502
- -1 (S)-N-((R)-1-(4-(4-methoxybenzyl)-5-phenyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol- 3-yl)ethyl)piperidin-3-carboxamide Chemical compound 0.000 claims description 87
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 28
- 239000000556 agonist Substances 0.000 claims description 25
- 239000003814 drug Substances 0.000 claims description 19
- 239000013543 active substance Substances 0.000 claims description 18
- JZCPYUJPEARBJL-UHFFFAOYSA-N rimonabant Chemical compound CC=1C(C(=O)NN2CCCCC2)=NN(C=2C(=CC(Cl)=CC=2)Cl)C=1C1=CC=C(Cl)C=C1 JZCPYUJPEARBJL-UHFFFAOYSA-N 0.000 claims description 17
- BRYCUMKDWMEGMK-UHFFFAOYSA-N piperazine-2-carboxamide Chemical compound NC(=O)C1CNCCN1 BRYCUMKDWMEGMK-UHFFFAOYSA-N 0.000 claims description 16
- 229940079593 drug Drugs 0.000 claims description 13
- 239000000203 mixture Substances 0.000 claims description 10
- 239000000126 substance Substances 0.000 claims description 9
- CQGFWVSHFMZYIX-SSEXGKCCSA-N 2-amino-n-[(1r)-1-[5-benzyl-4-(naphthalen-1-ylmethyl)-1,2,4-triazol-3-yl]-2-(1h-indol-3-yl)ethyl]-2-methylpropanamide Chemical compound C=1C=CC2=CC=CC=C2C=1CN1C([C@@H](CC=2C3=CC=CC=C3NC=2)NC(=O)C(C)(N)C)=NN=C1CC1=CC=CC=C1 CQGFWVSHFMZYIX-SSEXGKCCSA-N 0.000 claims description 8
- IFOQRGBXSMPXLY-SSEXGKCCSA-N 2-amino-n-[(1r)-2-(1h-indol-3-yl)-1-[5-[2-(1h-indol-3-yl)ethyl]-4-[(3-methoxyphenyl)methyl]-1,2,4-triazol-3-yl]ethyl]-2-methylpropanamide Chemical compound COC1=CC=CC(CN2C(=NN=C2CCC=2C3=CC=CC=C3NC=2)[C@@H](CC=2C3=CC=CC=C3NC=2)NC(=O)C(C)(C)N)=C1 IFOQRGBXSMPXLY-SSEXGKCCSA-N 0.000 claims description 8
- 229940125904 compound 1 Drugs 0.000 claims description 8
- XODVYEFJWLHZAE-AREMUKBSSA-N (1r)-1-[4-[(2,4-dimethoxyphenyl)methyl]-5-[2-(1h-indol-3-yl)ethyl]-1,2,4-triazol-3-yl]-2-(1h-indol-3-yl)ethanamine Chemical compound COC1=CC(OC)=CC=C1CN1C([C@H](N)CC=2C3=CC=CC=C3NC=2)=NN=C1CCC1=CNC2=CC=CC=C12 XODVYEFJWLHZAE-AREMUKBSSA-N 0.000 claims description 7
- BLVAQCTVXRMXDP-GDLZYMKVSA-N 2-amino-n-[(1r)-1-[4-benzyl-5-[2-(1h-indol-3-yl)ethyl]-1,2,4-triazol-3-yl]-2-(1h-indol-3-yl)ethyl]-2-methylpropanamide Chemical compound C1([C@@H](CC=2C3=CC=CC=C3NC=2)NC(=O)C(C)(N)C)=NN=C(CCC=2C3=CC=CC=C3NC=2)N1CC1=CC=CC=C1 BLVAQCTVXRMXDP-GDLZYMKVSA-N 0.000 claims description 7
- NQKIWLUUQGGHDS-SSEXGKCCSA-N 2-amino-n-[(1r)-1-[4-benzyl-5-[3-(1h-indol-3-yl)propyl]-1,2,4-triazol-3-yl]-2-(1h-indol-3-yl)ethyl]-2-methylpropanamide Chemical compound C1([C@@H](CC=2C3=CC=CC=C3NC=2)NC(=O)C(C)(N)C)=NN=C(CCCC=2C3=CC=CC=C3NC=2)N1CC1=CC=CC=C1 NQKIWLUUQGGHDS-SSEXGKCCSA-N 0.000 claims description 7
- WCWCRSIZVYPVNK-HHHXNRCGSA-N 2-amino-n-[(1r)-1-[5-benzyl-4-[(3-methoxyphenyl)methyl]-1,2,4-triazol-3-yl]-2-(1h-indol-3-yl)ethyl]-2-methylpropanamide Chemical compound COC1=CC=CC(CN2C(=NN=C2CC=2C=CC=CC=2)[C@@H](CC=2C3=CC=CC=C3NC=2)NC(=O)C(C)(C)N)=C1 WCWCRSIZVYPVNK-HHHXNRCGSA-N 0.000 claims description 7
- 150000001200 N-acyl ethanolamides Chemical class 0.000 claims description 7
- 239000002621 endocannabinoid Substances 0.000 claims description 7
- 229960003015 rimonabant Drugs 0.000 claims description 7
- DSKXYHYADVMGDR-ROJLCIKYSA-N (2r)-n-[(1r)-2-(1h-indol-3-yl)-1-[5-[2-(1h-indol-3-yl)ethyl]-4-[(4-methoxyphenyl)methyl]-1,2,4-triazol-3-yl]ethyl]pyrrolidine-2-carboxamide Chemical compound C1=CC(OC)=CC=C1CN1C([C@@H](CC=2C3=CC=CC=C3NC=2)NC(=O)[C@@H]2NCCC2)=NN=C1CCC1=CNC2=CC=CC=C12 DSKXYHYADVMGDR-ROJLCIKYSA-N 0.000 claims description 6
- DSKXYHYADVMGDR-AJQTZOPKSA-N (2s)-n-[(1r)-2-(1h-indol-3-yl)-1-[5-[2-(1h-indol-3-yl)ethyl]-4-[(4-methoxyphenyl)methyl]-1,2,4-triazol-3-yl]ethyl]pyrrolidine-2-carboxamide Chemical compound C1=CC(OC)=CC=C1CN1C([C@@H](CC=2C3=CC=CC=C3NC=2)NC(=O)[C@H]2NCCC2)=NN=C1CCC1=CNC2=CC=CC=C12 DSKXYHYADVMGDR-AJQTZOPKSA-N 0.000 claims description 6
- STHADNJZIQEPNZ-AREMUKBSSA-N 2-amino-n-[(1r)-1-(4,5-dibenzyl-1,2,4-triazol-3-yl)-2-(1h-indol-3-yl)ethyl]-2-methylpropanamide Chemical compound C=1C=CC=CC=1CN1C([C@@H](CC=2C3=CC=CC=C3NC=2)NC(=O)C(C)(N)C)=NN=C1CC1=CC=CC=C1 STHADNJZIQEPNZ-AREMUKBSSA-N 0.000 claims description 6
- BLFNAIFLVINSMV-RUZDIDTESA-N 2-amino-n-[(1r)-1-(5-benzyl-4-hexyl-1,2,4-triazol-3-yl)-2-(1h-indol-3-yl)ethyl]-2-methylpropanamide Chemical compound N=1N=C([C@@H](CC=2C3=CC=CC=C3NC=2)NC(=O)C(C)(C)N)N(CCCCCC)C=1CC1=CC=CC=C1 BLFNAIFLVINSMV-RUZDIDTESA-N 0.000 claims description 6
- OGHUYUKIMSORCD-PSXMRANNSA-N 2-amino-n-[(1r)-1-[4-(2,2-diphenylethyl)-5-[2-(1h-indol-3-yl)ethyl]-1,2,4-triazol-3-yl]-2-(1h-indol-3-yl)ethyl]-2-methylpropanamide Chemical compound C1([C@@H](CC=2C3=CC=CC=C3NC=2)NC(=O)C(C)(N)C)=NN=C(CCC=2C3=CC=CC=C3NC=2)N1CC(C=1C=CC=CC=1)C1=CC=CC=C1 OGHUYUKIMSORCD-PSXMRANNSA-N 0.000 claims description 6
- GBUPAIRVVQWJCN-GDLZYMKVSA-N 2-amino-n-[(1r)-1-[4-[(3,5-dimethoxyphenyl)methyl]-5-(2-phenylethyl)-1,2,4-triazol-3-yl]-2-(1h-indol-3-yl)ethyl]-2-methylpropanamide Chemical compound COC1=CC(OC)=CC(CN2C(=NN=C2CCC=2C=CC=CC=2)[C@@H](CC=2C3=CC=CC=C3NC=2)NC(=O)C(C)(C)N)=C1 GBUPAIRVVQWJCN-GDLZYMKVSA-N 0.000 claims description 6
- OMQXCGLSXYUOJX-HHHXNRCGSA-N 2-amino-n-[(1r)-1-[4-[(4-fluorophenyl)methyl]-5-(2-phenylethyl)-1,2,4-triazol-3-yl]-2-(1h-indol-3-yl)ethyl]-2-methylpropanamide Chemical compound C=1C=C(F)C=CC=1CN1C([C@@H](CC=2C3=CC=CC=C3NC=2)NC(=O)C(C)(N)C)=NN=C1CCC1=CC=CC=C1 OMQXCGLSXYUOJX-HHHXNRCGSA-N 0.000 claims description 6
- LJTZGMFMAQPASO-MUUNZHRXSA-N 2-amino-n-[(1r)-1-[5-[2-(1h-indol-3-yl)ethyl]-4-[(4-methoxyphenyl)methyl]-1,2,4-triazol-3-yl]-2-phenylethyl]-2-methylpropanamide Chemical compound C1=CC(OC)=CC=C1CN1C([C@@H](CC=2C=CC=CC=2)NC(=O)C(C)(C)N)=NN=C1CCC1=CNC2=CC=CC=C12 LJTZGMFMAQPASO-MUUNZHRXSA-N 0.000 claims description 6
- VRPQAMNHYIYBFL-MGBGTMOVSA-N 2-amino-n-[(1r)-1-[5-benzyl-4-(2,2-diphenylethyl)-1,2,4-triazol-3-yl]-2-(1h-indol-3-yl)ethyl]-2-methylpropanamide Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)CN1C([C@@H](CC=2C3=CC=CC=C3NC=2)NC(=O)C(C)(N)C)=NN=C1CC1=CC=CC=C1 VRPQAMNHYIYBFL-MGBGTMOVSA-N 0.000 claims description 6
- PWQYLDSMPYWAPW-HHHXNRCGSA-N 2-amino-n-[(1r)-1-[5-benzyl-4-[(2,4-dimethoxyphenyl)methyl]-1,2,4-triazol-3-yl]-2-(1h-indol-3-yl)ethyl]-2-methylpropanamide Chemical compound COC1=CC(OC)=CC=C1CN1C([C@@H](CC=2C3=CC=CC=C3NC=2)NC(=O)C(C)(C)N)=NN=C1CC1=CC=CC=C1 PWQYLDSMPYWAPW-HHHXNRCGSA-N 0.000 claims description 6
- XQLDKPBHSNVITF-AREMUKBSSA-N 2-amino-n-[(1r)-1-[5-benzyl-4-[(4-bromophenyl)methyl]-1,2,4-triazol-3-yl]-2-(1h-indol-3-yl)ethyl]-2-methylpropanamide Chemical compound C=1C=C(Br)C=CC=1CN1C([C@@H](CC=2C3=CC=CC=C3NC=2)NC(=O)C(C)(N)C)=NN=C1CC1=CC=CC=C1 XQLDKPBHSNVITF-AREMUKBSSA-N 0.000 claims description 6
- FHXUIOKRAFFICC-HHHXNRCGSA-N 2-amino-n-[(1r)-1-[5-benzyl-4-[(4-methylphenyl)methyl]-1,2,4-triazol-3-yl]-2-(1h-indol-3-yl)ethyl]-2-methylpropanamide Chemical compound C1=CC(C)=CC=C1CN1C([C@@H](CC=2C3=CC=CC=C3NC=2)NC(=O)C(C)(C)N)=NN=C1CC1=CC=CC=C1 FHXUIOKRAFFICC-HHHXNRCGSA-N 0.000 claims description 6
- SQMGDAVUTWCURS-GDLZYMKVSA-N 2-amino-n-[(1r)-1-[5-benzyl-4-[2-(1h-indol-3-yl)ethyl]-1,2,4-triazol-3-yl]-2-(1h-indol-3-yl)ethyl]-2-methylpropanamide Chemical compound C=1NC2=CC=CC=C2C=1CCN1C([C@@H](CC=2C3=CC=CC=C3NC=2)NC(=O)C(C)(N)C)=NN=C1CC1=CC=CC=C1 SQMGDAVUTWCURS-GDLZYMKVSA-N 0.000 claims description 6
- FIIGFCHOLCYSCT-HSZRJFAPSA-N 2-amino-n-[(1r)-2-(1h-indol-3-yl)-1-[4-[2-(1h-indol-3-yl)ethyl]-1,2,4-triazol-3-yl]ethyl]-2-methylpropanamide Chemical compound C1=CC=C2C(CCN3C=NN=C3[C@@H](CC=3C4=CC=CC=C4NC=3)NC(=O)C(C)(N)C)=CNC2=C1 FIIGFCHOLCYSCT-HSZRJFAPSA-N 0.000 claims description 6
- LNXNSJSFRCLLIC-GDLZYMKVSA-N 2-amino-n-[(1r)-2-(1h-indol-3-yl)-1-[4-[2-(4-methoxyphenyl)ethyl]-5-(2-phenylethyl)-1,2,4-triazol-3-yl]ethyl]-2-methylpropanamide Chemical compound C1=CC(OC)=CC=C1CCN1C([C@@H](CC=2C3=CC=CC=C3NC=2)NC(=O)C(C)(C)N)=NN=C1CCC1=CC=CC=C1 LNXNSJSFRCLLIC-GDLZYMKVSA-N 0.000 claims description 6
- REABAAMVKCLEJA-GDLZYMKVSA-N 2-amino-n-[(1r)-2-(1h-indol-3-yl)-1-[5-(1h-indol-3-ylmethyl)-4-(2-phenylethyl)-1,2,4-triazol-3-yl]ethyl]-2-methylpropanamide Chemical compound C1([C@@H](CC=2C3=CC=CC=C3NC=2)NC(=O)C(C)(N)C)=NN=C(CC=2C3=CC=CC=C3NC=2)N1CCC1=CC=CC=C1 REABAAMVKCLEJA-GDLZYMKVSA-N 0.000 claims description 6
- ZYIOQMMUZFYJNO-JOCHJYFZSA-N 2-amino-n-[(1r)-2-(1h-indol-3-yl)-1-[5-(1h-indol-3-ylmethyl)-4-methyl-1,2,4-triazol-3-yl]ethyl]-2-methylpropanamide Chemical compound C1=CC=C2C(C[C@H](C3=NN=C(CC=4C5=CC=CC=C5NC=4)N3C)NC(=O)C(C)(C)N)=CNC2=C1 ZYIOQMMUZFYJNO-JOCHJYFZSA-N 0.000 claims description 6
- OBUHPSWJFKQUJC-AREMUKBSSA-N 2-amino-n-[(1r)-2-(1h-indol-3-yl)-1-[5-(2-phenylethyl)-4-(pyridin-2-ylmethyl)-1,2,4-triazol-3-yl]ethyl]-2-methylpropanamide Chemical compound C=1C=CC=NC=1CN1C([C@@H](CC=2C3=CC=CC=C3NC=2)NC(=O)C(C)(N)C)=NN=C1CCC1=CC=CC=C1 OBUHPSWJFKQUJC-AREMUKBSSA-N 0.000 claims description 6
- BLWXMLGBPKKLSW-HSZRJFAPSA-N 2-amino-n-[(1r)-2-(1h-indol-3-yl)-1-[5-[2-(1h-indol-3-yl)ethyl]-4-methyl-1,2,4-triazol-3-yl]ethyl]-2-methylpropanamide Chemical compound C1=CC=C2C(C[C@H](C3=NN=C(CCC=4C5=CC=CC=C5NC=4)N3C)NC(=O)C(C)(C)N)=CNC2=C1 BLWXMLGBPKKLSW-HSZRJFAPSA-N 0.000 claims description 6
- DCAIAEDSMBLLML-MHZLTWQESA-N 2-amino-n-[(1s)-1-[5-benzyl-4-[(4-methoxyphenyl)methyl]-1,2,4-triazol-3-yl]-2-(1h-indol-3-yl)ethyl]-2-methylpropanamide Chemical compound C1=CC(OC)=CC=C1CN1C([C@H](CC=2C3=CC=CC=C3NC=2)NC(=O)C(C)(C)N)=NN=C1CC1=CC=CC=C1 DCAIAEDSMBLLML-MHZLTWQESA-N 0.000 claims description 6
- WNCKTUWHWHEBJE-NDEPHWFRSA-N 2-amino-n-[(1s)-2-(1h-indol-3-yl)-1-[4-[(4-methoxyphenyl)methyl]-5-(2-phenylethyl)-1,2,4-triazol-3-yl]ethyl]-2-methylpropanamide Chemical compound C1=CC(OC)=CC=C1CN1C([C@H](CC=2C3=CC=CC=C3NC=2)NC(=O)C(C)(C)N)=NN=C1CCC1=CC=CC=C1 WNCKTUWHWHEBJE-NDEPHWFRSA-N 0.000 claims description 6
- QEEMISQABWDGFJ-LJAQVGFWSA-N 2-amino-n-[(1s)-2-(1h-indol-3-yl)-1-[4-[(4-methoxyphenyl)methyl]-5-(3-phenylpropyl)-1,2,4-triazol-3-yl]ethyl]-2-methylpropanamide Chemical compound C1=CC(OC)=CC=C1CN1C([C@H](CC=2C3=CC=CC=C3NC=2)NC(=O)C(C)(C)N)=NN=C1CCCC1=CC=CC=C1 QEEMISQABWDGFJ-LJAQVGFWSA-N 0.000 claims description 6
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- SZUVGFMDDVSKSI-WIFOCOSTSA-N (1s,2s,3s,5r)-1-(carboxymethyl)-3,5-bis[(4-phenoxyphenyl)methyl-propylcarbamoyl]cyclopentane-1,2-dicarboxylic acid Chemical compound O=C([C@@H]1[C@@H]([C@](CC(O)=O)([C@H](C(=O)N(CCC)CC=2C=CC(OC=3C=CC=CC=3)=CC=2)C1)C(O)=O)C(O)=O)N(CCC)CC(C=C1)=CC=C1OC1=CC=CC=C1 SZUVGFMDDVSKSI-WIFOCOSTSA-N 0.000 claims description 3
- GCTFTMWXZFLTRR-GFCCVEGCSA-N (2r)-2-amino-n-[3-(difluoromethoxy)-4-(1,3-oxazol-5-yl)phenyl]-4-methylpentanamide Chemical compound FC(F)OC1=CC(NC(=O)[C@H](N)CC(C)C)=CC=C1C1=CN=CO1 GCTFTMWXZFLTRR-GFCCVEGCSA-N 0.000 claims description 3
- LTZQHKKUJQVOBT-FIRIVFDPSA-N (2r)-n-[(1r)-1-[4-[(2,4-dimethoxyphenyl)methyl]-5-(2-phenylethyl)-1,2,4-triazol-3-yl]-2-(1h-indol-3-yl)ethyl]piperidine-2-carboxamide Chemical compound COC1=CC(OC)=CC=C1CN1C([C@@H](CC=2C3=CC=CC=C3NC=2)NC(=O)[C@@H]2NCCCC2)=NN=C1CCC1=CC=CC=C1 LTZQHKKUJQVOBT-FIRIVFDPSA-N 0.000 claims description 3
- QDDCAAMEEYUGOX-ROJLCIKYSA-N (2r)-n-[(1r)-1-[4-[(4-ethylphenyl)methyl]-5-(2-phenylethyl)-1,2,4-triazol-3-yl]-2-(1h-indol-3-yl)ethyl]piperidine-2-carboxamide Chemical compound C1=CC(CC)=CC=C1CN1C([C@@H](CC=2C3=CC=CC=C3NC=2)NC(=O)[C@@H]2NCCCC2)=NN=C1CCC1=CC=CC=C1 QDDCAAMEEYUGOX-ROJLCIKYSA-N 0.000 claims description 3
- ZYAIAJWIMAJKGE-FIRIVFDPSA-N (2r)-n-[(1r)-2-(1h-indol-3-yl)-1-[4-[(4-methoxyphenyl)methyl]-5-(2-phenylethyl)-1,2,4-triazol-3-yl]ethyl]piperidine-2-carboxamide Chemical compound C1=CC(OC)=CC=C1CN1C([C@@H](CC=2C3=CC=CC=C3NC=2)NC(=O)[C@@H]2NCCCC2)=NN=C1CCC1=CC=CC=C1 ZYAIAJWIMAJKGE-FIRIVFDPSA-N 0.000 claims description 3
- GYSPFGJFPWKCMM-LOYHVIPDSA-N (2r)-n-[(1r)-2-(1h-indol-3-yl)-1-[4-[(4-methoxyphenyl)methyl]-5-(2-phenylethyl)-1,2,4-triazol-3-yl]ethyl]pyrrolidine-2-carboxamide Chemical compound C1=CC(OC)=CC=C1CN1C([C@@H](CC=2C3=CC=CC=C3NC=2)NC(=O)[C@@H]2NCCC2)=NN=C1CCC1=CC=CC=C1 GYSPFGJFPWKCMM-LOYHVIPDSA-N 0.000 claims description 3
- FAURKORJKUNELM-CZNDPXEESA-N (2r)-n-[(1r)-2-(1h-indol-3-yl)-1-[5-[2-(1h-indol-3-yl)ethyl]-4-[(4-methoxyphenyl)methyl]-1,2,4-triazol-3-yl]ethyl]piperidine-2-carboxamide Chemical compound C1=CC(OC)=CC=C1CN1C([C@@H](CC=2C3=CC=CC=C3NC=2)NC(=O)[C@@H]2NCCCC2)=NN=C1CCC1=CNC2=CC=CC=C12 FAURKORJKUNELM-CZNDPXEESA-N 0.000 claims description 3
- JPUIVPWHWCVOHQ-KWRHIPAJSA-N (2r)-n-[1-[4-[(2,4-dimethoxyphenyl)methyl]-5-[2-(1h-indol-3-yl)ethyl]-1,2,4-triazol-3-yl]-2-(1h-indol-3-yl)ethyl]piperidine-2-carboxamide Chemical compound COC1=CC(OC)=CC=C1CN1C(C(CC=2C3=CC=CC=C3NC=2)NC(=O)[C@@H]2NCCCC2)=NN=C1CCC1=CNC2=CC=CC=C12 JPUIVPWHWCVOHQ-KWRHIPAJSA-N 0.000 claims description 3
- YJLIKUSWRSEPSM-WGQQHEPDSA-N (2r,3r,4s,5r)-2-[6-amino-8-[(4-phenylphenyl)methylamino]purin-9-yl]-5-(hydroxymethyl)oxolane-3,4-diol Chemical compound C=1C=C(C=2C=CC=CC=2)C=CC=1CNC1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O YJLIKUSWRSEPSM-WGQQHEPDSA-N 0.000 claims description 3
- VLKCIZDYSQANPO-PZGXJGMVSA-N (2s)-2-amino-n-[(1r)-1-[4-[(4-ethylphenyl)methyl]-5-(2-phenylethyl)-1,2,4-triazol-3-yl]-2-(1h-indol-3-yl)ethyl]propanamide Chemical compound C1=CC(CC)=CC=C1CN1C([C@@H](CC=2C3=CC=CC=C3NC=2)NC(=O)[C@H](C)N)=NN=C1CCC1=CC=CC=C1 VLKCIZDYSQANPO-PZGXJGMVSA-N 0.000 claims description 3
- MCDRDYFDQCMLIS-UZNNEEJFSA-N (2s)-2-amino-n-[(1r)-2-(1h-indol-3-yl)-1-[4-[(4-methoxyphenyl)methyl]-5-(2-phenylethyl)-1,2,4-triazol-3-yl]ethyl]-3-phenylpropanamide Chemical compound C1=CC(OC)=CC=C1CN1C([C@@H](CC=2C3=CC=CC=C3NC=2)NC(=O)[C@@H](N)CC=2C=CC=CC=2)=NN=C1CCC1=CC=CC=C1 MCDRDYFDQCMLIS-UZNNEEJFSA-N 0.000 claims description 3
- BRWMPFXAMGDTEZ-RBTNQOKQSA-N (2s)-2-amino-n-[(1r)-2-(1h-indol-3-yl)-1-[4-[(4-methoxyphenyl)methyl]-5-(2-phenylethyl)-1,2,4-triazol-3-yl]ethyl]propanamide Chemical compound C1=CC(OC)=CC=C1CN1C([C@@H](CC=2C3=CC=CC=C3NC=2)NC(=O)[C@H](C)N)=NN=C1CCC1=CC=CC=C1 BRWMPFXAMGDTEZ-RBTNQOKQSA-N 0.000 claims description 3
- KXINUWXQXWZNNY-AJQTZOPKSA-N (2s)-n-[(1r)-1-[4-(4-ethylphenyl)-5-[2-(1h-indol-3-yl)ethyl]-1,2,4-triazol-3-yl]-2-(1h-indol-3-yl)ethyl]pyrrolidine-2-carboxamide Chemical compound C1=CC(CC)=CC=C1N1C([C@@H](CC=2C3=CC=CC=C3NC=2)NC(=O)[C@H]2NCCC2)=NN=C1CCC1=CNC2=CC=CC=C12 KXINUWXQXWZNNY-AJQTZOPKSA-N 0.000 claims description 3
- PBQKDJJUTIMWGR-IOWSJCHKSA-N (2s)-n-[(1r)-1-[4-[(4-ethylphenyl)methyl]-5-(2-phenylethyl)-1,2,4-triazol-3-yl]-2-(1h-indol-3-yl)ethyl]pyrrolidine-2-carboxamide Chemical compound C1=CC(CC)=CC=C1CN1C([C@@H](CC=2C3=CC=CC=C3NC=2)NC(=O)[C@H]2NCCC2)=NN=C1CCC1=CC=CC=C1 PBQKDJJUTIMWGR-IOWSJCHKSA-N 0.000 claims description 3
- ZYAIAJWIMAJKGE-IOWSJCHKSA-N (2s)-n-[(1r)-2-(1h-indol-3-yl)-1-[4-[(4-methoxyphenyl)methyl]-5-(2-phenylethyl)-1,2,4-triazol-3-yl]ethyl]piperidine-2-carboxamide Chemical compound C1=CC(OC)=CC=C1CN1C([C@@H](CC=2C3=CC=CC=C3NC=2)NC(=O)[C@H]2NCCCC2)=NN=C1CCC1=CC=CC=C1 ZYAIAJWIMAJKGE-IOWSJCHKSA-N 0.000 claims description 3
- GYSPFGJFPWKCMM-XZWHSSHBSA-N (2s)-n-[(1r)-2-(1h-indol-3-yl)-1-[4-[(4-methoxyphenyl)methyl]-5-(2-phenylethyl)-1,2,4-triazol-3-yl]ethyl]pyrrolidine-2-carboxamide Chemical compound C1=CC(OC)=CC=C1CN1C([C@@H](CC=2C3=CC=CC=C3NC=2)NC(=O)[C@H]2NCCC2)=NN=C1CCC1=CC=CC=C1 GYSPFGJFPWKCMM-XZWHSSHBSA-N 0.000 claims description 3
- MXZIZDCJSOJXBW-WUFINQPMSA-N (2s)-n-[(1r)-2-(1h-indol-3-yl)-1-[4-phenyl-5-(2-phenylethyl)-1,2,4-triazol-3-yl]ethyl]pyrrolidine-2-carboxamide Chemical compound C=1C=CC=CC=1N1C([C@@H](CC=2C3=CC=CC=C3NC=2)NC(=O)[C@H]2NCCC2)=NN=C1CCC1=CC=CC=C1 MXZIZDCJSOJXBW-WUFINQPMSA-N 0.000 claims description 3
- VJKVFVWCKGGYPU-AJQTZOPKSA-N (2s)-n-[(1r)-2-(1h-indol-3-yl)-1-[5-[2-(1h-indol-3-yl)ethyl]-4-[(4-methoxyphenyl)methyl]-1,2,4-triazol-3-yl]ethyl]-2,5-dihydro-1h-pyrrole-2-carboxamide Chemical compound C1=CC(OC)=CC=C1CN1C([C@@H](CC=2C3=CC=CC=C3NC=2)NC(=O)[C@@H]2C=CCN2)=NN=C1CCC1=CNC2=CC=CC=C12 VJKVFVWCKGGYPU-AJQTZOPKSA-N 0.000 claims description 3
- STBLNCCBQMHSRC-BATDWUPUSA-N (2s)-n-[(3s,4s)-5-acetyl-7-cyano-4-methyl-1-[(2-methylnaphthalen-1-yl)methyl]-2-oxo-3,4-dihydro-1,5-benzodiazepin-3-yl]-2-(methylamino)propanamide Chemical compound O=C1[C@@H](NC(=O)[C@H](C)NC)[C@H](C)N(C(C)=O)C2=CC(C#N)=CC=C2N1CC1=C(C)C=CC2=CC=CC=C12 STBLNCCBQMHSRC-BATDWUPUSA-N 0.000 claims description 3
- UDQTXCHQKHIQMH-KYGLGHNPSA-N (3ar,5s,6s,7r,7ar)-5-(difluoromethyl)-2-(ethylamino)-5,6,7,7a-tetrahydro-3ah-pyrano[3,2-d][1,3]thiazole-6,7-diol Chemical compound S1C(NCC)=N[C@H]2[C@@H]1O[C@H](C(F)F)[C@@H](O)[C@@H]2O UDQTXCHQKHIQMH-KYGLGHNPSA-N 0.000 claims description 3
- OOKAZRDERJMRCJ-KOUAFAAESA-N (3r)-7-[(1s,2s,4ar,6s,8s)-2,6-dimethyl-8-[(2s)-2-methylbutanoyl]oxy-1,2,4a,5,6,7,8,8a-octahydronaphthalen-1-yl]-3-hydroxy-5-oxoheptanoic acid Chemical compound C1=C[C@H](C)[C@H](CCC(=O)C[C@@H](O)CC(O)=O)C2[C@@H](OC(=O)[C@@H](C)CC)C[C@@H](C)C[C@@H]21 OOKAZRDERJMRCJ-KOUAFAAESA-N 0.000 claims description 3
- JEBWQRLWYAVSFG-MXBOTTGLSA-N (3r)-n-[(1r)-2-(1h-indol-3-yl)-1-[4-[(4-methoxyphenyl)methyl]-5-(2-phenylethyl)-1,2,4-triazol-3-yl]ethyl]piperidine-3-carboxamide Chemical compound C1=CC(OC)=CC=C1CN1C([C@@H](CC=2C3=CC=CC=C3NC=2)NC(=O)[C@H]2CNCCC2)=NN=C1CCC1=CC=CC=C1 JEBWQRLWYAVSFG-MXBOTTGLSA-N 0.000 claims description 3
- QIYOXEQGZPLGBP-NHYGQJMQSA-N (3r)-n-[1-[4-[(2,4-dimethoxyphenyl)methyl]-5-[2-(1h-indol-3-yl)ethyl]-1,2,4-triazol-3-yl]-2-(1h-indol-3-yl)ethyl]piperidine-3-carboxamide Chemical compound COC1=CC(OC)=CC=C1CN1C(C(CC=2C3=CC=CC=C3NC=2)NC(=O)[C@H]2CNCCC2)=NN=C1CCC1=CNC2=CC=CC=C12 QIYOXEQGZPLGBP-NHYGQJMQSA-N 0.000 claims description 3
- DESJRSILBBZHEG-PSPFREQMSA-N (3r)-n-[1-[4-benzyl-5-[2-(1h-indol-3-yl)ethyl]-1,2,4-triazol-3-yl]-2-(1h-indol-3-yl)ethyl]piperidine-3-carboxamide Chemical compound O=C([C@H]1CNCCC1)NC(CC=1C2=CC=CC=C2NC=1)C1=NN=C(CCC=2C3=CC=CC=C3NC=2)N1CC1=CC=CC=C1 DESJRSILBBZHEG-PSPFREQMSA-N 0.000 claims description 3
- SKYNFUYLPSUPDZ-OEXUWWALSA-N (3r)-n-[2-(1h-indol-3-yl)-1-[5-(2-phenylethyl)-4-(pyridin-2-ylmethyl)-1,2,4-triazol-3-yl]ethyl]piperidine-3-carboxamide Chemical compound O=C([C@H]1CNCCC1)NC(CC=1C2=CC=CC=C2NC=1)C(N1CC=2N=CC=CC=2)=NN=C1CCC1=CC=CC=C1 SKYNFUYLPSUPDZ-OEXUWWALSA-N 0.000 claims description 3
- HUWSZNZAROKDRZ-RRLWZMAJSA-N (3r,4r)-3-azaniumyl-5-[[(2s,3r)-1-[(2s)-2,3-dicarboxypyrrolidin-1-yl]-3-methyl-1-oxopentan-2-yl]amino]-5-oxo-4-sulfanylpentane-1-sulfonate Chemical compound OS(=O)(=O)CC[C@@H](N)[C@@H](S)C(=O)N[C@@H]([C@H](C)CC)C(=O)N1CCC(C(O)=O)[C@H]1C(O)=O HUWSZNZAROKDRZ-RRLWZMAJSA-N 0.000 claims description 3
- SINROGNKCLMROR-GMCHKSTQSA-N (3s)-n-[(1r)-1-[4-[(4-ethylphenyl)methyl]-5-(2-phenylethyl)-1,2,4-triazol-3-yl]-2-(1h-indol-3-yl)ethyl]piperidine-3-carboxamide Chemical compound C1=CC(CC)=CC=C1CN1C([C@@H](CC=2C3=CC=CC=C3NC=2)NC(=O)[C@@H]2CNCCC2)=NN=C1CCC1=CC=CC=C1 SINROGNKCLMROR-GMCHKSTQSA-N 0.000 claims description 3
- FABXLMBOGKCWFI-OOOSNSGVSA-N (3s)-n-[(1r)-2-(1h-indol-3-yl)-1-[5-[2-(1h-indol-3-yl)ethyl]-4-[(4-methoxyphenyl)methyl]-1,2,4-triazol-3-yl]ethyl]piperidine-3-carboxamide Chemical compound C1=CC(OC)=CC=C1CN1C([C@@H](CC=2C3=CC=CC=C3NC=2)NC(=O)[C@@H]2CNCCC2)=NN=C1CCC1=CNC2=CC=CC=C12 FABXLMBOGKCWFI-OOOSNSGVSA-N 0.000 claims description 3
- YQOLEILXOBUDMU-KRWDZBQOSA-N (4R)-5-[(6-bromo-3-methyl-2-pyrrolidin-1-ylquinoline-4-carbonyl)amino]-4-(2-chlorophenyl)pentanoic acid Chemical compound CC1=C(C2=C(C=CC(=C2)Br)N=C1N3CCCC3)C(=O)NC[C@H](CCC(=O)O)C4=CC=CC=C4Cl YQOLEILXOBUDMU-KRWDZBQOSA-N 0.000 claims description 3
- OIIOPWHTJZYKIL-PMACEKPBSA-N (5S)-5-[[[5-[2-chloro-3-[2-chloro-3-[6-methoxy-5-[[[(2S)-5-oxopyrrolidin-2-yl]methylamino]methyl]pyrazin-2-yl]phenyl]phenyl]-3-methoxypyrazin-2-yl]methylamino]methyl]pyrrolidin-2-one Chemical compound C1(=C(N=C(C2=C(C(C3=CC=CC(=C3Cl)C3=NC(OC)=C(N=C3)CNC[C@H]3NC(=O)CC3)=CC=C2)Cl)C=N1)OC)CNC[C@H]1NC(=O)CC1 OIIOPWHTJZYKIL-PMACEKPBSA-N 0.000 claims description 3
- NFCQMFMYGHXJQB-MGBGTMOVSA-N (r)-[4-[(2,4-dimethoxyphenyl)methyl]-5-(2-phenylethyl)-1,2,4-triazol-3-yl]-[2-(1h-indol-3-yl)phenyl]methanesulfonamide Chemical compound COC1=CC(OC)=CC=C1CN1C([C@@H](C=2C(=CC=CC=2)C=2C3=CC=CC=C3NC=2)S(N)(=O)=O)=NN=C1CCC1=CC=CC=C1 NFCQMFMYGHXJQB-MGBGTMOVSA-N 0.000 claims description 3
- KKHFRAFPESRGGD-UHFFFAOYSA-N 1,3-dimethyl-7-[3-(n-methylanilino)propyl]purine-2,6-dione Chemical compound C1=NC=2N(C)C(=O)N(C)C(=O)C=2N1CCCN(C)C1=CC=CC=C1 KKHFRAFPESRGGD-UHFFFAOYSA-N 0.000 claims description 3
- KQZLRWGGWXJPOS-NLFPWZOASA-N 1-[(1R)-1-(2,4-dichlorophenyl)ethyl]-6-[(4S,5R)-4-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]-5-methylcyclohexen-1-yl]pyrazolo[3,4-b]pyrazine-3-carbonitrile Chemical compound ClC1=C(C=CC(=C1)Cl)[C@@H](C)N1N=C(C=2C1=NC(=CN=2)C1=CC[C@@H]([C@@H](C1)C)N1[C@@H](CCC1)CO)C#N KQZLRWGGWXJPOS-NLFPWZOASA-N 0.000 claims description 3
- VCUXVXLUOHDHKK-UHFFFAOYSA-N 2-(2-aminopyrimidin-4-yl)-4-(2-chloro-4-methoxyphenyl)-1,3-thiazole-5-carboxamide Chemical compound ClC1=CC(OC)=CC=C1C1=C(C(N)=O)SC(C=2N=C(N)N=CC=2)=N1 VCUXVXLUOHDHKK-UHFFFAOYSA-N 0.000 claims description 3
- QEBYEVQKHRUYPE-UHFFFAOYSA-N 2-(2-chlorophenyl)-5-[(1-methylpyrazol-3-yl)methyl]-4-[[methyl(pyridin-3-ylmethyl)amino]methyl]-1h-pyrazolo[4,3-c]pyridine-3,6-dione Chemical compound C1=CN(C)N=C1CN1C(=O)C=C2NN(C=3C(=CC=CC=3)Cl)C(=O)C2=C1CN(C)CC1=CC=CN=C1 QEBYEVQKHRUYPE-UHFFFAOYSA-N 0.000 claims description 3
- QTMAZYGAVHCKKX-UHFFFAOYSA-N 2-[(4-amino-5-bromopyrrolo[2,3-d]pyrimidin-7-yl)methoxy]propane-1,3-diol Chemical compound NC1=NC=NC2=C1C(Br)=CN2COC(CO)CO QTMAZYGAVHCKKX-UHFFFAOYSA-N 0.000 claims description 3
- FMKGJQHNYMWDFJ-CVEARBPZSA-N 2-[[4-(2,2-difluoropropoxy)pyrimidin-5-yl]methylamino]-4-[[(1R,4S)-4-hydroxy-3,3-dimethylcyclohexyl]amino]pyrimidine-5-carbonitrile Chemical compound FC(COC1=NC=NC=C1CNC1=NC=C(C(=N1)N[C@H]1CC([C@H](CC1)O)(C)C)C#N)(C)F FMKGJQHNYMWDFJ-CVEARBPZSA-N 0.000 claims description 3
- VVCMGAUPZIKYTH-VGHSCWAPSA-N 2-acetyloxybenzoic acid;[(2s,3r)-4-(dimethylamino)-3-methyl-1,2-diphenylbutan-2-yl] propanoate;1,3,7-trimethylpurine-2,6-dione Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O.CN1C(=O)N(C)C(=O)C2=C1N=CN2C.C([C@](OC(=O)CC)([C@H](C)CN(C)C)C=1C=CC=CC=1)C1=CC=CC=C1 VVCMGAUPZIKYTH-VGHSCWAPSA-N 0.000 claims description 3
- MSFIVLSDUGNPCO-RUZDIDTESA-N 2-amino-n-[(1r)-1-[4-(2,4-dimethoxyphenyl)-5-(2-phenylethyl)-1,2,4-triazol-3-yl]-2-(1h-indol-3-yl)ethyl]acetamide Chemical compound COC1=CC(OC)=CC=C1N1C([C@@H](CC=2C3=CC=CC=C3NC=2)NC(=O)CN)=NN=C1CCC1=CC=CC=C1 MSFIVLSDUGNPCO-RUZDIDTESA-N 0.000 claims description 3
- ZKRKDYYBSBSWFU-GDLZYMKVSA-N 2-amino-n-[(1r)-1-[4-(4-ethylphenyl)-5-[2-(1h-indol-3-yl)ethyl]-1,2,4-triazol-3-yl]-2-(1h-indol-3-yl)ethyl]acetamide Chemical compound C1=CC(CC)=CC=C1N1C([C@@H](CC=2C3=CC=CC=C3NC=2)NC(=O)CN)=NN=C1CCC1=CNC2=CC=CC=C12 ZKRKDYYBSBSWFU-GDLZYMKVSA-N 0.000 claims description 3
- XNTQSXSHCYEQKO-RUZDIDTESA-N 2-amino-n-[(1r)-1-[4-(furan-2-ylmethyl)-5-(2-phenylethyl)-1,2,4-triazol-3-yl]-2-(1h-indol-3-yl)ethyl]-2-methylpropanamide Chemical compound C=1C=COC=1CN1C([C@@H](CC=2C3=CC=CC=C3NC=2)NC(=O)C(C)(N)C)=NN=C1CCC1=CC=CC=C1 XNTQSXSHCYEQKO-RUZDIDTESA-N 0.000 claims description 3
- UBXHWKKKGGECRZ-HHHXNRCGSA-N 2-amino-n-[(1r)-1-[4-[(2,4-dimethoxyphenyl)methyl]-5-(2-phenylethyl)-1,2,4-triazol-3-yl]-2-(1h-indol-3-yl)ethyl]acetamide Chemical compound COC1=CC(OC)=CC=C1CN1C([C@@H](CC=2C3=CC=CC=C3NC=2)NC(=O)CN)=NN=C1CCC1=CC=CC=C1 UBXHWKKKGGECRZ-HHHXNRCGSA-N 0.000 claims description 3
- WWQWKRWAIHYINO-GDLZYMKVSA-N 2-amino-n-[(1r)-1-[4-[(2,4-dimethoxyphenyl)methyl]-5-[2-(1h-indol-3-yl)ethyl]-1,2,4-triazol-3-yl]-2-(1h-indol-3-yl)ethyl]acetamide Chemical compound COC1=CC(OC)=CC=C1CN1C([C@@H](CC=2C3=CC=CC=C3NC=2)NC(=O)CN)=NN=C1CCC1=CNC2=CC=CC=C12 WWQWKRWAIHYINO-GDLZYMKVSA-N 0.000 claims description 3
- JGPAAQUPTQVZKR-UUWRZZSWSA-N 2-amino-n-[(1r)-1-[4-[(2,4-dimethoxyphenyl)methyl]-5-[2-(1h-indol-3-yl)ethyl]-1,2,4-triazol-3-yl]-2-(1h-indol-3-yl)ethyl]benzamide Chemical compound COC1=CC(OC)=CC=C1CN1C([C@@H](CC=2C3=CC=CC=C3NC=2)NC(=O)C=2C(=CC=CC=2)N)=NN=C1CCC1=CNC2=CC=CC=C12 JGPAAQUPTQVZKR-UUWRZZSWSA-N 0.000 claims description 3
- FCJVKIMYXMJFFZ-WJOKGBTCSA-N 2-amino-n-[(1r)-1-[4-[(2,4-dimethoxyphenyl)methyl]-5-[3-(1h-indol-3-yl)propyl]-1,2,4-triazol-3-yl]-2-(1h-indol-3-yl)ethyl]-2-methylpropanamide Chemical compound COC1=CC(OC)=CC=C1CN1C([C@@H](CC=2C3=CC=CC=C3NC=2)NC(=O)C(C)(C)N)=NN=C1CCCC1=CNC2=CC=CC=C12 FCJVKIMYXMJFFZ-WJOKGBTCSA-N 0.000 claims description 3
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- ZZEZRIIRTIXNFC-HHHXNRCGSA-N 2-amino-n-[(1r)-1-[4-benzyl-5-(2-phenylethyl)-1,2,4-triazol-3-yl]-2-(1h-indol-3-yl)ethyl]-2-methylpropanamide Chemical compound C=1C=CC=CC=1CN1C([C@@H](CC=2C3=CC=CC=C3NC=2)NC(=O)C(C)(N)C)=NN=C1CCC1=CC=CC=C1 ZZEZRIIRTIXNFC-HHHXNRCGSA-N 0.000 claims description 3
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- ACNDZZGAEOBNLV-MUUNZHRXSA-N 2-amino-n-[(1r)-1-[5-benzyl-4-[(3,5-dimethoxyphenyl)methyl]-1,2,4-triazol-3-yl]-2-(1h-indol-3-yl)ethyl]-2-methylpropanamide Chemical compound COC1=CC(OC)=CC(CN2C(=NN=C2CC=2C=CC=CC=2)[C@@H](CC=2C3=CC=CC=C3NC=2)NC(=O)C(C)(C)N)=C1 ACNDZZGAEOBNLV-MUUNZHRXSA-N 0.000 claims description 3
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- XFJBGINZIMNZBW-CRAIPNDOSA-N 5-chloro-2-[4-[(1r,2s)-2-[2-(5-methylsulfonylpyridin-2-yl)oxyethyl]cyclopropyl]piperidin-1-yl]pyrimidine Chemical compound N1=CC(S(=O)(=O)C)=CC=C1OCC[C@H]1[C@@H](C2CCN(CC2)C=2N=CC(Cl)=CN=2)C1 XFJBGINZIMNZBW-CRAIPNDOSA-N 0.000 claims description 3
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- LJOOWESTVASNOG-UFJKPHDISA-N [(1s,3r,4ar,7s,8s,8as)-3-hydroxy-8-[2-[(4r)-4-hydroxy-6-oxooxan-2-yl]ethyl]-7-methyl-1,2,3,4,4a,7,8,8a-octahydronaphthalen-1-yl] (2s)-2-methylbutanoate Chemical compound C([C@H]1[C@@H](C)C=C[C@H]2C[C@@H](O)C[C@@H]([C@H]12)OC(=O)[C@@H](C)CC)CC1C[C@@H](O)CC(=O)O1 LJOOWESTVASNOG-UFJKPHDISA-N 0.000 claims description 3
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- CKCDVZMWTACYFZ-HHHXNRCGSA-N n-[(1r)-1-[4-(2,4-dimethoxyphenyl)-5-(2-phenylethyl)-1,2,4-triazol-3-yl]-2-(1h-indol-3-yl)ethyl]pyrazine-2-carboxamide Chemical compound COC1=CC(OC)=CC=C1N1C([C@@H](CC=2C3=CC=CC=C3NC=2)NC(=O)C=2N=CC=NC=2)=NN=C1CCC1=CC=CC=C1 CKCDVZMWTACYFZ-HHHXNRCGSA-N 0.000 claims description 3
- BRUMDNDVRRAAGH-GDLZYMKVSA-N n-[(1r)-1-[4-(2,4-dimethoxyphenyl)-5-(2-phenylethyl)-1,2,4-triazol-3-yl]-2-(1h-indol-3-yl)ethyl]pyridine-2-carboxamide Chemical compound COC1=CC(OC)=CC=C1N1C([C@@H](CC=2C3=CC=CC=C3NC=2)NC(=O)C=2N=CC=CC=2)=NN=C1CCC1=CC=CC=C1 BRUMDNDVRRAAGH-GDLZYMKVSA-N 0.000 claims description 3
- HBKGKPNCTBCWSU-UUWRZZSWSA-N n-[(1r)-1-[4-(4-ethylphenyl)-5-[2-(1h-indol-3-yl)ethyl]-1,2,4-triazol-3-yl]-2-(1h-indol-3-yl)ethyl]-2-pyridin-2-ylacetamide Chemical compound C1=CC(CC)=CC=C1N1C([C@@H](CC=2C3=CC=CC=C3NC=2)NC(=O)CC=2N=CC=CC=2)=NN=C1CCC1=CNC2=CC=CC=C12 HBKGKPNCTBCWSU-UUWRZZSWSA-N 0.000 claims description 3
- MPVJQHAOPFGHKE-MGBGTMOVSA-N n-[(1r)-1-[4-(4-ethylphenyl)-5-[2-(1h-indol-3-yl)ethyl]-1,2,4-triazol-3-yl]-2-(1h-indol-3-yl)ethyl]pyridine-2-carboxamide Chemical compound C1=CC(CC)=CC=C1N1C([C@@H](CC=2C3=CC=CC=C3NC=2)NC(=O)C=2N=CC=CC=2)=NN=C1CCC1=CNC2=CC=CC=C12 MPVJQHAOPFGHKE-MGBGTMOVSA-N 0.000 claims description 3
- QFFMNYRWGUWLOU-MUUNZHRXSA-N n-[(1r)-1-[4-(furan-2-ylmethyl)-5-(2-phenylethyl)-1,2,4-triazol-3-yl]-2-(1h-indol-3-yl)ethyl]piperidine-4-carboxamide Chemical compound C=1C=COC=1CN1C([C@@H](CC=2C3=CC=CC=C3NC=2)NC(=O)C2CCNCC2)=NN=C1CCC1=CC=CC=C1 QFFMNYRWGUWLOU-MUUNZHRXSA-N 0.000 claims description 3
- ZSHWSYGIDLHPCD-MUUNZHRXSA-N n-[(1r)-1-[4-(furan-2-ylmethyl)-5-(2-phenylethyl)-1,2,4-triazol-3-yl]-2-(1h-indol-3-yl)ethyl]pyridine-2-carboxamide Chemical compound C=1C=COC=1CN1C([C@@H](CC=2C3=CC=CC=C3NC=2)NC(=O)C=2N=CC=CC=2)=NN=C1CCC1=CC=CC=C1 ZSHWSYGIDLHPCD-MUUNZHRXSA-N 0.000 claims description 3
- AHUYDFSFCADXGB-WJOKGBTCSA-N n-[(1r)-1-[4-[(2,4-dimethoxyphenyl)methyl]-5-(2-phenylethyl)-1,2,4-triazol-3-yl]-2-(1h-indol-3-yl)ethyl]pyridine-4-carboxamide Chemical compound COC1=CC(OC)=CC=C1CN1C([C@@H](CC=2C3=CC=CC=C3NC=2)NC(=O)C=2C=CN=CC=2)=NN=C1CCC1=CC=CC=C1 AHUYDFSFCADXGB-WJOKGBTCSA-N 0.000 claims description 3
- HJYWAHOPJYSWJW-UUWRZZSWSA-N n-[(1r)-1-[4-[(2,4-dimethoxyphenyl)methyl]-5-[2-(1h-indol-3-yl)ethyl]-1,2,4-triazol-3-yl]-2-(1h-indol-3-yl)ethyl]-2-pyridin-2-ylacetamide Chemical compound COC1=CC(OC)=CC=C1CN1C([C@@H](CC=2C3=CC=CC=C3NC=2)NC(=O)CC=2N=CC=CC=2)=NN=C1CCC1=CNC2=CC=CC=C12 HJYWAHOPJYSWJW-UUWRZZSWSA-N 0.000 claims description 3
- WEBYIRLNLFDUTM-PGUFJCEWSA-N n-[(1r)-1-[4-[(2,4-dimethoxyphenyl)methyl]-5-[2-(1h-indol-3-yl)ethyl]-1,2,4-triazol-3-yl]-2-(1h-indol-3-yl)ethyl]-4-methylbenzenesulfonamide Chemical compound COC1=CC(OC)=CC=C1CN1C([C@@H](CC=2C3=CC=CC=C3NC=2)NS(=O)(=O)C=2C=CC(C)=CC=2)=NN=C1CCC1=CNC2=CC=CC=C12 WEBYIRLNLFDUTM-PGUFJCEWSA-N 0.000 claims description 3
- BRFWOWNZIQIQTQ-MGBGTMOVSA-N n-[(1r)-1-[4-[(2,4-dimethoxyphenyl)methyl]-5-[2-(1h-indol-3-yl)ethyl]-1,2,4-triazol-3-yl]-2-(1h-indol-3-yl)ethyl]piperidine-4-carboxamide Chemical compound COC1=CC(OC)=CC=C1CN1C([C@@H](CC=2C3=CC=CC=C3NC=2)NC(=O)C2CCNCC2)=NN=C1CCC1=CNC2=CC=CC=C12 BRFWOWNZIQIQTQ-MGBGTMOVSA-N 0.000 claims description 3
- BJWKSORGVUPDIJ-MGBGTMOVSA-N n-[(1r)-1-[4-[(4-ethylphenyl)methyl]-5-(2-phenylethyl)-1,2,4-triazol-3-yl]-2-(1h-indol-3-yl)ethyl]-2-pyridin-3-ylacetamide Chemical compound C1=CC(CC)=CC=C1CN1C([C@@H](CC=2C3=CC=CC=C3NC=2)NC(=O)CC=2C=NC=CC=2)=NN=C1CCC1=CC=CC=C1 BJWKSORGVUPDIJ-MGBGTMOVSA-N 0.000 claims description 3
- PROMAYDRALXCHH-JGCGQSQUSA-N n-[(1r)-1-[4-[(4-ethylphenyl)methyl]-5-(2-phenylethyl)-1,2,4-triazol-3-yl]-2-(1h-indol-3-yl)ethyl]piperidine-4-carboxamide Chemical compound C1=CC(CC)=CC=C1CN1C([C@@H](CC=2C3=CC=CC=C3NC=2)NC(=O)C2CCNCC2)=NN=C1CCC1=CC=CC=C1 PROMAYDRALXCHH-JGCGQSQUSA-N 0.000 claims description 3
- NWROGXWDHBHKFM-SSEXGKCCSA-N n-[(1r)-1-[4-[(4-ethylphenyl)methyl]-5-(2-phenylethyl)-1,2,4-triazol-3-yl]-2-(1h-indol-3-yl)ethyl]pyrazine-2-carboxamide Chemical compound C1=CC(CC)=CC=C1CN1C([C@@H](CC=2C3=CC=CC=C3NC=2)NC(=O)C=2N=CC=NC=2)=NN=C1CCC1=CC=CC=C1 NWROGXWDHBHKFM-SSEXGKCCSA-N 0.000 claims description 3
- BGUVYVNLIDHFQO-JGCGQSQUSA-N n-[(1r)-1-[4-[(4-ethylphenyl)methyl]-5-(2-phenylethyl)-1,2,4-triazol-3-yl]-2-(1h-indol-3-yl)ethyl]pyridine-2-carboxamide Chemical compound C1=CC(CC)=CC=C1CN1C([C@@H](CC=2C3=CC=CC=C3NC=2)NC(=O)C=2N=CC=CC=2)=NN=C1CCC1=CC=CC=C1 BGUVYVNLIDHFQO-JGCGQSQUSA-N 0.000 claims description 3
- YEWQJAVVBPPTER-JGCGQSQUSA-N n-[(1r)-1-[4-[(4-ethylphenyl)methyl]-5-(2-phenylethyl)-1,2,4-triazol-3-yl]-2-(1h-indol-3-yl)ethyl]pyridine-4-carboxamide Chemical compound C1=CC(CC)=CC=C1CN1C([C@@H](CC=2C3=CC=CC=C3NC=2)NC(=O)C=2C=CN=CC=2)=NN=C1CCC1=CC=CC=C1 YEWQJAVVBPPTER-JGCGQSQUSA-N 0.000 claims description 3
- DMVJJUBFYGEKLA-MGBGTMOVSA-N n-[(1r)-1-[4-benzyl-5-[2-(1h-indol-3-yl)ethyl]-1,2,4-triazol-3-yl]-2-(1h-indol-3-yl)ethyl]-2-pyridin-2-ylacetamide Chemical compound N([C@H](CC=1C2=CC=CC=C2NC=1)C=1N(C(CCC=2C3=CC=CC=C3NC=2)=NN=1)CC=1C=CC=CC=1)C(=O)CC1=CC=CC=N1 DMVJJUBFYGEKLA-MGBGTMOVSA-N 0.000 claims description 3
- FRKGNEAURFFNKA-JGCGQSQUSA-N n-[(1r)-1-[4-benzyl-5-[2-(1h-indol-3-yl)ethyl]-1,2,4-triazol-3-yl]-2-(1h-indol-3-yl)ethyl]piperidine-4-carboxamide Chemical compound C1([C@@H](CC=2C3=CC=CC=C3NC=2)NC(=O)C2CCNCC2)=NN=C(CCC=2C3=CC=CC=C3NC=2)N1CC1=CC=CC=C1 FRKGNEAURFFNKA-JGCGQSQUSA-N 0.000 claims description 3
- RHLOWCZCPRHIBS-MUUNZHRXSA-N n-[(1r)-1-[5-benzyl-4-(pyridin-2-ylmethyl)-1,2,4-triazol-3-yl]-2-(1h-indol-3-yl)ethyl]piperidine-4-carboxamide Chemical compound C=1C=CC=NC=1CN1C([C@@H](CC=2C3=CC=CC=C3NC=2)NC(=O)C2CCNCC2)=NN=C1CC1=CC=CC=C1 RHLOWCZCPRHIBS-MUUNZHRXSA-N 0.000 claims description 3
- CVUVJIZDDNCJGJ-MUUNZHRXSA-N n-[(1r)-1-[5-benzyl-4-(pyridin-2-ylmethyl)-1,2,4-triazol-3-yl]-2-(1h-indol-3-yl)ethyl]pyridine-2-carboxamide Chemical compound C=1C=CC=NC=1CN1C([C@@H](CC=2C3=CC=CC=C3NC=2)NC(=O)C=2N=CC=CC=2)=NN=C1CC1=CC=CC=C1 CVUVJIZDDNCJGJ-MUUNZHRXSA-N 0.000 claims description 3
- ACHCODWTLRKKLY-MUUNZHRXSA-N n-[(1r)-1-[5-benzyl-4-(pyridin-4-ylmethyl)-1,2,4-triazol-3-yl]-2-(1h-indol-3-yl)ethyl]pyridine-2-carboxamide Chemical compound C=1C=NC=CC=1CN1C([C@@H](CC=2C3=CC=CC=C3NC=2)NC(=O)C=2N=CC=CC=2)=NN=C1CC1=CC=CC=C1 ACHCODWTLRKKLY-MUUNZHRXSA-N 0.000 claims description 3
- OJPVUTCNFAKIOB-JGCGQSQUSA-N n-[(1r)-2-(1h-indol-3-yl)-1-[4-[(4-methoxyphenyl)methyl]-5-(2-phenylethyl)-1,2,4-triazol-3-yl]ethyl]-2-pyridin-3-ylacetamide Chemical compound C1=CC(OC)=CC=C1CN1C([C@@H](CC=2C3=CC=CC=C3NC=2)NC(=O)CC=2C=NC=CC=2)=NN=C1CCC1=CC=CC=C1 OJPVUTCNFAKIOB-JGCGQSQUSA-N 0.000 claims description 3
- PNQBZVBPSDSZJW-JGCGQSQUSA-N n-[(1r)-2-(1h-indol-3-yl)-1-[4-[(4-methoxyphenyl)methyl]-5-(2-phenylethyl)-1,2,4-triazol-3-yl]ethyl]-2-pyridin-4-ylacetamide Chemical compound C1=CC(OC)=CC=C1CN1C([C@@H](CC=2C3=CC=CC=C3NC=2)NC(=O)CC=2C=CN=CC=2)=NN=C1CCC1=CC=CC=C1 PNQBZVBPSDSZJW-JGCGQSQUSA-N 0.000 claims description 3
- MLQFNVRSAARMTA-MGBGTMOVSA-N n-[(1r)-2-(1h-indol-3-yl)-1-[4-[(4-methoxyphenyl)methyl]-5-(2-phenylethyl)-1,2,4-triazol-3-yl]ethyl]-3-pyridin-3-ylpropanamide Chemical compound C1=CC(OC)=CC=C1CN1C([C@@H](CC=2C3=CC=CC=C3NC=2)NC(=O)CCC=2C=NC=CC=2)=NN=C1CCC1=CC=CC=C1 MLQFNVRSAARMTA-MGBGTMOVSA-N 0.000 claims description 3
- QTSGXYVXJUEVSD-JGCGQSQUSA-N n-[(1r)-2-(1h-indol-3-yl)-1-[4-[(4-methoxyphenyl)methyl]-5-(2-phenylethyl)-1,2,4-triazol-3-yl]ethyl]benzamide Chemical compound C1=CC(OC)=CC=C1CN1C([C@@H](CC=2C3=CC=CC=C3NC=2)NC(=O)C=2C=CC=CC=2)=NN=C1CCC1=CC=CC=C1 QTSGXYVXJUEVSD-JGCGQSQUSA-N 0.000 claims description 3
- DKRAQXRUFKWDKN-JGCGQSQUSA-N n-[(1r)-2-(1h-indol-3-yl)-1-[4-[(4-methoxyphenyl)methyl]-5-(2-phenylethyl)-1,2,4-triazol-3-yl]ethyl]cyclohexanecarboxamide Chemical compound C1=CC(OC)=CC=C1CN1C([C@@H](CC=2C3=CC=CC=C3NC=2)NC(=O)C2CCCCC2)=NN=C1CCC1=CC=CC=C1 DKRAQXRUFKWDKN-JGCGQSQUSA-N 0.000 claims description 3
- CFLZHCPYSNNYAY-GDLZYMKVSA-N n-[(1r)-2-(1h-indol-3-yl)-1-[4-[(4-methoxyphenyl)methyl]-5-(2-phenylethyl)-1,2,4-triazol-3-yl]ethyl]pyrazine-2-carboxamide Chemical compound C1=CC(OC)=CC=C1CN1C([C@@H](CC=2C3=CC=CC=C3NC=2)NC(=O)C=2N=CC=NC=2)=NN=C1CCC1=CC=CC=C1 CFLZHCPYSNNYAY-GDLZYMKVSA-N 0.000 claims description 3
- JMSLKPFDIUWLEK-WJOKGBTCSA-N n-[(1r)-2-(1h-indol-3-yl)-1-[4-[(4-methoxyphenyl)methyl]-5-(2-phenylethyl)-1,2,4-triazol-3-yl]ethyl]pyridine-4-carboxamide Chemical compound C1=CC(OC)=CC=C1CN1C([C@@H](CC=2C3=CC=CC=C3NC=2)NC(=O)C=2C=CN=CC=2)=NN=C1CCC1=CC=CC=C1 JMSLKPFDIUWLEK-WJOKGBTCSA-N 0.000 claims description 3
- BKNPXHDCNXUZAJ-XMMPIXPASA-N n-[(1r)-2-(1h-indol-3-yl)-1-[4-methyl-5-(2-phenylethyl)-1,2,4-triazol-3-yl]ethyl]pyridine-2-carboxamide Chemical compound N=1N=C([C@@H](CC=2C3=CC=CC=C3NC=2)NC(=O)C=2N=CC=CC=2)N(C)C=1CCC1=CC=CC=C1 BKNPXHDCNXUZAJ-XMMPIXPASA-N 0.000 claims description 3
- ZCNVJJBYAGHHPB-SSEXGKCCSA-N n-[(1r)-2-(1h-indol-3-yl)-1-[4-phenyl-5-(2-phenylethyl)-1,2,4-triazol-3-yl]ethyl]-2-pyridin-2-ylacetamide Chemical compound N([C@H](CC=1C2=CC=CC=C2NC=1)C=1N(C(CCC=2C=CC=CC=2)=NN=1)C=1C=CC=CC=1)C(=O)CC1=CC=CC=N1 ZCNVJJBYAGHHPB-SSEXGKCCSA-N 0.000 claims description 3
- HTCGKPAHGQFWCF-GDLZYMKVSA-N n-[(1r)-2-(1h-indol-3-yl)-1-[4-phenyl-5-(2-phenylethyl)-1,2,4-triazol-3-yl]ethyl]piperidine-4-carboxamide Chemical compound C=1C=CC=CC=1N1C([C@@H](CC=2C3=CC=CC=C3NC=2)NC(=O)C2CCNCC2)=NN=C1CCC1=CC=CC=C1 HTCGKPAHGQFWCF-GDLZYMKVSA-N 0.000 claims description 3
- UCIBWGYYBJMBBJ-GDLZYMKVSA-N n-[(1r)-2-(1h-indol-3-yl)-1-[4-phenyl-5-(2-phenylethyl)-1,2,4-triazol-3-yl]ethyl]pyridine-2-carboxamide Chemical compound C=1C=CC=CC=1N1C([C@@H](CC=2C3=CC=CC=C3NC=2)NC(=O)C=2N=CC=CC=2)=NN=C1CCC1=CC=CC=C1 UCIBWGYYBJMBBJ-GDLZYMKVSA-N 0.000 claims description 3
- TVWIMSXDTYKRGD-MUUNZHRXSA-N n-[(1r)-2-(1h-indol-3-yl)-1-[5-(2-phenylethyl)-4-(thiophen-2-ylmethyl)-1,2,4-triazol-3-yl]ethyl]piperidine-4-carboxamide Chemical compound C=1C=CSC=1CN1C([C@@H](CC=2C3=CC=CC=C3NC=2)NC(=O)C2CCNCC2)=NN=C1CCC1=CC=CC=C1 TVWIMSXDTYKRGD-MUUNZHRXSA-N 0.000 claims description 3
- NPJGTSFJEBZQFM-UUWRZZSWSA-N n-[(1r)-2-(1h-indol-3-yl)-1-[5-[2-(1h-indol-3-yl)ethyl]-4-[(4-methoxyphenyl)methyl]-1,2,4-triazol-3-yl]ethyl]-2-pyridin-2-ylacetamide Chemical compound C1=CC(OC)=CC=C1CN1C([C@@H](CC=2C3=CC=CC=C3NC=2)NC(=O)CC=2N=CC=CC=2)=NN=C1CCC1=CNC2=CC=CC=C12 NPJGTSFJEBZQFM-UUWRZZSWSA-N 0.000 claims description 3
- FSFNTCWXZWJZBW-UUWRZZSWSA-N n-[(1r)-2-(1h-indol-3-yl)-1-[5-[2-(1h-indol-3-yl)ethyl]-4-[(4-methoxyphenyl)methyl]-1,2,4-triazol-3-yl]ethyl]-2-pyridin-4-ylacetamide Chemical compound C1=CC(OC)=CC=C1CN1C([C@@H](CC=2C3=CC=CC=C3NC=2)NC(=O)CC=2C=CN=CC=2)=NN=C1CCC1=CNC2=CC=CC=C12 FSFNTCWXZWJZBW-UUWRZZSWSA-N 0.000 claims description 3
- GQRRMXRDZHSZNL-WJOKGBTCSA-N n-[(1r)-2-(1h-indol-3-yl)-1-[5-[2-(1h-indol-3-yl)ethyl]-4-phenyl-1,2,4-triazol-3-yl]ethyl]piperidine-4-carboxamide Chemical compound C1([C@@H](CC=2C3=CC=CC=C3NC=2)NC(=O)C2CCNCC2)=NN=C(CCC=2C3=CC=CC=C3NC=2)N1C1=CC=CC=C1 GQRRMXRDZHSZNL-WJOKGBTCSA-N 0.000 claims description 3
- XUWHDHMMZZMAMW-WJOKGBTCSA-N n-[(1r)-2-(1h-indol-3-yl)-1-[5-[2-(1h-indol-3-yl)ethyl]-4-phenyl-1,2,4-triazol-3-yl]ethyl]pyridine-2-carboxamide Chemical compound C1([C@@H](CC=2C3=CC=CC=C3NC=2)NC(=O)C=2N=CC=CC=2)=NN=C(CCC=2C3=CC=CC=C3NC=2)N1C1=CC=CC=C1 XUWHDHMMZZMAMW-WJOKGBTCSA-N 0.000 claims description 3
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- LPOIGVZLNWEGJG-UHFFFAOYSA-N n-benzyl-5-(4-methylpiperazin-1-yl)-2-nitroaniline Chemical compound C1CN(C)CCN1C1=CC=C([N+]([O-])=O)C(NCC=2C=CC=CC=2)=C1 LPOIGVZLNWEGJG-UHFFFAOYSA-N 0.000 claims description 3
- IOMMMLWIABWRKL-WUTDNEBXSA-N nazartinib Chemical compound C1N(C(=O)/C=C/CN(C)C)CCCC[C@H]1N1C2=C(Cl)C=CC=C2N=C1NC(=O)C1=CC=NC(C)=C1 IOMMMLWIABWRKL-WUTDNEBXSA-N 0.000 claims description 3
- PIDFDZJZLOTZTM-KHVQSSSXSA-N ombitasvir Chemical compound COC(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@H]1C(=O)NC1=CC=C([C@H]2N([C@@H](CC2)C=2C=CC(NC(=O)[C@H]3N(CCC3)C(=O)[C@@H](NC(=O)OC)C(C)C)=CC=2)C=2C=CC(=CC=2)C(C)(C)C)C=C1 PIDFDZJZLOTZTM-KHVQSSSXSA-N 0.000 claims description 3
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- KSAVQLQVUXSOCR-UHFFFAOYSA-M sodium lauroyl sarcosinate Chemical compound [Na+].CCCCCCCCCCCC(=O)N(C)CC([O-])=O KSAVQLQVUXSOCR-UHFFFAOYSA-M 0.000 claims description 3
- 239000004480 active ingredient Substances 0.000 claims description 2
- OMBVEVHRIQULKW-DNQXCXABSA-M (3r,5r)-7-[3-(4-fluorophenyl)-8-oxo-7-phenyl-1-propan-2-yl-5,6-dihydro-4h-pyrrolo[2,3-c]azepin-2-yl]-3,5-dihydroxyheptanoate Chemical compound O=C1C=2N(C(C)C)C(CC[C@@H](O)C[C@@H](O)CC([O-])=O)=C(C=3C=CC(F)=CC=3)C=2CCCN1C1=CC=CC=C1 OMBVEVHRIQULKW-DNQXCXABSA-M 0.000 claims 2
- MHSLDASSAFCCDO-UHFFFAOYSA-N 1-(5-tert-butyl-2-methylpyrazol-3-yl)-3-(4-pyridin-4-yloxyphenyl)urea Chemical compound CN1N=C(C(C)(C)C)C=C1NC(=O)NC(C=C1)=CC=C1OC1=CC=NC=C1 MHSLDASSAFCCDO-UHFFFAOYSA-N 0.000 claims 2
- NPRYCHLHHVWLQZ-TURQNECASA-N 2-amino-9-[(2R,3S,4S,5R)-4-fluoro-3-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-7-prop-2-ynylpurin-8-one Chemical compound NC1=NC=C2N(C(N(C2=N1)[C@@H]1O[C@@H]([C@H]([C@H]1O)F)CO)=O)CC#C NPRYCHLHHVWLQZ-TURQNECASA-N 0.000 claims 2
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Abstract
Foreliggende oppfinnelse tilveiebringer nye triazolderivater som grelinanalogligander til veksthorrnonutskillende reseptorer med formel (I) som anvendes ved behandling eller profylakse av fysiologiske og/eller patofysiologiske tilstander hos pattedyr, foretrukket mennesker, som medieres av GHS-reseptorer. Foreliggende oppfinnelse tilveiebringer videre GHS-reseptorantagonister og agonister som kan anvendes for modulering av disse reseptorene og er anvendelige for behandling av tilstandene ovenfor, særlig vekstretardasjon, kakeksi, kort-, middels- og/eller langtidsregulering av energibalanse, kort-, middels- og/eller langtidsregulering (stimulering og/eller inhibering) av matinntak, adipogenese, adipositet og/eller fedme; kroppsvektøkning og/eller reduksjon; diabetes, diabetes type I, diabetes type II, tumorcelleproliferasjon, inflammasjon, inflammatoriske effekter, gastrisk postoperativ ileus, postoperativ ileus og/eller gastrektomi (ghrelinerstatningsbehandling).
Description
Nye triazolderivater som ghrelinanalogligander av veksthormonutskillende reseptorer, anvendelse derav og farmasøytiske sammensetninger som inneholder slike.
Foreliggende oppfinnelse angår nye triazolderivater som virker som ghrelinanalogligander av veksthormonutskillende reseptorer. Disse forbindelsene er anvendelige ved modulering av veksthormonplasmanivåer hos pattedyr så vel som ved behandling og/eller regulering av forskjellige fysiologiske og patofysiologiske tilstander, slik som vekstretardasjon, fedme, matinntak, energibalanse, tumorcelleproliferasjon, sår/brannskadehelbredning, metabolske forstyrrelser og inflammasjon.
Ghrelin, et 28 aminosyrepeptid med en unik oktanoylmodifikasjon på Ser-3 (Kojima M et al., Nature 1999, 402: 656-660), ble identifisert som en endogen ligand for veksthormonutskillende reseptortype 1a (GHS-R 1a), en G-proteinkoblet reseptor (Howard AD et al., Science 1996, 273: 974-977). Ghrelin blir først og fremst produsert i øvre intestinaltrakt/mage, men mindre mengder ble også detektert i tarm, bukspyttkjertel, nyre, immunsystem, placenta, testikler, hypofyse, lunge og i hypotalamus (van der Lely AJ et al., Endocrine Rev. 2004, 25: 426-457; Cowley M et al., Neuron 2003, 37: 649-661).
Hos mennesker stimulerer ghrelin vekthormon (GH) via en reaksjonsvei uavhengig av GHRH-reseptoren og i synergi med GHRH ved GH-sekresjon (Arvat E et al., J. Clin. Endocrinol. Metab.2001, 86: 1169-1174). I tillegg stimulerer den også ACTH, prolaktin-, kortisol-, aldosteron- og epinefrinsekresjon (Arvat E et al., J. Clin.
Endocrinol. Metab.2001, 86: 1169-1174; Nagaya N et al., Am. J. Physiol. Regul.
Integr. Comp. Physiol.2001, 280: R1483-1487; Takaya K et al., J. Clin. Endocrinol. Metab. 2000, 85: 4908-4911).
Ghrelin antas å delta i metabolismeregulering og energiforbruk, slik at ghrelinekspresjon og sekresjon inn i generell sirkulasjon fra magen forventes å være influert av metabolske hormoner. Hos mennesker rammet av fedme blir plasmaghelinnivåer redusert, som viser at hevede insulin- og leptinnivåer hos subjekter rammet av fedme, reduserer ghrelinsekresjon (Tschop M et al, Diabetes 2001, 50: 707-709).
Frigivelse av veksthormon hos mennesker og dyr antas å behandle fysiologiske eller patofysiologiske tilstander kjennetegnet ved en svekkelse i veksthormonsekresjon så vel som å behandle disse tilstandene som forbedres ved de anabolske effektene til vekthormon.
Initielt ble kliniske anvendelser med GH begrenset til behandling av barn med for lavt GH, men kommersialisering av rekombinant humant veksthormon (rhGH) muliggjorde mange studier som viste andre potensielle, kliniske anvendelser av GH (Strobl JS et al., Pharmacol. Rev. 1994, 46: 1-34; Torosian MH, J. Pediatr. Endocrinol.1993, 6: 93-97). rhGH har vist seg lovende ved behandling av pasienter med brannskader, sår, beinfrakturer og mer nylig når det gjelder å reversere katabolske effekter av glukokortikoider, kjemoterapi og AIDS, så vel som å modifisere kroppssammensetning (Rudman D et al., N. Engl. J. Med.1990, 323:1-6; Papadakis MA et al., Ann. Intern. Med. 1996,124: 708-716; Welle S et al., J. Clin. Endocrinol. Metab.1996, 81: 3239-3243).
GH, syntetisert og lagret i hypofysekjertelen, frigis under kontroll av to kjente hypotalmiske hormoner: veksthormonfrigivende hormon (GHRH) og det inhiberende hormonet somatostatin (SRIF). I de fleste tilfeller er GH-underskudd relatert til en hypotalmisk defekt og ikke til et bukspyttkjertelunderskudd i GH. Derfor, som en alternativ behandling for rhGH, kan GH-underskuddspasienter også behandles med en hvilken som helst forbindelsesom frigir endogen GH fra hypofysekjertelen. Dette kan enten utføres med GHRH som stimulerer GH-frigivelse, men også med syntetisk veksthormonutskillende forbindelser (GHS).
Mange syntetiske peptidyl- og ikke-peptidyl GHS, slik som GHRP-er 1, 2 og 6, heksarelin, MK-0677, EP-01572, er vist spesifikt å binde til orfanreseptoren "GHS-reseptor", flere av dem lenge før ghrelin og ghrelin/GHS-reseptoren ble funnet (se "Camanni F et al., Front Neuroendocrinol.1998, 19: 47-72"; "Casanueva FF et al., Trends Endocrinol. Metab.1999, 10: 30-38"; "van der Lely AJ et al., Endocrine Rev.
2004, 25: 426-457" for ytterligere referanse). GHS har vist potent GH-frigivende virkning og har de samme biologiske aktivitetene som er nevnt ovenfor for ghrelin.
GHS ble også beskrevet i følgende patenter eller patentsøknader (ikke uttømmende liste): US 6071 926, US 6329 342, US 6 194 578, US 2001/0041673,
US 6251 902, US 2001/0020012, US 2002/0013320, US 2002/0002137,
WO 95/14666, WO 96/15148, WO 01/96300.
Mens ghrelin/GHS-indusert GH-sekresjon medieres ved aktiveringen av ghrelin/GHS-reseptortype 1a (GHS-R 1a), er det bevis så langt for at i det minste noen andre effekter av ghrelin og GHS også medieres ved forskjellige reseptorer i GHS-reseptorfamilien eller til og med forskjellige bindingsseter på en gitt GHS-reseptor.
GHS-reseptorer er konsentrert i hypotalamus-hypofyseområdet, men synes også å være fordelt i andre sentrale og periferale vev (Hattori N et al., J. Clin. Endocrinol. Metab. 2001, 86: 4284-4291; Gnanapavan S et al., J. Clin. Endocrinol. Metab.2002, 87: 2988-2991; Muccioli G et al., J. Endocrinol.2000, 157: 99-106; Muccioli G et al., Ann.
Endocrinol. 2000, 61: 27-31; Muccioli G et al., Eur. J. Pharmacol.2002, 440: 235-254; Papotti M et al., J. Clin. Endocrinol. Metab.2000, 85: 3803-3807; Cassoni P et al., J. Clin. Endocrinol. Metab.2001, 86: 1738-1745; Guan XM et al., Brain Res. Mol. Brain Res. 1997, 48: 23-29; Bluet-Pajot MT et al., Endocrine 2001, 14: 1-8; Korbonits M et al., J. Clin. Endocrinol. Metab.1998, 83: 3624-3630).
To GHS-type 1 reseptorer har blitt identifisert, GHS-R1a og GHS-R 1b,som hos mennesker trolig uttrykkes med et enkelt gen og alternativt spleises (van der Lely AJ et al., Endocrine Rev.2004, 25: 426-457; Howard AD et al., Science 1996, 273: 974-977; Smith RG et al., Endocr. Rev.1997, 18: 621-645; Smith RG et al., Endocrine 2001, 14: 9-14; McKee KK et al., Mol. Endocrinol.1997, 11: 415-423; Petersenn S, Minerva Endocrinol. 2002; 27: 243-256). Blant pattedyrarter har høy grad av sekvensidentitet blitt rapportert for GHS-R 1a (Petersenn S, Minerva Endocrinol.2002; 27: 243-256: mellom 91,8 % og 95,6 %).
Motilinreseptor ble funnet som medlem av GHS-reseptorfamilien som har 52 % identitet (Smith RG et al., Endocrine 2001, 14: 9-14; McKee KK et al., Genomics 1997, 46: 426-434). Gastrointestinal motilinreseptor 1a og GHS-R 1a viser høy likhet (Smith RG et al., Endocrine 2001, 14: 9-14; Feighner SD et al., Science 1999, 284: 2184-2188).
Andre GHS-reseptorfamiliemedlemmer synes å være neurotensinreseptor, TRH-reseptor, GPR38 (FM1), GPR39 (FM2) og FM3 (Smith RG et al., Endocr. Rev.1997, 18: 621-645;; Smith RG et al., Horm. Res.1999, 51 (Suppl.3): 1-8; Tan CP et al., Genomics 1998, 52: 223-229; Howard AD et al., Science 1996, 273: 974-977). Videre GHS-reseptorundertyper synes å eksistere i et stort spekter av sentrale og periferale vev (van der Lely AJ et al., Endocrine Rev.2004, 25: 426-457). For eksempel har en hjerte-GHS-R blitt rapportert (Bodart V et al., Circ. Res.1999, 85: 796-802) med en predikert sekvens tilsvarende den til CD36, en multifunksjonell reseptor kjent som glykoprotein IV (Bodart V et al., Circ. Res.2002, 90: 844-849). Cassoni et al. (J. Clin. Endocrinol. Metab. 2001, 86: 1738-1745) rapporterte eksistensen av GHS-R-undertyper i neoplastiske brystceller som aktiveres av ligander som binder til spesifikke bindingsseter forskjellig fra den klassiske GHS-R-type 1. Videre støtter data generert av disse forfatterne, hypotesen om at selv forskjellige bindingsseteundertyper eksisterer for GHS-R i periferale organer som trolig er på grunn av deres endokrine eller ikke-endokrine, men også deres normale eller neoplastiske, natur.
Allestedsnærværenheten av GHS-bindingsseter forklarer at, uavhengig av deres sterke veksthormonutskillende egenskaper, er ghrelin, så vel som syntetisk GHS, implisert i flere viktige fysiologiske og patofysiologiske tilstander.
Følgelig inkluderer potensielle, kliniske anvendelser blant annet
a) Kort-, middels- og langtidsregulering av energibalanse og/eller matinntak (Tschop M et al., Nature 2000, 407: 908-913; Asakawa A et al., Gut 2003, 52: 947-952; US 2001/0020012; Kojima M et al., Curr. Opin. Pharmacol. 2002, 2: 665-668; Horvath TL et al., Curr. Pharm. Des.2003, 9: 1383-1395; Wren AM et al., J. Clin. Endocrinol. Metab. 2001, 86: 5992-5995).
Ekspresjon av GHS-R1a har vist seg på neuroner til hypotalamusparaventrikulære kjerner. Disse neuronene sender referenter til nøkkel hypotalmiske kretser for kontroll av matinntak, som arkuatkjernen som produserer mediatoren NPY. Det antas at stimuleringen av matinntak ved ghrelin og/eller GHS medieres av en økning av NPY i arkuatkjernen (Willesen MG et al., Neuroendocrin.1999, 70: 306-316). Enkel administrasjon (icv eller ip) av anti-ghrelin IgG undertrykket akutt mating hos magre rotter (Bagnasco M et al., Regul. Pept.2003, 111: 161-167). Kronisk, to ganger daglig icv-administrasjon av anti-ghrelin IgGreduserte kroppsvekt over en femdagers periode (Murakami N et al., J. Endocrinol.2002, 174: 283-288).
En nylig studie som anvender en peptid GHS-R 1a-antagonist, [D-Lys-3]-GHRP-6, viser en reduksjon av matinntak og kroppsvektøkning hos diettinduserte mus med fedme (Asakawa A et al., Gut, 2003, 52: 947-952). Faktumet at peptidylforbindelser, initielt karakterisert som veksthormonutskillende forbindelser, er i stand til å stimulere selektivt matinntak hos rotter uten å indusere veksthormonsekresjon, viser eksistensen av en GHS-R-undertype forskjellig fra GHS-R1ai hypotalamus (Torsello A et al., Neuroendocrin.2000, 72: 327-332; Torsello A et al., Eur. J. Pharmacol.1998, 360: 123-129).
b) Behandling av adipogenese, adipositet og/eller fedme og reduksjon av kroppsvekt (Tschop M et al., Nature 2000, 407: 908-913; Asakawa A et al., Gut 2003, 52: 947-952).
Kronisk administrasjon av ghrelin og/eller GHS hos frittmatende mus og rotter resulterer i økt kroppsvekt og redusert fettanvendelse (Tschop M et al., Nature 2000, 407: 908-913). Videre har det blitt rapportert at ghrelin og des-oktanoylghrelin fremmer adipogenese in vivo (Thompson NM et al., Endocrinol.2004, 145: 234-242) og inhiberer isoproterenolindusert lipolyse i rotteadipocytter via en ikke-type GHS-R 1a (Muccioli G et al., Eur. J. Pharmacol.2004, 498: 27-35). På den annen side er det også en rapport som beskriver at ekspresjonen av GHS-R1a i rotteadipocytter øker med alderen og i løpet av adipogenese (Choi K et al., Endocrinol. 2003, 144, 754-759).
c) Behandling av tumorcelleproliferasjon
Som tilfellet er for andre medlemmer av hypotalmus-hypofyseaksen som regulerer sekresjon av veksthormon, er det i økende grad bevis for å indikere at ghrelin og GHS-reseptorer kan spille en viktig autokrin/parakrin rolle i noen kreftformer (Jeffery PL et al., Cytokine Growth Factor Rev. 2003, 14:113-122). Spesifikke bindingsseter for ghrelin, peptidyl- og ikke-peptidyl-GHS er til stede i tumorvev som prostatakreftcellelinjen PC3 (Jeffery PL et al., J. Endocrinology 2002, 172: R7-R11), tyroidvev (Cassoni P et al., J. Endocrinol.2000, 165: 139-146), lungekarsinomceller CALU-1 (Ghè C et al., Endocrinol.2002, 143: 484-491) og brystkarsinomer (Cassoni P et al., J. Clin. Endocrinol. Metab.2001, 86: 1738-1745).
I tilfellet bryst ble spesifikke bindingsseter for GHS funnet i tumoralt vev mens det normale brystparenchym avdekket ingen slike reseptorer. Syntetisk GHS har blitt rapportert å inhibere proliferasjon av lungekarsinomceller CALU-1 (Ghè C et al., Endocrinol. 2002, 143: 484-491) og den til brystkarsinomcellelinjer (Cassoni P et al., J. Clin. Endocrinol. Metab.2001, 86: 1738-1745).
Både ghrelin og ikke-acylert ghrelin binder til tumoralt vev. På grunn av ikkeacylert ghrelin er ute av stand til å binde GHS-R1a, er det trolig at bindingssetet til GHS til tumoralt vev er forskjellig fra GHS-R1a. Fra disse data kan man anta at bindingssetet i tumoralt vev gjenkjenner ligander til GHS-R1a og i tillegg andre ennå ikke karakteriserte, kjemiske strukturer. Syntetiske ligander til GHS-R1a kan derfor ha potensialet til å inhibere proliferasjon av tumorceller som uttrykker undertyper av GHS-reseptorer.
d) Behandling av inflammasjon/antiinflammatoriske effekter
Den antiinflammatoriske effekten til ghrelinagonistvekstfaktorfrigivende peptid-2 (GHRP-2) ved kronisk artritt med kliniske manifestasjoner av hypermetabolisme og kakeksi ble demonstrert (Granado M et al., Am. J. Physiol. Endocrinol. Metab.
2005, 288: E486-492). Disse data viser at den antiinflammatoriske virkningen til GHRP-2 medieres ved aktivering av ghrelinreseptorer uttrykt ved immunkompetente celler.
e) Behandling av kakeksi
Antikakeksieffekten ved administrering av rekombinant veksthormon i en dyremodell for kakeksi (Roubenoff R et al., Arthritis Rheum. 1997, 40(3): 534-539) kan demonstreres (Ibanez de Caceres I et al., J. Endocrin.2000, 165(3): 537-544). Funnene er også i tråd med data for pasienter med reumatoid artritt (Roubenoff R et al., J Clin Invest.1994, 93(6): 2379-2386).
f) Behandling av gastrektomi (ghrelinerstatningsbehandling)
Gastrisk hormonghrelin ble gitt til mus gjort til gjenstand for gastrektomi eller narreoperasjon (Dornonville de la Cour C et al., Gut 2005, 54(7): 907-913).
Resultatene som er presentert, viser at ghrelinerstatningsbehandling kan i det minste delvis reversere gastrektomiindusert reduksjon i kroppsvekt og kroppsfett.
g) Behandling av (gastrisk) postoperativ ileus
Effekten av ghrelin på motorisk funksjon i gastrointestinaltrakten hos rotte ble evaluert. Det kan vises at ghrelin reverserer den forsinkede gastriske evakuasjonen og er et sterkt prokinetisk middel anvendelig for behandling/reversering av postoperativ gastrisk ileus (Trudel L et al., Am J Physiol Gastrointest Liver Physiol 2002, 282(6): G948-G952).
h) Behandling av diabetes (diabetes type I og diabetes type II)
Effekten av ablasjon av ghrelin hos leptinunderskuddsmus ble studert (Sun et al., Cell Metabolism 2006, 3: 379-386). Resultatene viser at fjerning av ghrelin øker insulinsekresjon som respons på glukoseutfordring som indikerer at inhibering av ghrelin eller motvirkning av dens aktivitet, kan være en positiv måte for behandling av diabetes som inkluderer dens undertyper I og II (se også
WO 03/051389).
Ytterligere anvendelsesområder innbefatter akselerering av friskgjøring av pasienter som har gjennomgått større kirurgi (for eksempel US 6194 578); akselerering av friskgjøring av brannskadepasienter (for eksempel US 6194 578); attenuering av proteinkatabolsk respons etter større operasjon (for eksempel US 6194 578); redusert kakeksi og proteintap på grunn av akutt eller kronisk sykdom (for eksempel US
6 194 578); behandling av sentralnervesystemforstyrrelser hos pasienter som gjennomgår et medisinsk inngrep i kombinasjon med antidepressive midler (for eksempel US 2002/0002137 A1); akselerasjon av beinfrakturreparering og bruskvekst (for eksempel US 6194 578); behandling eller hindring av osteoporose; stimulering av immunsystem; akselerert sårhelbredning (for eksempel US 6194 578); behandling av vekstretardasjon assosiert med Prader-Willi-syndromet, Turners syndrom og fedme; behandling av intrauterinvekstretardasjon, skjellettdysplasi, hyperkortisolisme og Cushings syndrom; behandling av osteokondrodysplasier, Noonans syndrom, schizofreni, depresjoner og Alzheimers sykdom; behandling av lungedysfunksjon og ventilatoravhengighet, behandling av hyperinsulinemiindusert nesidioblastosi; adjuvansbehandling for ovalusjonsinduksjon; hindring av aldersrelatert svekkelse av tymisk funksjon; forbedring i muskelstyrke og mobilitet (for eksempel US 6194 578); opprettholdelse av hudtykkelse (for eksempel US 6194 578); forbedring av søvnkvalitet (for eksempel US 6071 926); hindring av kongestiv hjertesvikt alene (for eksempel US 6 329 342; US 6194 578) og i kombinasjon med kortikotropinfrigjørende faktorantagonister (for eksempel US 2001/0041673); metabolsk homeostasi eller renal homeostasi (for eksempel hos skrøpelige eldre (for eksempel US 6194 578); forbedring av glykemisk kontroll (for eksempel US 6251 902); behandling av systemisk lupus erytematose og inflammatorisk tarmsykdom (for eksempel US 2002/0013320); behandling eller hindring av skralhet assosiert med aldring eller fedme (for eksempel US 6194 578); så vel som stimulering av osteoblaster.
Dyr er ikke glemt når det gjelder potensielle anvendelser slik som stimulering av matinntak (Wren AM et al., Diabetes 2001, 50: 2540-2547), stimulering av immunsystem hos ledsagerdyr og behandling av forstyrrelser med aldring, vekstfremmelse hos buskap og stimulering av ullvekst hos sauer.
Forbindelsene som inneholder triazolbestanddeler, har i stor grad blitt anerkjent innen medisinsk kjemi på grunn av deres forskjellige, biologiske aktiviteter. Følgende patentfamilier er alle rettet mot heterosykliske forbindelser som hevdes å vise visse biologiske virkninger for anvendelse ved forskjellige medisinske indikasjoner. Triazolbestanddeler er implisitt eller eksplisitt innbefattet. Imidlertid nevner ingen av disse patentfamiliene ghrelinanalogligander av GHS-reseptorfamilien og heller ikke modulering av disse reseptorene og heller ikke GH-utskillende egenskaper eller lignende.
WO 2004/111015 beskriver modulatorer av glukokortikoidreseptoren.
WO 2004/052280 beskriver antiangiogene forbindelser som inhibitorer av tyrosinkinaseaktivitet til VEGF-reseptorer og deres anvendelse ved kreft. WO 2004/096795 beskriver også tyrosinkinaseinhibitorer, foretrukket C-FMS-inhibitorer. WO 03/011831 og WO 03/011210 beskriver begge heteroarylheteroalkylaminderivater som inhibitorer av nitrogenoksidsyntase. WO 02/00651 angår faktor XA-inhibitorer for anvendelse i tromboemboliske forstyrrelser. WO 01/94318 og WO 01/94317 beskriver begge kjemiske biblioteker avsubstituerte azolderivater og fremgangsmåter for deres syntese for anvendelse ved legemiddelutforskning i høygjennomstrømningsscreeninger.
Imidlertid tilveiebringer de ikke en biologisk aktivitet eller noen medisinsk anvendelse og heller ikke navngir de spesifikke forbindelser. WO 00/76971 og WO 00/76970 beskriver begge serinproteaseinhibitorer anvendelige som antitrombotiske midler. WO 01/36395 beskriver triazolderivater som farnesyltransferaseinhibitorer. WO 96/33176 og US 5703 092 beskriver hydroksaminsyreforbindelser som metalloprotease og TNF-inhibitorer. WO 93/09095 beskriver 2-heterosykliske etylaminderivater for deres anvendelse ved neurologiske og neurodegenerative forstyrrelser. WO 2004/103270 beskriver forbindelser for behandling av trombose, særlig faktor XIa-inhibitorer. WO 98/38177, US 6506 782, US 6849 650 og US 2003/0130188 beskriver alle heterosykliske forbindelser som inhibitorer av beta-amyloidpeptidfrigivelse eller deres syntese for anvendelse ved Alzheimers sykdom.
Heterosykliske forbindelser som kan være anvendelige som GHS, har også blitt beskrevet i litteraturen.
WO 00/54729 beskriver for eksempel heterosykliske, aromatiske forbindelser som GH-utskillende forbindelser som sies å stimulere endogen produksjon og/eller frigivelse av GH og kan også inneholde triazolbestanddeler. I tillegg er en fremgangsmåte for å øke nivået av endogen GH eller øke endogen produksjon eller frigivelse av GH ved administrering av slike GHS, beskrevet. Videre er en fremgangsmåte tilveiebrakt for hindring eller behandling av osteoporose (forbedring av beintetthet og/eller styrke) eller behandling av fedme eller for å øke muskelmasse og/eller muskelstyrke og funksjon hos eldre mennesker eller reversering eller hindring av skrøpelighet hos eldre mennesker ved administrering av slike GHS.
Imidlertid, selv om in vivo-GH-frigivelse er beskrevet i WO 00/54729 er det ikke bevist slik effekt. Heller ikke in vitro- eller in vivo-data er innbefattet som demonstrerer noen stimulering av eller økning i endogen produksjon og/eller frigivelse av GH.
I tillegg beskriver WO 00/54729 ikke og viser ikke virkningen til de angitte forbindelsene ovenfor noe biologisk mål, det vil si forbindelsene ifølge oppfinnelsen er ikke vist/beskrevet å være ligander av én eller flere spesifikke reseptorer, for eksempel av en reseptorfamilie som binder til dem og modulerer deres aktivitet.
I tillegg beskriver WO 00/54729 ikke og demonstrer ikke inhiberings- og/eller antagonistisk aktivitet for forbindelsene ifølge oppfinnelsen. Som et faktum er slike forbindelser ikke vist å redusere nivåer av endogent GH og/eller inhibere eller redusere endogen produksjon og/eller frigivelse av GH. Heller ikke er en inhiberende virkning på en hvilken som helst protektor nevnt eller gjort nærliggende.
US 6525 203, US 6518 292, US 6660 760 er medlemmer av samme patentfamilie som WO 00/54729 som imidlertid ikke innbefatter triazolbestanddeler lenger som søknadsgjenstand. Med hensyn til biologisk aktivitet gjelder samme fakta som for WO 00/54729.
WO 2004/021984 beskriver heterosykliske, aromatiske forbindelser som GH-utskillende forbindelser som sies å være anvendelige ved stimulering av endogen produksjon eller frigivelse av GH. Imidlertid består de angitte forbindelsene av bi- eller tetrasykliske, aromatiske ringer og inneholder ikke triazoler.
Analogt med WO 00/54729 beskrives in vivo GH-frigivelse, men verken in vitro- eller in vivo-data er innbefattet som demonstrerer noen stimulering av eller økning i endogen produksjon og/eller frigivelse av GH. Med hensyn til biologisk aktivitet gjelder de samme faktaene som for WO 00/54729.
WO 97/23508 beskriver forbindelser av peptidetterlignende natur som GHS, og sies å virke direkte på hypofyseceller in vitro for å frigi GH derfra og viser forbedrede egenskaper, slik som forbedret resistens ovenfor proteolytisk nedbryting og forbedret biotilgjengelighet. I tillegg kan de angitte forbindelsene også administreres in vivo for å øke GH-frigivelse. Forbindelsene er peptidderivater og inneholder ikke eksplisitt triazolbestanddeler.
Imidlertid, én gang til og analogt med ovenfor angitte WO 00/54729 og
WO 2004/021984, fremviser WO 97/23508 ingen in vitro- eller in vivo-data som demonstrerer de angitte effektene slik som rettet virkning på hypofyseceller, GH-frigivelse derfra og forbedrede egenskaper. Videre med hensyn til biologiske mål og inhiberende/antagonistisk aktivitet, gjelder de ovenfor angitte faktaene som for WO 00/54729.
US 6127 391, US 5977 178 og US 6555 570 er medlemmer av samme patentfamilie som WO 97/23508. Faktaene angitt for WO 97/23508 gjelder.
Foreliggende oppfinnelse har som formål å tilveiebringe nye forbindelser som kan anvendes for behandling av fysiologiske og/eller patofysiologiske tilstander hos pattedyr, særlig mennesker, som medieres av GHS-reseptorer. Det er et annet formål ved foreliggende oppfinnelse å tilveiebringe forbindelser for den ovenfor angitte behandlingen hvor behandlingen oppnås ved modulering av GHS-reseptorer. Et ytterligere formål med foreliggende oppfinnelse er å tilveiebringe antagonister av GHS-reseptorer for de behandlingene. Det er et ytterligere formål med foreliggende oppfinnelse å tilveiebringe agonister av GHS-reseptorer for disse behandlinger.
Formålet med foreliggende oppfinnelse har overraskende blitt oppnådd i ett aspekt ved å tilveiebringe anvendelse av en forbindelse valgt fra gruppen som består av forbindelse 1-190 nedenfor, for fremstilling av et medikament for behandling eller profylakse av fysiologiske og/eller patofysiologiske tilstander valgt fra gruppen som består av a)”kort-, middels- og/eller langtidsregulering av energibalanse, kort-, middelsog/eller langtidsregulering (stimulering og/eller inhibering) av matinntak, behandling av adipogenese, adipositet, kroppsvektøkning og/eller reduksjon” hos pattedyr som medieres av GHS-reseptorer, hvor behandlingen oppnås ved modulering av GHS-reseptorer og hvor forbindelsen er en GHS reseptor antagonist; eller
b) ”vekstretardasjon, kakeksi, inflammasjon, inflammatoriske effekter, gastrisk postoperativ ileus, postoperativ ileus og/eller gastrektomi (ghrelinerstatningsbehandling)” hos pattedyr som medieres av GHS-reseptorer, hvor behandlingen oppnås ved en GHS-reseptorer agonist.
I et ytterligere aspekt har formålet med foreliggende oppfinnelse overraskende blitt oppnådd ved å tilveiebringe nye triazolforbindelser valgt fra gruppen som består av:
forbindelse 1 (R)-N-(1-(5-(2-(1H-indol-3-yl)etyl)-4-(2,4-dimetoksybenzyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid,
forbindelse 2 (R)-N-(1-(5-(2-(1H-indol-3-yl)etyl)-4-fenetyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid,
forbindelse 3 (R)-N-(1-(5-(3-(1H-indol-3-yl)propyl)-4-fenetyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid,
forbindelse 4 (R)-N-(1-(5-benzyl-4-(naftalen-1-ylmetyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid,
forbindelse 5 (R)-N-(1-(5-(2-(1H-indol-3-yl)etyl)-4(naftalen-1-ylmetyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid,
forbindelse 6 (R)-N-(1-(5-(2-(1H-indol-3-yl)etyl)-4-(3-metoksybenzyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid,
forbindelse 7 (R)-N-(1-(4-(3-metoksybenzyl)-5-benzyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid,
forbindelse 8 (R)-N-(1-(5-(2-(1H-indol-3-yl)etyl)-4-benzyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid,
forbindelse 9 (R)-N-(1-(5-(3-(1H-indol-3-yl)propyl)-4-benzyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid,
forbindelse 10 (R)-N-(1-(5-(3-(1H-indol-3-yl)propyl}-4-(3-metoksybenzyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid,
forbindelse 11 (R)-N-(1-(5-(3-(1H-indol-3-yl)propyl)-4-(naftalen-1-ylmetyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid,
forbindelse 12 (R)-N-(1-(5-(2-(1H-indol-3-yl)etyl)-4-(4-metoksybenzyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid,
forbindelse 13 (R)-N-(1-(4-(4-metoksybenzyl)-5-benzyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid,
forbindelse 14 (R)-N-(1-(5-(3-(1H-indol-3-yl)propyl)-4-(4-brombenzyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid,
forbindelse 15 (R)-N-(1-(5-(2-(1H-indol-3-yl)etyl)-4-heksyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid,
forbindelse 16 (R)-N-(1-(5-(3-(1H-indol-3-yl)propyl)-4-heksyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid,
forbindelse 17 (R)-N-(1-(4,5-bis-(2-(1H-indol-3-yl)etyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid,
forbindelse 18 (S)-N-(1-(5-(2-(1H-indol-3-yl)etyl)-4-(2,4-dimetoksybenzyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid,
forbindelse 19 (R)-N-(1-(4-(3-metoksybenzyl)-5-fenetyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid,
forbindelse 20 (R)-N-(1-(4-(4-metoksybenzyl)-5-fenetyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid,
forbindelse 21 (R)-N-(1-(5-(2-(1H-indol-3-yl)etyl)-4-(3,5-dimetoksybenzyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid,
forbindelse 22 (R)-N-(1-(4-(4-metoksybenzyl)-5-(3-fenylpropyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid,
forbindelse 23 (R)-N-(1-(5-(3-(1H-indol-3-yl)propyl)-4-(4-metoksybenzyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid,
forbindelse 24 (R)-N-(1-(4-(2-(1H-indol-3-yl)etyl)-5-(3-(1H-indol-3-yl)propyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid,
forbindelse 25 (R)-N-(1-(5-(2-(1H-indol-3-yl)etyl)-4-(2-metoksy)benzyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid,
forbindelse 26 (R)-N-(1-(4-(2-metoksybenzyl)-5-fenetyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid,
forbindelse 27 (R)-N-(2-(1H-indol-3-yl)-1-(4-(naftalen-1-ylmetyl)-5-fenetyl-4H-1,2,4-triazol-3-yl)etyl)-2-amino-2-metylpropanamid,
forbindelse 28 (R)-N-(1-(5-(2-(1H-indol-3-yl)etyl)-4-(3,4-diklorbenzyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid,
forbindelse 29 (R)-N-(1-(5-(2-(1H-indol-3-yl)etyl)-4-(4-fluorbenzyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid,
forbindelse 30 (R)-N-(1-(4-(4-fluorbenzyl)-5-benzyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid,
forbindelse 31 (R)-N-(1-(5-(2-(1H-indol-3-yl)etyl)-4-(2,4-dimetoksybenzyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)piperidin-4-karboksamid,
forbindelse 32 (R)-N-(1-(5-(2-(1H-indol-3-yl)etyl)-4-(2,4-dimetoksybenzyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)piperidin-3-karboksamid,
forbindelse 33 (R)-N-(1-(4-(4-metylbenzyl)-5-(3-fenylpropyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid,
forbindelse 34 (R)-N-(1-(5-(2-(1H-indol-3-yl)etyl)-4-(4-metylbenzyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid,
forbindelse 36 (R)-N-(1-(5-(2-(1H-indol-3-yl)etyl)-4-(2,4-dimetoksybenzyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)piperidin-2-karboksamid,
forbindelse 37 (R)-N-(1-(4-(4-metylbenzyl)-5-fenetyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid,
forbindelse 38 (R)-N-(1-(5-(2-(1H-indol-3-yl)etyl)-4-(2,4-dimetoksybenzyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-aminobenzamid,
forbindelse 39 (R)-N-(1-(5-benzyl-4-(pyndin-2-ylmetyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid,
forbindelse 40 (2S,4R)-N((R)-1-(4-(4-metoksybenzyl)-5-fenetyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-4-hydroksypyrrolidin-2-karboksamid,
forbindelse 41 (S)-N-((R)-1-(4-(4-metoksybenzyl)-5-fenyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)piperidin-3-karboksamid,
forbindelse 42 (R)-N-((R)-1-(4-(4-metoksybenzyl)-5-fenetyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)piperidin-3-karboksamid,
forbindelse 43 (R)-N-(1-(4-(4-etylbenzyl)-5-fenetyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid,
forbindelse 44 (R)-N-(1-(4-(4-metoksybenzyl)-5-fenetyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)piperidin-4-karboksamid,
forbindelse 45 (R)-N-(1-(5-(2-(1H-indol-3-yl)etyl)-4-(4-metoksybenzyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)piperidin-4-karboksamid,
forbindelse 46 (S)-N-((R)-1-(4-(4-metoksybenzyl)-5-fenetyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)pyrrolidin-2-karboksamid,
forbindelse 47 (R)-N-((R)-1-(4-(4-metoksybenzyl)-5-fenetyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)pyrrolidin-2-karboksamid,
forbindelse 48 (S)-N-((R)-1-(4-(4-metoksybenzyl)-5-fenetyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)piperidin-2-karboksamid,
forbindelse 49 (R)-N-((R)-1-(4-(4-metoksybenzyl)-5-fenetyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)piperidin-2-karboksamid,
forbindelse 50 (R)-N-(1-(4-(4-metoksybenzyl)-5-fenetyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-aminoacetamid,
forbindelse 51 (R)-N-(1-(4-(4-metoksybenzyl)-5-fenetyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-(pyridin-2-yl)acetamid,
forbindelse 52 (R)-N-(1-(4-(4-metoksybenzyl)-5-fenetyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-(pyridin-4-yl)acetamid,
forbindelse 53 (R)-N-(1-(4-(4-metoksybenzyl)-5-fenetyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)sykloheksankarboksamid,
forbindelse 54 (R)-N-(1-(5-(2-(1H-indol-3-yl)etyl)-4-benzyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)piperidin-4-karboksamid,
forbindelse 55 (R)-N-(1-(5-(2-(1H-indol-3-yl)etyl)-4-benzyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)piperidin-3-karboksamid,
forbindelse 56 (R)-N-(1-(4-(4-metoksybenzyl-5-fenetyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-3-aminopropanamid,
forbindelse 57 (S)-N-((R)-1-(4-(4-metoksybenzyl)-5-fenetyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-aminopropanamid,
forbindelse 58 (R)-N-(1-(4-(4-metoksybenzyl)-5-fenetyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-(pyridin-3-yl)acetamid,
forbindelse 59 (R)-N-(1-(4-(4-metoksybenzyl)-5-fenetyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-3-(pyridin-3-yl)propanamid,
forbindelse 60 (R)-N-(1-(5-(2-(1H-indol-3-yl)etyl)-4-benzyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-(pyridin-2-yl)acetamid,
forbindelse 61 (R)-N-(1-(5-(2-(1H-indol-3-yl)etyl)-4-(2,4-dimetoksybenzyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-(pyridin-2-yl)acetamid,
forbindelse 62 (R)-N-(1-(4-(2,4-dimetoksybenzyl)-5-fenetyl-4H-1,2,4-triazol-3-yl-2-(1H-indol-3-yl)etyl)piperidin-4-karboksamid,
forbindelse 63 (R)-N-((R)-1-(4-(2,4-dimetoksybenzyl)-5-fenetyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)piperidin-2-karboksamid,
forbindelse 64 (R)-N-(1-(4-(2,4-dimetoksybenzyl)-5-fenetyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)pikolinamid,
forbindelse 65 (R)-N-(1-(4-(2,4-dimetoksybenzyl)-5-fenetyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)isonikotinamid,
forbindelse 66 (R)-N-(1-(4-(2,4-dimetoksybenzyl)-5-fenetyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)pyrazin-2-karboksamid,
forbindelse 67 (R)-N-1-(4-(2,4-dimetoksybenzyl)-5-fenetyl-4H-1,2,4-triazol-3-yl)-1H-indol-3-yl)etyl)piperazin-2-karboksamid,
forbindelse 68 (S)-N-((R)-1-(4-(2,4-dimetoksybenzyl)-5-fenyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)pyrrolidin-2-karboksamid,
forbindelse 69 (R)-N-(1-(5-(2-(1H-indol-3-yl)etyl)-4-(2,4-dimetoksybenzyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-aminoacetamid,
forbindelse 70 (S)-N-((R)-1-(5-(2-(1H-indol-3-yl)etyl)-4-(2,4-dimetoksybenzyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)pyrrolidin-2-karboksamid,
forbindelse 71 (R)-N-(1-(5-(2-(1H-indol-3-yl)etyl)-4-(2,4-dimetoksybenzyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)pyrazin-2-karboksamid,
forbindelse 72 (R)-N-1-(5-(2-(1H-indol-3-yl)etyl)-4-(2,4-dimetoksybenzyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)piperazin-2-karboksamid,
forbindelse 73 (R)-N-(1-(5-(2-(1H-indol-3-yl)etyl)-4-(2,4-dimetoksybenzyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)pikolinamid,
forbindelse 74 (R)-1-(5-(2-(1H-indol-3-yl)etyl)-4-(2,4-dimetoksybenzyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etanamin,
forbindelse 75 (R)-N-(1-(4-(2,4-dimetoksybenzyl)-5-fenetyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-aminoacetamid,
forbindelse 76 (R)-N-(1-(4-(4-metoksybenzyl)-5-fenetyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)pyrazin-2-karboksamid,
forbindelse 77 (R)-N-(1-(4-(4-metoksybenzyl)-5-fenetyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)isonikotinamid,
forbindelse 78 (R)-N-1-(4-(4-metoksybenzyl)-5-fenetyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)piperazin-2-karboksamid,
forbindelse 79 (R)-N-1-(4-(4-metoksybenzyl)-5-fenetyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)pikolinamid,
forbindelse 80 (R)-N-(1-(5-(2-(1H-indol-3-yl)etyl)-4-(4-metoksybenzyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)pikolinamid,
forbindelse 81 (R)-N-1-(5-(2-(1H-indol-3-yl)etyl)-4-(4-metoksybenzyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)piperazin-2-karboksamid,
forbindelse 82 (R)-N-1-(4-(4-etylbenzyl)-5-fenetyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-(pyridin-2-yl)acetamid,
forbindelse 83 (R)-N-(1-(4-(4-etylbenzyl)-5-fenetyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)piperidin-4-karboksamid,
forbindelse 84 (R)-N-1-(4-(4-etylbenzyl)-5-fenetyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)piperazin-2-karboksamid,
forbindelse 85 (R)-N-(1-(4-(4-etylbenzyl)-5-fenetyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)pyrazin-2-karboksamid,
forbindelse 86 (R)-N-(1-(5-(2-(1H-indol-3-yl)etyl)-4-(2,4-dimetoksybenzyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-cisaminosykloheksankarboksamid,
forbindelse 87 (S)-N-((R)-1-(5-(2-(1H-indol-3-yl)etyl)-4-(4-metoksybenzyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)piperidin-3-karboksamid,
forbindelse 88 (R)-N-((R)-1-(5-(2-(1H-indol-3-yl)etyl)-4-(4-metoksybenzyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)piperidin-2-karboksamid,
forbindelse 89 (S)-N-((R)-1-(5-(2-(1H-indol-3-yl)etyl)-4-(4-metoksybenzyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)pyrrolidin-2-karboksamid,
forbindelse 90 (R)-N-((R)-1-(5-(2-(1H-indol-3-yl)etyl)-4-(4-metoksybenzyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)pyrrolidin-2-karboksamid,
forbindelse 91 (R)-N-(1-(5-(2-(1H-indol-3-yl)etyl)-4-(4-metoksybenzyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-(pyridin-2-yl)-acetamid,
forbindelse 92 (R)-N-(1-(5-(2-(1H-indol-3-yl)etyl)-4-(4-brombenzyl}-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid,
forbindelse 93 (R)-N-(1-(5-(2-(1H-indol-3-yl)etyl)-4-(4-metoksybenzyl)-4H-1,2,4-triazol-3-yl)-2-fenyletyl)-2-amino-2-metylpropanamid,
forbindelse 94 (R)-N-(2-(1H-indol-3-yl)-1-(5-fenetyl-4-(tiofen-2-ylmetyl)-4H-1,2,4-triazol-3-yl)etyl)piperidin-4-karboksamid,
forbindelse 95 (R)-N-(1-(4-(2-(1H-indol-3-yl)etyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid,
forbindelse 96 (R)-N-(1-(5-((1H-indol-3-yl)metyl)-4-metyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid,
forbindelse 97 (R)-N-(1-(5-(2-(1H-indol-3-yl)etyl)-4-metyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid,
forbindelse 98 (R)-N-(1-(5-((1H-indol-3-yl)metyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid,
forbindelse 99 (R)-N-(1-(5-((1H-indol-3-yl)metyl)-4-(2,4-dimetoksybenzyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid,
forbindelse 100 (R)-N-(1-(4-(2,4-dimetoksybenzyl)-5-metyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid,
forbindelse 101 (R)-N-(1-(5-((1H-indol-3-yl)metyl)-4(4-metoksybenzyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid,
forbindelse 102 (R)-N-(1-(4-(2,4-dimetoksybenzyl)-5-benzyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid,
forbindelse 103 (R)-N-(1-(5-(3-(1H-indol-3-yl)propyl)-4-(2,4-dimetoksybenzyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid,
forbindelse 104 (R)-N-(1-(5-((1H-indol-3-yl)metyl)-4-fenetyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid,
forbindelse 105 (R)-N-(1-(5-benzyl-4-fenetyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid,
forbindelse 106 (R)-N-(1-(5-benzyl-4-(2,2-difenyletyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid,
forbindelse 107 (R)-N-(1-(5-(2-(1H-indol-3-yl)etyl)-4-(2,2-difenyletyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid,
forbindelse 108 (R)-N-(1-(4-(3,5-dimetoksybenzyl)-5-benzyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid,
forbindelse 109 (R)-N-(1-(4,5-dibenzyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid,
forbindelse 110 (R)-N-(1-(5-benzyl-4-heksyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid,
forbindelse 111 (R)-N-(1-(4-(2-(1H-indol-3-yl)etyl)-5-benzyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid,
forbindelse 112 (S)-N-(1-(4-(2,4-dimetoksybenzyl)-5-benzyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid,
forbindelse 113 (R)-N-(1-(4-(3,5-dimetoksybenzyl)-5-fenetyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid,
forbindelse 114 (R)-N-(1-(4-(4-brombenzyl)-5-benzyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid,
forbindelse 115 (R)-N-1-(4-(2-metoksybenzyl)-5-benzyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid,
forbindelse 116 (S)-N-(1-(4-(2,4-dimetoksybenzyl)-5-fenetyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid,
forbindelse 117 (R)-N-(1-(4,5-difentyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid,
forbindelse 118 (R)-N-(1-(4-(3,4-diklorbenzyl)-5-benzyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid,
forbindelse 119 (R)-1-(5-(2-(1H-indol-3-yl)etyl)-4-(2,4-dimetoksybenzyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etanamin,
forbindelse 120 (R)-N-(1-(4-(4-metoksybenzyl)-5-benzyl-4H-1,2,4-triazol-3-yl)-2-fenyletyl)-2-amino-2-metylpropanamid,
forbindelse 121 (R)-N-(1-(4-(4-fluorbenzyl)-5-fenetyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid,
forbindelse 122 (R)-N-(1-(4-(3,4-diklorbenzyl)-5-fenetyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid,
forbindelse 124 (R)-N-(1-(4-(4-metylbenzyl)-5-benzyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid,
forbindelse 125 (S)-N-(1-(4-(4-metoksybenzyl)-5-(3-fenylpropyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid,
forbindelse 126 (S)-N-(1-(4-(4-metoksybenzyl)-5-benzyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid,
forbindelse 128 N-((R)-1-(4-(4-nitrobenzyl)-5-fenetyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid,
forbindelse 129 (S)-N-(1-(4-(4-metoksybenzyl)-5-fenetyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid,
forbindelse 130 (R)-N-(1-(4-(4-metoksyfenetyl)-5-fenetyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid,
forbindelse 131 (R)-N-(2-(1H-indol-3-yl)-1-(5-fenetyl-4-(tiofen-2-ylmetyl)-4H-1,2,4-triazol-3-yl)etyl)-2-amino-2-metylpropanamid,
forbindelse 132 (R)-N-(2-(1H-indol-3-yl)-1-(5-fenetyl-4-(pyridin-2-ylmetyl)-4H-1,2,4-triazol-3-yl)etyl)-2-amino-2-metylpropanamid,
forbindelse 133 (R)-N-(2-(1H-indol-3-yl)-1-(5-fenetyl-4-(pyridin-2-ylmetyl)-4H-1,2,4-triazol-3-yl)etyl)piperidin-3-karboksamid,
forbindelse 134 (S)-N-((R)-1-(4-(4-etylbenzyl)-5-fenetyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)pyrrolidin-2-karboksamid,
forbindelse 135 N-((R)-1-(4-(4-etylbenzyl)-5-fenetyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-aminoacetamid,
forbindelse 136 N-((R)-1-(5-(2-(1H-indol-3-yl)etyl)-4-(4-metoksybenzyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-(pyridin-4-yl)-acetamid,
forbindelse 137 (2R)-N-((R)-1-(4-(4-etylbenzyl)-5-fenetyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)piperidin-2-karboksamid,
forbindelse 138 N-((R)-1-(4-(4-etylbenzyl)-5-fenetyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)pikolinamid,
forbindelse 139 N-((R)-1-(4-(4-etylbenzyl)-5-fenetyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-aminopyridin-3-karboksamid,
forbindelse 140 (2S)-N-((R)-1-(4-(4-etylbenzyl)-5-fenetyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-aminopropanamid,
forbindelse 141 N-((R)-1-(4-(4-etylbenzyl)-5-fenetyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)isonikotinamid,
forbindelse 142 N-((R)-2-(1H-indol-3-yl)-1-(5-fenetyl-4-fenyl-4H-1,2,4-triazol-3-yl)etyl)piperidin-4-karboksamid,
forbindelse 143 (2S)-N-((R)-2-(1H-indol-3-yl)-1-(5-fenetyl-4-fenyl-4H-1,2,4-triazol-3-yl)etyl)pyrrolidin-2-karboksamid,
forbindelse 144 N-((R)-2-(1H-indol-3-yl)-1-(5-fenetyl-4-fenyl-4H-1,2,4-triazol-3-yl)etyl)-2-aminoacetamid,
forbindelse 145 N-((R)-2-(1H-indol-3-yl)-1-(5-fenetyl-4-fenyl-4H-1,2,4-triazol-3-yl)etyl)-2-(pyridin-2-yl)acetamid,
forbindelse 146 N-((R)-2-(1H-indol-3-yl)-1-(5-fenetyl-4-fenyl-4H-1,2,4-triazol-3-yl)etyl)pikolinamid,
forbindelse 147 N-((R)-1-(5-(2-(1H-indol-3-yl)etyl)-4-(4-etylfenyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)pikolinamid,
forbindelse 148 N-((R)-1-(5-(2-(1H-indol-3-yl)etyl)-4-(4-etylfenyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-(pyridin-2-yl)acetamid,
forbindelse 149 N-((R)-1-(5-(2-(1H-indol-3-yl)etyl)-4-(4-etylfenyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-aminoacetamid,
forbindelse 150 (2S)-N-((R)-1-(5-(2-(1H-indol-3-yl)etyl)-4-(4-etylfenyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)pyrrolidin-2-karboksamid,
forbindelse 152 N-((R)-1-(5-(2-(1H-indol-3-yl)etyl)-4-(4-metoksybenzyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-aminoacetamid,
forbindelse 153 N-((R)-1-(4-(4-metoksybenzyl)-5-fenetyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-trans-aminosykloheksankarboksamid,
forbindelse 154 N-((R)-1-(4-(4-etylbenzyl)-5-fenetyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-(pyridin-3-yl)acetamid,
forbindelse 155 (3S)-N-((R)-1-(4-(4-etylbenzyl)-5-fenetyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)piperidin-3-karboksamid,
forbindelse 156 N-((R)-1-(4-(4-etylbenzyl)-5-fenetyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-aminobenzamid,
forbindelse 157 N-((R)-1-(5-(2-(1H-indol-3-yl)etyl)-4-fenyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)pikolinamid,
forbindelse 158 N-((R)-1-(5-(2-(1H-indol-3-yl)etyl)-4-fenyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)piperidin-4-karboksamid,
forbindelse 159 N-((R)-2-(1H-indol-3-yl)-1-(4-(2,4-dimetoksyfenyl)-5-fenetyl-4H-1,2,4-triazol-3-yl)etyl)pikolinamid,
forbindelse 160 N-((R)-2-(1H-indol-3-yl)-1-(4-(2,4-dimetoksyfenyl)-5-fenetyl-4H-1,2,4-triazol-3-yl)etyl)-2-(pyridin-2-yl)acetamid,
forbindelse 161 N-((R)-2-(1H-indol-3-yl)-1-(4-(2,4-dimetoksyfenyl)-5-fenetyl-4H-1,2,4-triazol-3-yl)etyl)pyrazin-2-karboksamid,
forbindelse 162 N-((R)-2-(1H-indol-3-yl)-1-(4-(2,4-dimetoksyfenyl)-5-fenetyl-4H-1,2,4-triazol-3-yl)etyl)-2-aminoacetamid,
forbindelse 163 N-((R)-2-(1H-indol-3-yl)-1-(4-(2,4-dimetoksyfenyl)-5-fenetyl-4H-1,2,4-triazol-3-yl)etyl)piperidin-4-karboksamid,
forbindelse 164 N-((R)-1-(5-benzyl-4-((pyridin-2-yl)metyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)pikolinamid,
forbindelse 165 N-((R)-1-(5-benzyl-4-((pyridin-2-yl)metyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-aminoacetamid,
forbindelse 166 N-((R)-1-(5-benzyl-4-((pyridin-2-yl)metyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)piperidin-4-karboksamid,
forbindelse 167 N-((R)-1-(5-benzyl-4-((pyridin-4-yl)metyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid,
forbindelse 168 N-((R)-1-(5-(4-metoksybenzyl)-4-fenetyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid,
forbindelse 169 N-((R)-1-(5-benzyl-4-((pyridin-4-yl)metyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)pikolinamid,
forbindelse 170 N-((R)-1-(5-benzyl-4-((pyridin-4-yl)metyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-acetamid,
forbindelse 171 (R)-benzyl-3-(2-aminoisobutyramido)-3-(5-(2-(1H-indol-3-yl)etyl)-4-(4-metoksybenzyl)-4H-1,2,4-triazol-3-yl)-propanoat,
forbindelse 172 N-((R)-1-(5-benzyl-4-((pyridin-3-yl)metyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid,
forbindelse 173 N-((R)-1-(4-benzyl-5-fenetyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid,
forbindelse 174 N-((R)-2-(1H-indol-3-yl)-1-(4-metyl-5-fenetyl-4H-1,2,4-triazol-3-yl)etyl)pikolinamid,
forbindelse 175 N-((R)-1-(5-(2-(1H-indol-3-yl)etyl)-4-fenyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid,
forbindelse 176 N-((R)-1-(4-(4-metoksybenzyl)-5-fenetyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)benzamid,
forbindelse 177 (R)-1-(4-(2,4-dimetoksybenzyl)-5-fenetyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)-N-fenylmetansulfonylamin,
forbindelse 178 (R)-1-(4-(2,4-dimetoksybenzyl)-5-fenetyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)-N-tosyletanamin,
forbindelse 179 N-((R)-1-(4-(2,4-dimetoksybenzyl)-5-fenetyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid,
forbindelse 180 N-1-((R)-1-(4-(2,4-dimetoksybenzyl)-5-fenetyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)etan-1,2-diamin,
forbindelse 181 N-((R)-1-(4-((furan-2-yl)metyl)-5-fenetyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid,
forbindelse 182 N-((R)-1-(4-((furan-2-yl)metyl)-5-fenetyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)pikolinamid,
forbindelse 183 N-((R)-1-(4-((furan-2-yl)metyl)-5-fenetyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)piperidin-4-karboksamid,
forbindelse 184 N-((R)-1-(4-(4-metoksybenzyl)-5-fenetyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-tetrahydro-2H-pyran-4-karboksamid,
forbindelse 185 N-((R)-1-(5-((1H-indol-3-yl)metyl)-4-(3-metoksybenzyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid,
forbindelse 186 (2S)-N-((R)-1-(4-(4-metoksybenzyl)-5-fenetyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-3-penylpropanamid,
forbindelse 187 (R)-1-(5-(2-(1H-indol-3-yl)etyl)-4-(2,4-dimetoksybenzyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)-N-tosyletanamin,
forbindelse 188 N-((R)-1-(4-(2,4-dimetoksybenzyl)-5-fenetyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-4-azidobenzamid,
forbindelse 189 N-benzyl-(R)-1-(4-(2,4-dimetoksybenzyl)-5-fenetyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etanamin,
forbindelse 190 (2S)-N-((R)-1-(5-(2-(1H-indol-3-yl)etyl)-4-(4-metoksybenzyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2,5-dihydro-1H-pyrrol-2-karboksamid,
For å unngå tvil, hvis kjemisk navn og kjemisk struktur og de ovenfor illustrerte forbindelsene ikke korresponderer ved en feil, er det den kjemiske strukturen som definerer forbindelsen.
I en foretrukket utførelsesform kan disse forbindelsene anvendes for fremstilling av et medikament for behandling eller profylakse av fysiologiske og/eller patofysiologiske tilstander hos pattedyr som medieres av GHS-reseptorer.
I en ytterligere foretrukket utførelsesform kan alle triazolforbindelsene slik det er illustrert heri, i det følgende referert til som forbindelsene ifølge oppfinnelsen, anvendes for fremstilling av et medikament for behandling eller profylakse av fysiologiske og/eller patofysiologiske tilstander hos pattedyr som medieres av GHS-reseptorer og hvor behandling oppnås ved modulering av GHS-reseptorer.
I en ytterligere annen foretrukket utførelsesform er alle forbindelsene ifølge oppfinnelsen antagonister av GHS-reseptorer.
Mer foretrukket er antagonister av GHS-reseptorer forbindelser valgt fra gruppen som består av:
forbindelse 1, 3, 12, 13, 14, 18, 20, 22, 23, 33, 36, 37, 38, 41, 46, 47, 48, 49, 50, 51, 52, 53, 57, 58, 59, 60, 61, 63, 64, 65, 66, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 79, 80, 82, 85, 86, 87, 88, 89, 90, 91, 93, 101, 102, 109, 114, 116, 119, 134, 135, 136, 137, 138, 139, 140, 145, 146, 147, 148, 150, 152, 153, 154, 156, 157, 159, 160, 161, 164, 171, 174, 176, 178, 179, 182, 184, 186, 188 og/eller forbindelse 190.
I en ytterligere annen foretrukket utførelsesform er alle forbindelser ifølge oppfinnelsen agonister av GHS-reseptorer.
Mer foretrukket er agonister av GHS-reseptorer forbindelser valgt fra gruppen som består av:
forbindelse 2, 4, 5, 6, 7, 8, 9, 10, 11, 15, 16, 17, 19, 21, 24, 25, 26, 27, 28, 29, 30, 31, 32, 34, 39, 40, 42, 43, 44, 45, 54, 55, 56, 62, 67, 78, 81, 83, 84, 87, 92, 94, 99, 103, 104, 105, 106, 107, 108, 110, 111, 115, 117, 118, 121, 122, 124, 130, 131, 142, 155, 158, 163, 173, 175, 180, 181, 183, 185 og/eller forbindelse 187.
Alle stereoisomerer av forbindelsene ifølge oppfinnelsen er tiltenkt, enten i blanding eller i ren eller i det vesentlige ren form. Som en konsekvens kan forbindelser ifølge oppfinnelsen eksistere i form av deres racemater, i form av de rene enantiomerene og/eller diastereomerene eller i form av blandinger av disse enantiomerene og/eller diastereomerene. Blandingene kan ha et hvilket som helst ønsket blandeforhold av stereoisomerene. Alle disse forskjellige stereokjemiske formene og blandinger er innenfor omfanget av foreliggende oppfinnelse.
Således kan for eksempel forbindelsene ifølge oppfinnelsen som har ett eller flere kiralitetssentre og som opptrer som racemater eller som diastereomere blandinger, fraksjoneres ved i og for seg kjente fremgangsmåter i deres optisk rene isomerer, det vil si enantiomerer eller diastereomerer. Separasjonen av forbindelsene ifølge oppfinnelsen kan finne sted ved kolonneseparasjon på kirale eller ikke-kirale faser eller ved rekrystallisasjon fra et optisk aktivt løsemiddel eller ved anvendelse av en optisk aktiv syre eller base eller ved derivatisering med et optisk aktivt reagens, slik som for eksempel en optisk aktiv alkohol, og deretter eliminering av radikalet.
Hvis mulig kan forbindelsene ifølge oppfinnelsen være i form av tautomerene.
Det er på samme måte mulig for forbindelsene ifølge oppfinnelsen å være i form av et hvilket som helst ønsket prodrug slik som for eksempel estere, karbonater eller fosfater, i hvilke tilfeller den aktuelle biologisk aktive formen frigis kun ved metabolisme. En hvilken som helst forbindelse som kan omdannes in vivo for å gi det bioaktive midlet (det vil si en forbindelse ifølge oppfinnelsen) er et prodrug innenfor omfanget og ånden til oppfinnelsen.
Forskjellige prodrugformer er godt kjente i litteraturen og er for eksempel beskrevet i:
(i) The Practice of Medicinal Chemistry (Wermuth CG et al., kapittel 31, Academic Press 1996);
(ii) Design of Prodrugs (redaktør: Bundgaard H, Elsevier 1985); og
(iii) A Textbook of Drug Design and Development (Krogsgaard-Larson P og Bundgaard H, redaktører, kapittel 5: 113 - 191, Harwood Academic Publishers 1991).
Nevnte referanser er innbefattet med referanse.
Det er ytterligere kjent at kjemiske substanser omdannes i kroppen til metabolitter som kan hvis hensiktsmessig på samme måte frembringe den ønskede, biologiske effekten, under noen omstendigheter kan den være ytterligere uttalt.
En hvilken som helst biologisk aktiv forbindelse som omdannes in vivo ved metabolisme fra en hvilken som helst forbindelse ifølge oppfinnelsen, er en metabolitt innenfor omfanget og ånden til oppfinnelsen.
Forbindelsene ifølge oppfinnelsen kan hvis de har en tilstrekkelig basisk gruppe, slik som for eksempel et primært, sekundært eller tertiært amin, omdannes med uorganiske og organiske syrer til salter. De farmasøytisk akseptable saltene av forbindelsene ifølge oppfinnelsen blir foretrukket dannet med saltsyre, hydrobromsyre, jodsyre, svovelsyre, fosforsyre, metansulfonsyre, p-toluensulfonsyre, karbonsyre, maursyre, eddiksyre, sulfoeddiksyre, trifluoreddiksyre, oksalsyre, malonsyre, maleinsyre, ravsyre, vinsyre, racemsyre, eplesyre, embonsyre, mandelsyre, fumarsyre, melkesyre, sitronsyre, taurokolinsyre, glutarsyre, stearinsyre, glutamsyre eller aspartansyre. Saltene som dannes er blant annet hydroklorider, klorider, hydrobromider, bromider, jodider, sulfater, fosfater, metansulfonater, tosylater, karbonater, bikarbonater, formater, acetater, sulfoacetater, triflater, oksalater, malonater, maleater, succinater, tartrater, malater, embonater, mandelater, fumarater, laktater, citrater, glutarat, stearat, aspartater og glutamater. Støkiometrien til saltene som dannes fra forbindelsene ifølge oppfinnelsen kan videre være en integral eller ikke-integral multippel av én.
Forbindelsene ifølge oppfinnelsen kan, hvis de inneholder en tilstrekkelig sur gruppe, slik som for eksempel karboksy, sulfonsyre, fosforsyre eller en fenolgruppe, omdannes med uorganiske og organiske baser til deres fysiologisk akseptable salter. Eksempler på egnede uorganiske baser er ammonium, natriumhydroksid, kaliumhydroksid, kalsiumhydroksid, og på organiske baser er etanolamin, dietanolamin, trietanolamin, etylendiamin, t-butylamin, t-oktylamin, dehydroabietylamin, sykloheksylamin, dibenzyletylendiamin og lysin. Støkiometrien til saltene dannet fra forbindelsene ifølge oppfinnelsen, kan videre være en integral eller ikke-integral multippel av én.
Det er på samme måte mulig for forbindelsene ifølge oppfinnelsen å være i form av deres solvater og særlig hydrater som kan oppnås for eksempel ved krystallisering fra et løsemiddel eller fra vandig løsning. Det er videre mulig for én, to, tre eller et hvilket som helst antall solvat eller vannmolekyler å kombinere med forbindelsene ifølge oppfinnelsen for å gi solvater og hydrater.
Det er kjent at kjemiske substansformfaststoffer som eksisterer i forskjellige grader av tilstander som blir referert til som polymorfe former eller modifikasjoner. De forskjellige modifikasjoner av en polymorf substans kan variere i stor grad når det gjelder fysiske egenskaper. Forbindelsene ifølge oppfinnelsen kan eksistere i forskjellige polymorfe former og visse modifikasjoner kan videre være metastabile. Alle disse polymorfe formene av forbindelsene ifølge oppfinnelsen anses å tilhøre foreliggende oppfinnelse.
Triazolderivatene (forbindelser ifølge oppfinnelsen) slik de er illustrert heri, er ghrelinanaloge ligander av GHS-reseptorer. Således er de ovenfor nevnte forbindelsene ifølge oppfinnelsen egnet for behandling eller profylakse av fysiologiske og/eller patofysiologiske tilstander mediert av GHS-reseptorer og/eller fysiologiske og/eller patofysiologiske tilstander som kan influeres ved modulering av disse reseptorene og således hindres, behandles og/eller lindres.
I sammenheng med foreliggende oppfinnelse er begrepet "behandling" også tiltenkt å inkludere profylaktisk behandling eller lindring.
Begrepet "ghrelinanalogligand" eller "ligand" er tiltenkt å referere til i sammenheng med foreliggende oppfinnelse, enhver forbindelse som binder på en hvilken som helst måte til en reseptor (reseptorene ifølge oppfinnelsen værende GHS-reseptorer) og induserer enten aktivering, inhibering og/eller en annen mulig effekt av denne reseptoren. Begrepet "ghrelinanalog ligand" eller "ligand" inkluderer således agonister, antagonister, delvis agonister/antagonister, inverse agonister og andre ligander som forårsaker en effekt ved reseptoren som er tilsvarende effekten til agonister, antagonister, delvis agonister/antagonister eller inverse agonister.
I sammenheng med foreliggende oppfinnelse refererer begrepet "GHS-reseptorantagonister" eller "antagonist ved GHS-reseptorer" til forbindelser ifølge oppfinnelsen som binder til GHS-reseptorer, men som ikke fremviser en passende aktivering av reseptorene slik de bestemmes ved avlesing av en økning av intracellulær kalsium som er karakteristisk for aktivering av G-proteinkoblede reseptorer (GPCR-er).
Evnen til passende aktivering av reseptorene slik de bestemmes for en hvilken som helst forbindelse ifølge oppfinnelsen med sammenligning av grad av aktivering (økning av intracellulær kalsium) til GHS-R 1a med forbindelsen som testes (ved 10<-6>M konsentrasjon) med grad av aktivering (økning av intracellulær kalsium) til GHS-R 1a med 10<-6>M ghrelin (100 %) og med grunnivået (0 %). Slik bestemmelse kan lett utføres av fagmannen på grunn av hans ekspertkunnskaper. Det som fremkommer er en prosentverdi for hver forbindelse som testes.
En hvilken som helst forbindelse ifølge oppfinnelsen som ikke fremviser en aktiveringsgrad (økning av intravaskulært kalsium) av GHS-R 1a på minst 20 % slik det bestemmes i henhold til beskrivelsen ovenfor, anses ikke å fremvise en tilfredsstillende aktivering og derfor som GHS-reseptorantagonist. Foretrukket viser slike forbindelser en antagoniserende effekt (motvirkning/reduksjon) på ghrelin og/eller annen GHS-stimulert intracellulær kalsiumøkning, hindrer slik stimulering eller til og med virker som inverse agonister (invers agonist er en ligand som binder til samme reseptorbindingssete som en agonist eller antagonist, men som forårsaker en inhibering av den basale/konstitutive aktiviteten til reseptoren, i prinsippet en agonist med en negativ iboende aktivitet). Slike forbindelser kan videre fremvise en inhiberende aktivitet på GH-sekresjon og/eller på andre fysiske eller patofysiologiske betingelser eller effekter, slik som matinntak eller lipogenese. Deres effekter kan bli dissosiert. Således kan de ha ingen virkning på GH-sekresjon, mens de inhiberer andre fysiologiske effekter. De kan til og med stimulere andre fysiologiske effekter.
I sammenheng med foreliggende oppfinnelse refererer begrepet "GHS-reseptoragonist" eller "agonist av GHS-reseptorer" til forbindelser ifølge oppfinnelsen som binder til GHS-reseptorer og fremviser en passende aktivering av reseptorer slik det bestemmes ved avlesning av en økning av intracellulært kalsium som er karakteristisk for aktivering av G-proteinkoblede reseptorer.
En hvilken som helst forbindelse ifølge oppfinnelsen som viser en grad av aktivering (reduksjon av intracellulær kalsium) av GHS-R 1a på minst 20 % slik det bestemmes i henhold til beskrivelsen ovenfor, anses å fremvise en passende aktivering og derfor som GHS-reseptoragonist. Slike forbindelser kan etterligne effektene til ghrelin og/eller GHS på GH-sekresjon og for eksempel matinntak eller lipogenese. Som for antagonister kan effektene av agonistforbindelser bli dissosiert fra GH-sekresjonseffekten. Slike forbindelser kan til og med antagonisere (motvirke/redusere) ghrelin og/eller annen GHS-stimulert intracellulær kalsiumøkning.
Begrepet "GHS-reseptor" eller "GHS-R" er tiltenkt å innbefatte i sammenheng med foreliggende oppfinnelse reseptorer som binder minst ett kjent peptidyl og/eller ikkepeptidyl-GHS og/eller ghrelin. Begrepet "GHS-reseptor" eller "GHS-R" er også tiltenkt å innbefatte forskjellige GHS-bindingsseter i forskjellige vev og/eller organer slik det er illustrert heri, som binder minst én kjent peptidyl og/eller ikke-peptidyl GHS og/eller ghrelin og som trolig ikke ennå er karakteriserte GHS-R-undertyper.
Binding av en gitt kjent peptidyl og/eller ikke-peptidyl-GHS og/eller ghrelin kan enkelt verifiseres av fagmannen på basis av hans ekspertkunnskap, for eksempel ved passende bindingsundersøkelser som kun representerer rutineeksperimentering.
Slike GHS-reseptorer kan stimuleres/aktiveres av ghrelin (ghrelinresponderende) eller kan ikke bli stimulert/aktivert av ghrelin (ghrelin ikke-responderende) - med hensyn til både acylert og ikke-acylert ghrelin, respektivt. Stimulering/aktivering av slike reseptorer kan forårsake, men må ikke fremvise GH-produksjon og/eller GH-sekresjon og/eller økte GH-plasmanivåer.
Foretrukket er slike GHS-reseptorer valgt fra gruppen som består av "GHS type 1-reseptor, GHS-R 1a, GHS-R 1b, motilinreseptor, motilinreseptor 1a, eurotensinreseptor, TRH-reseptor, GPR38 (FM1), GPR39 (FM2), FM3, GHS-bindingssete, GHS-R-undertype, hjerte GHS-R, bryst GHS-R".
Mer foretrukket er slike GHS-reseptorer valgt fra gruppen som består av "GHS type 1-reseptor, GHS-R 1a, GHS-R 1b" og er mest foretrukket GHS-R 1a.
Slik det er diskutert heri er GHS-reseptorer (som inkluderer GHS-bindingsseter og GHS-R-undertyper) kjent for å bli konsentrert i hypotalamus-hypofyseområdet, men også synes å være fordelt i annet sentralt og periferalt vev. Videre uttrykkes de også i forskjellige normale vev, selv i tumoralvev fra organer som ikke uttrykker disse reseptorene under fysiologiske betingelser.
I sammenheng med foreliggende oppfinnelse er alle disse GHS-reseptorer (som inkluderer GHS-bindingsseter og GHS-R-undertyper) som uttrykker organer og/eller vev, tiltenkt å være innbefattet innenfor omfanget av oppfinnelsen. Ekspresjon av GHS-reseptorer (som inkluderer GHS-bindingsseter og GHS-R-undertyper) i et gitt organ og/eller vev kan lett verifiseres av fagmannen på basis av hans ekspertkunnskap, for eksempel ved passende molekylære, biologiske undersøkelser, slik som immunofluorescens eller immunopresipitasjonsundersøkelser som kun representerer rutineeksperimentering.
Foretrukket er slike GHS-reseptorer lokalisert i vev og/eller organer valgt fra gruppen som består av "endokrinvev, eksokrinvev, periferalt vev, adipose/fettvev, hjerne, hypotalamus, talamus, hippocampus, stratum, cortex, hypofyse, sentralnervesystem, ryggrad, kjertel, adrenalkjertel, tyroidkjertel, spyttkjertel, brystkjertel, neuron, tarm, mage, hjerte, lever, bukspyttkjertel, nyre, galle, galleblære, prostata, milt, muskel, skjellettmuskel, aorta, arterie, vene, immuncelle, leukocytt, lymfocytt, T-celle, B-celle, granulocytt, monocytt, makrofag, dendrittcelle, mastcelle, NK-celle, neutrofil, eosinofil, basofil, lymfeknute, bein, beinmarg, tonsil, thymus, placenta, testikler, eggstokker, livmor, lunge, adipocytt, tumor/kreftcelle, karsinomcelle, prostatakreftcelle, tyroidkreftcelle, lungekreftcelle, brystkreftcelle".
Slik det er illustrert ovenfor er forbindelsene ifølge oppfinnelsen ghrelinanalogligander av GHS-reseptorer. De kan administreres til forskjellige pattedyrarter, som inkluderer et menneske for behandling eller profylakse av fysiologiske og/eller patofysiologiske betingelser hos slike pattedyr.
I sammenheng med foreliggende oppfinnelse anses alle pattedyrarter å være innbefattet. Foretrukket er slike pattedyr valgt fra gruppen som består av "mennesker, husdyr, kveg, buskap, kjeledyr, kuer, sauer, griser, geiter, hester, ponni, esler, mulesel, muldyr, hare, kanin, katt, hund, marsvin, hamster, rotte, mus". Mer foretrukket er slike pattedyr menneske.
Forbindelsene ifølge oppfinnelsen som er ikke-peptid-ghrelinanalogligander av GHS-reseptorer, er overraskende kjennetegnet ved en sterk bindingsaffinitet til slike reseptorer. Slike forbindelser kan for eksempel foretrukket fremvise en IC50-verdi på mindre enn 1000 nM for binding til GHS-R 1a. Mer foretrukket kan slike forbindelser fremvise en IC50-verdi på mindre enn 500 nM, enda mer foretrukket på mindre enn 300 nM og mest foretrukket mindre enn 100 nM for binding til GHS-R 1a.
På grunn av deres overraskende sterke reseptorbinding kan forbindelsene ifølge oppfinnelsen fordelaktig administreres ved lavere doser sammenlignet med andre mindre potente bindingsmidler mens det fremdeles oppnås ekvivalent eller til og med forbedrede, ønskede biologiske effekter. I tillegg kan en slik dosereduksjon fordelaktig føre til mindre eller til og med ingen medisinske bivirkninger. Videre kan den høye bindingsspesifisiteten til forbindelsene ifølge oppfinnelsen gi en reduksjon av uønskede bivirkninger alene uansett anvendt dose.
Videre er forbindelsene ifølge oppfinnelsen, værende ikke-peptidiske av natur, resistente overfor nedbryting av enzymer i gastrointestinaltrakten. Således gir de en fordel ved å bli tatt ved oral rute. De fremviser overraskende en forbedret metabolittisk stabilitet og/eller en forbedret biotilgjengelighet. Således kan igjen en fordelaktig dosereduksjon oppnås som kan forårsake mindre eller til og med ingen bivirkninger.
Forbindelsene ifølge oppfinnelsen kan enten være antagonister eller agonister av GHS-reseptorer slik det er illustrert og definert heri.
GHS-reseptorantagonister ifølge oppfinnelsen kan for eksempel anvendes for inhibering av GHS-reseptorer stimulert av ghrelin og/eller andre GHS som således reduserer og/eller blokkerer GH-produksjon oleaginøs gjær sekresjon og/eller GH-plasmanivåer. I tillegg kan slike GHS-reseptorantagonister også anvendes for inhibering eller hindring av fysiologiske eller patofysiologiske effekter av ghrelin som ikke er relatert til GH-produksjon og/eller GH-sekresjon.
Derfor er GHS-reseptorantagonister ifølge oppfinnelsen egnede for behandling og/eller profylakse av forskjellige fysiologiske og patofysiologiske tilstander slik det er beskrevet heri, særlig for korttids-, middels- og/eller langtidsregulering av energibalanse, korttids-, middels- og/eller langtidsregulering (stimulering og/eller inhibering) av matinntak, behandling av adipogenese, adipositet og/eller fedme, kroppsvektøkning og/eller reduksjon og behandling av tumorcelleproliferasjon.
Til forskjell fra dette kan GHS-reseptorantagonister ifølge oppfinnelsen for eksempel anvendes for aktivering av GHS-reseptorer og stimulering/økning av GH-produksjon og/eller GH-sekresjon og vil således ha tilsvarende effekter eller anvendelser som veksthormon i seg selv, ghrelin og/eller kjent GHS.
Således er GHS-reseptoragonister ifølge oppfinnelsen egnet for behandling og/eller profylakse av vesentlig fysiologiske og patofysiologiske tilstander som er beskrevet heri, særlig vektretardasjon, kakeksi, inflammasjon, inflammatoriske effekter, gastrisk postoperativ ileus, postoperativ ileus og/eller gastrektomi (ghrelin erstatningsbehandling).
I sammenheng med foreliggende oppfinnelse er alle fysiologiske og/eller patofysiologiske tilstander tiltenkt å være innbefattet som er kjent for å bli mediert av GHS-reseptorer.
Foretrukket er disse fysiologiske og/eller patofysiologiske tilstandene valgt fra gruppen som består av "akutt svekkelsessyndrom og muskeltap etterfølgende eleksjonskirurgi, adipogenese, adipositet, aldersrelatert reduksjon av tymisk funksjon, aldersrelatert funksjonell reduksjon ("ARFD") hos eldre, aldringsforstyrrelse hos husdyr, Alzheimers sykdom, anoreksi (for eksempel assosiert med kakeksi eller aldring); angst, blodtrykk (reduksjon), kroppsvektøkning/reduksjon, beinfrakturreparering (akselerasjon), beinremoduleringsstimulering, kakeksi og proteintapreduksjon på grunn av kronisk sykdom slik som kreft eller AIDS, hjertedysfunksjoner (for eksempel assosiert med valvulær sykdom, myokardiskt infarkt, hjertehypertrofi eller kongestiv hjertesvikt), kardiomyopati, bruskvekststimulering, katabolske forstyrrelser i forbindelse med lungedysfunksjon og ventilatoravhengighet, katabolske bivirkninger av glukokortikoider, katabolsk tilstand ved aldring, sentralnervesystemforstyrrelser (i kombinasjon med antidepressive midler), kronisk dialyse, kronisk svekkelsessyndrom (CFS), kognitiv funksjonsforbedring (for eksempel ved demens, Alzheimers sykdom), kompliserte frakturer (for eksempel distraksjonsosteogenese), komplikasjoner assosiert med transplantasjon, kongestiv hjertesvikt (alene/i kombinasjon med kortikotropinfrigivende faktorantagonister), Crohns sykdom og ulcerativ kolitt, Cushings syndrom, demens, depresjoner, korttids-, middels- og/eller langtidsregulering av energibalanse, korttids-, middels- og/eller langtidsregulering av matinntak (stimulering og/eller inhibering), skrøpelighet (for eksempel hos eldre mennesker), gastrektomi (ghrelinerstatningsbehandling), gastrisk postoperativ ileus, glykemisk kontrollforbedring, veksthormonfrigivelsestimulering hos eldre, veksthormonerstatning hos stressede pasienter, fremmelse av vekst hos husdyr, vekstretardasjon assosiert med Prader-Willisyndrom og Turners syndrom, vekstretardasjon i forbindelse med Crohns sykdom, vekstretardasjon, hår/neglevekstopprettholdelse, hoftefrakturer, hunger, hyperkortisolisme, hyperinsulinemi som inkluderer nesidioblastosi, hypotermi, immunsvekkelse hos individer med et nedsatt T4/T8-celleforhold, immunresponsforbedring ovenfor vaksinering, immunsystemstimulering hos ledsagerdyr, immunsystemstimulering, immunosuppresjon hos immunoundertrykte pasienter, inflammasjon eller inflammatoriske effekter, inflammatorisk tarmsykdom, insulinresistens i hjertet, insulinresistens hos type 2 diabetespasienter, insulinresistens som inkluderer NIDDM, diabetes, diabetes type I, diabetes II, intrauterinvekstretardasjon, irritabel tarmsyndrom, lipodystrofi (for eksempel HIV-indusert), metabolittisk homeostaseopprettholdelse, melkeproduksjonsøkning hos husdyr, muskelmasse/styrkeøkning, muskelmobilitetsforbedring, muskelstyrkeforbedring, muskelstyrke/funksjonsopprettholdelse hos eldre mennesker, muskulær atrofi, muskuloskjelettsvekkelse (for eksempel hos eldre), Noonans syndrom, fedme og vekstretardasjon assosiert med fedme, osteoblaststimulering, osteokondrodysplasier, osteoporose, ovulasjonsinduksjon (adjuvansbehandling), fysiologisk kort statur som inkluderer veksthormonunderskudd hos barn, postoperativ ileus, proteinkatabolsk responsattenuering etter større kirurgi/traume, proteinkinase B-aktivitetsforbedring, fysososial deprivering, lungedysfunksjon og ventilatoravhengighet, lungefunksjonsforbedring, pulsatil veksthormonfrigivelsesinduksjon, forbedring av brannskadepasienter og redusert sykehusopphold for brannskadepasienter (akselerasjon), renal svikt eller utilstrekkelighet som resultat av vekstretardasjon, renal homeostaseopprettholdelse hos skrøpelige eldre, sarkopeni, schizofreni, sensorfunksjonsopprettholdelse (for eksempel hørsel, syn, lukt og smak), kort tarmsyndrom, kort statur assosiert med kronisk sykdom, skjellettdysplasi, hudtykkelseopprettholdelse, søvnforstyrrelser, søvnkvalitetsforbedring, trombocytopeni, tymisk utviklingsstimulering, tannreparering eller vekst, tumorcelleproliferasjon, ventrikulær dysfunksjon eller reperfusjonshendelser, svinn i forbindelse med AIDS, svinn i forbindelse med kronisk leversykdom, svinn i forbindelse med kronisk obstruktiv lungesykdom (KOLS), svinn i forbindelse med multippel sklerose eller andre neurodegenerative forstyrrelser, svinn assosiert med frakturer, ullvekststimulering hos sauer, sårhelbredning (akselerasjon) og/eller sårhelbredningsforsinkelse".
Mer foretrukket er disse fysiologiske og/eller patofysiologiske tilstandene valgt fra gruppen som består av "vekstretardasjon, kakeksi, korttids-, middels- og/eller langtidsregulering av energibalanse, korttids-, middels- og/eller langtidsregulering (stimulering og/eller inhibering) av matinntak, adipogenese, adipositet og/eller fedme; kroppsvektøkning og/eller reduksjon; diabetes, diabetes type I, diabetes type II, tumorcelleproliferasjon, inflammasjon, inflammatoriske effekter, gastrisk postoperativ ileus, postoperativ ileus og/eller gastrektomi (ghrelinerstatningsbehandling)".
I et ytterligere aspekt av foreliggende oppfinnelse kan forbindelsene ifølge oppfinnelsen anvendes i kombinasjon med minst én ytterligere farmakologisk aktiv substans.
Slike ytterligere farmakologisk aktiv substans kan være andre forbindelser ifølge oppfinnelsen og/eller andre "egnede terapeutiske midler" anvendelige ved behandling og/eller profylakse av de tidligere nevnte fysiologiske og/eller patofysiologiske tilstandene. Den ytterligere farmakologisk aktive substansen kan være en antagonist av GHS-reseptorer og/eller en agonist av GHS-reseptorer avhengig av formålet med den kombinerte anvendelsen. Valg og kombinering av de ytterligere farmakologisk aktive substansene kan lett utføres av fagmannen på basis av hans ekspertkunnskap og avhengig av formålet med den kombinerte anvendelsen og de fysiologiske og/eller patofysiologiske tilstandene som behandlingen rettes mot.
I en foretrukket utførelsesform blir forbindelsene ifølge oppfinnelsen anvendt for behandling og/eller profylakse av de ovenfor nevnte fysiologiske og/eller patofysiologiske tilstandene i form av et medikament, hvor slikt medikament innbefatter minst én ytterligere farmakologisk aktiv substans.
I en annen foretrukket utførelsesform blir forbindelsene ifølge oppfinnelsen anvendt for behandling og/eller profylakse av de ovenfor nevnte fysiologiske og/eller patofysiologiske tilstandene i form av et medikament, hvor medikamentet anvendes før og/eller i løpet av og/eller etter behandling med den minst ene ytterligere farmakologisk aktive substansen.
De ovenfor nevnte "egnede farmasøytiske midlene" inkluderer: "GHS, antidiabetiske midler; anti-osteoporosemidler; anti-fedmemidler; anti-inflammatoriske midler; antiangstmidler; antidepressive midler; anti-hypertensive midler; anti-blodplatemidler; antitrombotiske og trombolytiske midler; hjerteglykosider; kolesterol/lipidreduserende midler; mineralokortikoidreseptorantagonister; fosfodiesteraseinhibitorer; proteintyrosinkinaseinhibitorer; tyroidetterlignende midler (som inkluderer tyroidreseptorantagonister); anabolske midler; HIV- eller AIDS-behandlinger; behandlinger anvendelige for behandling av Alzheimers sykdom og andre kognitive forstyrrelser; behandlinger anvendelige ved behandling av søvnforstyrrelser; antiproliferative midler; antitumormidler; anti-ulcer og gastro-spiserørreflukssykdomsmidler; progestinreseptoragonister ("PRA"); østrogen; testosteron; en selektiv østrogenreseptormodulator; en selektiv androgenreseptormodulator; paratyroidhormon; og/eller bisfosfonat", og foretrukket er "egnede terapeutiske midler" valgt fra gruppen som består av disse midlene.
Eksempler på egnet GHS for anvendelse i kombinasjon med forbindelsene ifølge oppfinnelsen inkluderer GHRP-6, GHRP-1 slik det er beskrevet i US-patent nr.
4 411 890; og publikasjoner WO 89/07110 og WO 89/07111 og B-HT920 eller veksthormonfrigivende faktor og dens analoger eller veksthormon og dens analoger eller somatomediner som inkluderer IGF-1 og IGF-2, så vel som GHS beskrevet i WO 01/96300.
Eksempler på egnede anti-diabetiske midler for anvendelse i kombinasjon med forbindelsene ifølge oppfinnelsen inkluderer biguanider (for eksempel metformin), glukosidaseinhibitorer (for eksempel akarbose), insuliner (som inkluderer insulinutskillende forbindelser eller insulinsensitiserere), meglitinider (for eksempel repaglinid), sulfonylurea (for eksempel glimepirid, glyburid og glipizid), biguanid/-glyburidkombinasjoner (for eksempel glucovance), tiozolidindioner (for eksempel troglitazon, rosiglitazon og pioglitazon), PPAR-alfa-agonister, PPAR-gamma-agonister, PPAR-alfa/gammaduale agonister, SGLT2-inhibitorer, inhibitorer av fettsyrebindings protein (aP2) slik som de som er beskrevet i US-patent 6548 529, glukagonlignende peptid-1 (GLP-1) og dipeptidylpeptidase IV(DP4)-inhibitorer.
Eksempler på egnede anti-osteoporosemidler for anvendelse i kombinasjon med forbindelsene ifølge oppfinnelsen inkluderer alendronat, risedronat, raloxifen, kalcitonin, ikke-steroidale progestinreseptoragonister, RANK-ligandagonister, kalsiumsensereseptorantagonister, TRAP-inhibitorer, selektive østrogenreseptormodulatorer (SERM), østrogen og AP-1-inhibitorer.
Eksempler på egnede anti-fedmemidler for anvendelse i kombinasjon med forbindelsene ifølge oppfinnelsen inkluderer endokannabinoidreseptorantagonister, for eksempel CB1-reseptorantagonister, slik som rimonabant (1H-pyrazol-3-karboksamid, 5-(4-klorfenyl)-1-(2,4-diklorfenyl)-4-metyl-N-1-piperidinyl-, monohydroklorid; CAS registreringsnummer: 158681-13-1; SR-141716A; US patent 5624 941), aP2-inhibitorer slik som de som er beskrevet i US patent 6548 529, PPAR gammaantagonister, PPAR delta-agonister og orlistat.
Eksempler på egnede anti-inflammatoriske midler for anvendelse i kombinasjon med forbindelsene ifølge oppfinnelsen inkluderer prednison, dexametason, Enbrel, syklooksygenaseinhibitorer (det vil si COX-1- og/eller COX-2-inhibitorer slik som NSAID-er, aspirin, indometacin, ibuprofen, piroxicam, Naproxen, Celebrex, Vioxx), CTLA4-lgagonister/antagonister, CD40 ligandantagonister, integrinantagonister, alfa4-beta7-integrinantagonister, celleadhesjoninhibitorer, interferon-gammaantagonister, ICAM-1, tumornekrosefaktor(TNF)-antagonister (for eksempel infliximab, OR1384), prostaglandinsynteseinhibitorer, budesonid, clofazimin, CNI-1493, CD4-antagonister (for eksempel priliximab), p38 mitogenaktivert proteinkinaseinhibitorer, proteintyrosinkinase(PTK)-inhibitorer, IKK-inhibitorer og behandlinger for behandling av irritabel tarmsyndrom (for eksempel zelmac og Maxi-K-åpnere slik som de som er beskrevet i US-patent nr.6 184 231).
Eksempler på egnede anti-angstmidler for anvendelse i kombinasjon med forbindelsene ifølge oppfinnelsen inkluderer diazepam, lorazepam, buspiron, oksazepam og hydroksyzinpamoat.
Eksempler på egnede anti-depressive midler for anvendelse i kombinasjon med forbindelsene ifølge oppfinnelsen, inkluderer citalopram, fluoxetin, nefazodon, sertralin og paroxetin.
Eksempler på egnede anti-hypertensive midler for anvendelse i kombinasjon med forbindelsene ifølge oppfinnelsen, inkluderer beta-adrenergiske blokkerere, kalsiumkanalblokkerere (L-type og T-type; for eksempel diltiazem, verapamil, nifedipin, amlodipin og mybefradii), diuretiske midler (for eksempel klortiazid, hydroklortiazid, flumetiazid, hydroflumetiazid, bendroflumetiazid, metylklortiazid, triklormetiazid, polytiazid, benztiazid, etacrynsyretricrynafen, klortalidon, furosemid, musolimin, bumetanid, triamtrenen, amilorid, spironolakton), renininhibitorer, ACE-inhibitorer (for eksempel captopril, zofenopril, fosinopril, enalapril, ceranopril, cilazopril, delapril, pentopril, kinapril, ramipril, lisinopril), AT-1-reseptorantagonister (for eksempel losartan, irbesartan, valsartan), ET-reseptorantagonister (for eksempel sitaxsentan, atrsentan og forbindelser beskrevet i US-patent nr.5 612 359 og 6043 265, Dual ET/AII-antagonist (for eksempel forbindelser beskrevet i WO 00/01389), nøytrale endopeptidase(NEP)-inhibitorer, vasopepsidaseinhibitorer (duale NEP-ACE-inhibitorer) (for eksempel omapatrilat og gemopatrilat) og nitrater.
Eksempler på egnede anti-blodplatemidler for anvendelse i kombinasjon med forbindelsene ifølge oppfinnelsen, inkluderer GPIIb/IIIa-blokkerere (for eksempel abciximab, eptifibatid, tirofiban), P2Y12-antagonister (for eksempel clopidogrel, ticlopidin, CS-747), tromboksanreseptorantagonister (for eksempel ifetroban), aspirin og PDE-III-inhibitorer (for eksempel dipyridamol) med eller uten aspirin.
Eksempler på egnede hjerteglykosider for anvendelse i kombinasjon med forbindelsene ifølge oppfinnelsen, inkluderer digitalis og ouabain.
Eksempler på egnede kolesterol/lipidreduserende midler for anvendelse i kombinasjon med forbindelsene ifølge oppfinnelsen, inkluderer HMG-CoA-reduktaseinhibitorer [for eksempel pravastatin, lovastatin, atorvastatin, simvastatin, NK-104 (a.k.a. itavastatin eller nisvastatin eller nisbastatin] og ZD-4522 (a.k.a. rosuvastatin eller atavastatin eller visastatin)), skvalénsyntaseinhibitorer, fibrater, gallesyresekvestranter, ACAT-inhibitorer, MTP-inhibitorer, lipooksygenaseinhibitorer, kolesterolabsorpsjonsinhibitorer og kolesterolesteroverføringsproteininhibitorer (for eksempel CP-529414).
Eksempler på egnede mineralokortikoidreseptorantagonister for anvendelse i kombinasjon med forbindelsene ifølge oppfinnelsen, inkluderer spironolakton og eplerinon.
Eksempler på egnede fosfodiesteraseinhibitorer for anvendelse i kombinasjon med forbindelsene ifølge oppfinnelsen, inkluderer PDE III-inhibitorer slik som cilostazol og PDE V-inhibitorer slik som sildenafil.
Eksempler på egnede tyroidetterlignende forbindelser for anvendelse i kombinasjon med forbindelsene ifølge oppfinnelsen, inkluderer tyrotropin, polytyroid, KB-130015 og dronedaron.
Eksempler på egnede anabole midler for anvendelse i kombinasjon med forbindelsene ifølge oppfinnelsen, inkluderer testosteron og SARM-er.
Eksempler på egnede HIV- eller AIDS-behandlinger for anvendelse i kombinasjon med forbindelsene ifølge oppfinnelsen, inkluderer indinavirsulfat, saquinavir, saquinavirmesylat, amprenavir, ritonavir, lopinavir, ritonavir/lopinavirkombinasjoner, lamivudin, zidovudin, lamivudin/zidovudinkombinasjoner, zalcitabin, didanosin, stavudin og megestrolacetat.
Eksempler på egnede behandlinger for behandling av Alzheimers sykdom og kognitive forstyrrelser for anvendelse i kombinasjon med forbindelsene ifølge oppfinnelsen, inkluderer donepezil, tacrin, revastigmin, 5HT6, gamma-sekretaseinhibitorer, betasekretaseinhibitorer, SK-kanalblokkerere, Maxi-K-blokkerere og KCNQ-er-blokkerere.
Eksempler på egnede behandlinger for behandling av søvnforstyrrelser for anvendelse i kombinasjon med forbindelsene ifølge oppfinnelsen, inkluderer melatoninanaloger, melatoninreseptorantagonister, ML1B-agonister og GABA/NMDA-reseptorantagonister.
Eksempler på egnede anti-proliferative midler for anvendelse i kombinasjon med forbindelsene ifølge oppfinnelsen, inkluderer syklosporin A, taxol, FK 506 og adriamycin.
Eksempler på egnede anti-tumormidler for anvendelse i kombinasjon med forbindelsene ifølge oppfinnelsen, inkluderer taxol, adriamycin, epotiloner, cisplatin og barboplatin.
Eksempler på egnede selektive østrogenreseptormodulatorer for anvendelse i kombinasjon med forbindelsene ifølge oppfinnelsen, inkluderer tamoxifen og raloxifen.
Eksempler på egnede selektive androgenreseptormodulatorer for anvendelse i kombinasjon med forbindelsene ifølge oppfinnelsen, inkluderer de som er beskrevet i Edwards, J. P. et al., Bio. Med. Chem. Let., 9, 1003-1008 (1999) og Hamann, L. G. et al., J. Med. Chem., 12, 210-212 (1999).
Eksempler på egnede bisfosfonater for anvendelse i kombinasjon med forbindelsene ifølge oppfinnelsen, inkluderer MK-217 (alendronat).
De ovenfor angitte andre terapeutiske midlene, når de anvendes i kombinasjon med forbindelsene ifølge oppfinnelsen, kan for eksempel anvendes i de mengdene indikert i "the Physicians' Desk Reference" (PDR) eller slik det bestemmes av fagmannen.
I en foretrukket utførelsesform blir forbindelsene ifølge oppfinnelsen anvendt for behandling og/eller profylakse av de ovenfor nevnte fysiologiske og/eller patofysiologiske tilstandene i form av et medikament, hvor slikt medikament innbefatter som ytterligere farmakologisk aktiv substans en endokannabinoidreseptorantagonist, foretrukket en CB1-reseptorantagonist, mest foretrukket rimonabant (1H-pyrazol-3-karboksamid, 5-(4-klorfenyl)-1-(2,4-diklorfenyl)-4-metyl-N-1-piperidinyl-, monohydroklorid; CAS-registreringsnummer: 158681-13-1; SR-141716A; US-patent 5 624 941) og som forbindelse ifølge oppfinnelsen en GHS-R-antagonist.
I en annen foretrukket utførelsesform blir forbindelsene ifølge oppfinnelsen anvendt for behandling og/eller profylakse av de ovenfor nevnte fysiologiske og/eller patofysiologiske tilstandene i form av et medikament, hvor medikamentet anvendes før og/eller i løpet av og/eller etter behandling med minst én ytterligere farmakologisk aktiv substans hvor slik ytterligere farmakologisk aktiv substans er en endokannabinoidreseptorantagonist, foretrukket en CB1-reseptorantagonist,mest foretrukket rimonabant (1H-pyrazol-3-karboksamid, 5-(4-klorfenyl)-1-(2,4-diklorfenyl)-4-metyl-N-1-piperidinyl-, monohydroklorid; CAS registreringsnummer: 158681-13-1; SR-141716A; US-patent 5624 941) og forbindelsen ifølge oppfinnelsen er en GHS-R-antagonist.
Forbindelsene ifølge oppfinnelsen kan administreres på kjent måte. Administrasjonsruten kan derved være en hvilken som helst rute som effektivt transporterer den aktive forbindelsen til passende eller ønsket virkningssete, for eksempel oralt eller ikke-oralt, særlig topisk, transdermalt, pulmonært, rektalt, intravaginalt, nasalt eller parenteralt eller ved implantering. Oral administrasjon er foretrukket.
Forbindelsene ifølge oppfinnelsen blir omdannet til en form som kan administreres og blandes hvis hensiktsmessig med farmasøytisk akseptable bærere eller fortynningsmidler. Egnede eksipienter og bærere er for eksempel beskrevet i Ullman's Encyclopedia of Technical Chemistry, Vol.4 (1953), 1-39; Journal of Pharmaceutical Sciences, Vol.52 (1963), 918 et seq.; H. v. Czetsch-Lindenwald, "Hilfsstoffe für Pharmazie and angrenzende Gebiete"; Pharm. Ind.2, 1961, 72 et seq.; Dr. H.P. Fiedler, "Lexikon der Hilfsstoffe für Pharmazie, Kosmetik and angrenzende Gebiete", Cantor KG, Aulendorf in Württemberg, 1971.
Oral administrasjon kan finne sted for eksempel i fast form som tablett, kapsel, gelkapsel, belagt tablett, granul eller pulver, men også i form av en drikkbar løsning.
Forbindelsene ifølge oppfinnelsen kan for oral administrasjon kombineres med kjente og vanlig anvendte, fysiologisk akseptable eksipienter og bærere slik som for eksempel gummi arabicum, talkum, stivelse, sukker slik som for eksempel mannitol, metylcellulose, laktose, gelatin, overflateaktive midler, magnesiumstearat, syklodekstriner, vandige eller ikke-vandige bærere, fortynningsmidler, dispergeringsmidler, emulgatorer, smøremidler, konserveringsmidler og smaksstoffer (for eksempel essensielle oljer). Forbindelsene ifølge oppfinnelsen kan også dispergeres i en mikropartikulær, for eksempel nanopartikulær, sammensetning.
Ikke-oral administrasjon kan finne sted for eksempel ved intravenøs, subkutan, intramuskulær injeksjon av sterile, vandige eller oljeløsninger, suspensjoner eller emulsjoner, ved hjelp av implantater eller ved salver, kremer eller stikkpiller. Administrasjon som vedvarende frigivelsesform er også mulig hvis hensiktsmessig. Implantater kan innbefatte inerte materialer, for eksempel bionedbrytbare polymerer eller syntetiske silikoner, slik som for eksempel silikongummi. Intravaginal administrasjon er for eksempel mulig ved hjelp av vaginale ringer. Intrauterin administrasjon er mulig for eksempel ved hjelp av diafragmaer eller andre egnede intrauterine innretninger.
Transdermal administrasjon er i tillegg tilveiebrakt, særlig ved hjelp av en formulering egnet for dette formål og/eller egnede midler slik som for eksempel plastre.
Doseringen kan variere innenfor et bredt område avhengig av type og/eller alvorlighet ved den fysiologiske og/eller patofysiologiske tilstanden, administrasjonsmåte, alder, kjønn, kroppsvekt og sensitiviteten til subjektet som behandles. Det er innenfor fagmannens kunnskap å bestemme en "farmasøytisk effektiv mengde" av en forbindelse ifølge oppfinnelsen og/eller ytterligere farmakologisk aktiv substans. Administrasjon kan finne sted i en enkel dose eller et antall separate doseringer.
En passende enhetsdose er for eksempel fra 0,001 mg til 100 mg av den aktive ingrediensen, det vil si minst én forbindelse ifølge oppfinnelsen og hvis hensiktsmessig minst én ytterligere farmakologisk aktiv substans, per kg av en pasients kroppsvekt.
I et annet aspekt angår foreliggende oppfinnelse en farmasøytisk sammensetning som innbefatter en farmakologisk aktiv mengde av minst én triazolforbindelse valgt fra gruppen som består av: forbindelse 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101,102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 124, 125, 126, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189 og/eller forbindelse 190.
I et ytterligere aspekt kan en slik farmasøytisk sammensetning ytterligere innbefatte minst én farmasøytisk akseptabel bærer og/eller eksipient og/eller kan innbefatte minst én ytterligere farmakologisk aktiv substans.
I en foretrukket utførelsesform er slik ytterligere farmakologisk aktiv substans en endokannabinoidreseptorantagonist, foretrukket en CB1-reseptorantagonist, mest foretrukket rimonabant [1H-pyrazol-3-karboksamid, 5-(4-klorfenyl)-1-(2,4-diklorfenyl)-4-metyl-N-1-piperidinyl-, monohydroklorid].
Angående de farmasøytiske sammensetningene ifølge oppfinnelsen er minst én av triazolforbindelsene listet ovenfor, til stede i en farmakologisk effektiv mengde, foretrukket i en enhetsdose, for eksempel den ovenfor nevnte enhetsdosen, spesifikt og foretrukket i en administrasjonsform som gjør oral administrasjon mulig. Derfor kan referanse gjøres til det som allerede er sagt i forbindelse med de mulige anvendelsene og administrasjonene av forbindelsene ifølge oppfinnelsen.
Forbindelsene ifølge oppfinnelsen kan fremstilles i henhold til følgende generelle synteseskjemaer, så vel som relevante, publiserte litteraturfremgangsmåter som er kjente for fagmannen (for eksempel WO 00/54729 og siterte referanser deri).
Eksempler på reagenser og fremgangsmåter for disse reaksjonene er beskrevet i det følgende og i arbeidseksemplene. Med mindre annet er spesifisert har de forskjellige substituentene (radikalene) til forbindelsene betydningene slik de er definert for formel (I) heri
hvori
R1 og R2 er uavhengig av hverandre valgt fra gruppen som består av "hydrogenatom, alkyl, alkenyl, alkynyl, sykloalkyl, sykloalkylalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterosyklyl, heterosyklylalkyl, alkylsulfonyl, arylsulfonyl, arylalkylsulfonyl" som eventuelt er substituert i alkyl-, sykloalkyl-, sykloalkylalkyl-, aryl-, heteroaryl-, arylalkyl-, heteroarylalkyl-, heterosyklyl- og/eller heterosyklylalkylgruppen med opp til 3 substituenter uavhengig valg fra gruppen som består av "halogen, -F, -Cl, -Br, -I, -N3, -CN, -NR7R8, -OH, -NO2, alkyl, aryl, arylalkyl, -O-alkyl, -O-aryl, -O-arylalkyl"; og er foretrukket valgt fra gruppen som består av "alkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl" som eventuelt er substituert med opp til 3 substituenter uavhengig valgt fra gruppen som består av "halogen, -F, -Cl, -Br, -I, -N3, -CN, -NR7R8, -OH, -NO2, alkyl, aryl, arylalkyl, -O-alkyl, -O-aryl, -O-arylalkyl";
ett av radikalene R3 og R4 er et hydrogenatom, mens det andre radikalet er valgt fra gruppen som består av "hydrogenatom, alkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterosyklyl, heterosyklylalkyl, -alkyl-O-aryl, -alkyl-O-arylalkyl, -alkyl-O-heteroaryl, -alkyl-O-heteroarylalkyl, -alkyl-O-heterosyklyl, alkyl-O-heterosyklylalkyl, -alkyl-CO-aryl, -alkyl-CO-arylalkyl, -alkyl-CO-heteroaryl, -alkyl-CO-heteroarylalkyl, -alkyl-CO-heterosyklyl, -alkyl-CO-heterosyklylalkyl, -alkyl-C(O)O-aryl, -alkyl-C(O)O-arylalkyl, -alkyl-C(O)O-heteroaryl, -alkyl-C(O)O-heteroarylalkyl, -alkyl-C(O)O-heterosyklyl, -alkyl-C(O)O-heterosyklylalkyl, -alkyl-CO-NH2, -alkyl-CO-OH, -alkyl-NH2, -alkyl-NH-C(NH)NH2, alkylsulfonyl, arylsulfonyl, arylalkylsulfonyl, alkyl-S-alkyl, alkyl-S-H" som eventuelt er substituert i aryl-, heteroaryl-, arylalkyl-, heteroarylalkyl-, heterosyklyl og/eller heterosyklylalkylgruppen med opp til 3 substituenter uavhengig valgt fra gruppen som består av "halogen, -F, -Cl, -Br, -I, -N3, -CN, -NR7R8, -OH, -NO2, alkyl, aryl, arylalkyl, -O-alkyl, -O-aryl, -O-arylalkyl"; og er foretrukket valgt fra gruppen som består av "arylalkyl, heteroarylalkyl, heterosyklylalkyl, -alkyl-O-aryl, -alkyl-O-arylalkyl, -alkyl-O-heteroaryl, -alkyl-O-heteroarylalkyl, -alkyl-O-heterosyklyl, alkyl-O-heterosyklylalkyl, -alkyl-CO-aryl, -alkyl-CO-arylalkyl, -alkyl-CO-heteroaryl, -alkyl-CO-heteroarylalkyl, -alkyl-CO-heterosyklyl, alkyl-CO-heterosyklylalkyl, -alkyl-C(O)O-aryl, -alkyl-C(O)O-arylalkyl, -alkyl-C(O)O-heteroaryl, -alkyl-C(O)O-heteroarylalkyl, -alkyl-C(O)O-heterosyklyl, -alkyl-C(O)O-heterosyklylalkyl, -alkyl-CO-NH2, -alkyl-CO-OH, -alkyl-NH2, -alkyl-NH-C(NH)-NH2", som eventuelt er substituert i aryl-, heteroaryl-, arylalkyl-, heteroarylalkyl-, heterosyklyl- og/eller heterosyklylalkylgruppen med opp til 3 substituenter uavhengig valgt fra gruppen som består av "halogen, -F, -Cl, -Br, -I, -N3, -CN, -NR7R8, -OH, -NO2, alkyl, aryl, arylalkyl, -O-alkyl, -O-aryl, -O-arylalkyl";
R5 er valgt fra gruppen som består av "hydrogenatom, alkyl, sykloalkyl, sykloalkylalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterosyklyl, heterosyklylalkyl, -CO-alkyl, -CO-sykloalkyl, -CO-sykloalkylalkyl, -CO-aryl, -CO-arylalkyl, -CO-heteroaryl, -CO-heteroarylalkyl, -CO-heterosyklyl, -CO-heterosyklylalkyl, -CO-C*(R9R10)-NH2, -CO-CH2-C*(R9R10)-NH2, -CO-C*(R9R10)-CH2-NH2, alkylsulfonyl, arylsulfonyl, arylalkylsulfonyl" som eventuelt er substituert med opp til 3 substituenter uavhengig valgt fra gruppen som består av "halogen, -F, - Cl, -Br, -I, -N3, -CN, -NR7R8, -OH, -NO2, alkyl, aryl, arylalkyl, -O-alkyl, -O-aryl, -Oarylalkyl"; og er foretrukket valgt fra gruppen som består av "hydrogenatom, -CO-alkyl, -CO-sykloalkyl, -CO-aryl, -CO-heteroaryl, -CO-arylalkyl, -CO-heteroarylalkyl, -CO-heterosyklyl, -CO-C*(R9R10)-NH2, -CO-CH2-C*(R9R10)-NH2, -CO-C*(R9R10)-CH2-NH2", eventuelt substituert med opp til 3 substituenter uavhengig valgt fra gruppen som består av "halogen, -F, - Cl, -Br, -I, -N3, -CN, -NR7R8, -OH, -NO2, alkyl, aryl, arylalkyl, -O-alkyl, -O-aryl, -O-arylalkyl";
R6 er valgt fra gruppen som består av "hydrogenatom, alkyl, sykloalkyl, sykloalkylalkyl" og er foretrukket et hydrogenatom;
R7 og R8 er uavhengig av hverandre valgt fra gruppen som består av "hydrogenatom, alkyl, sykloalkyl, sykloalkylalkyl" og er foretrukket et hydrogenatom;
R9 og R10 er uavhengig av hverandre valgt fra gruppen som består av 'hydrogenatom, alkyl, naturlig alfa-aminosyresidekjede, unaturlig alfaaminosyresidekjede" og er foretrukket valgt fra gruppen som består av "hydrogenatom, alkyl";
m er 0, 1 eller 2 og foretrukket 0; og
* betyr et karbonatom med R- eller S-konfigurasjon når kiralt.
Amidbindingsdannelse (peptidkobling) utføres under standard peptidkoblingsfremgangsmåter kjent i litteraturen. Eventuelt blir reaksjonen utført i et løsemiddel slik som diklormetan (DCM) ved anvendelse av benzotriazol-1-yl-oksytris(dimetylamino)-fosfoniumheksafluorfosfat (BOP) (Castro B et al., Tetrahedron Lett.1975, 14:1219-1222) og en base, for eksempel N-metyl-morfolin eller diisopropyletylamin.
Tionering av det dannede amidet utføres ved anvendelse av Lawessons reagens (Pons JF et al., Tetrahedron Lett.2000, 41: 4965-4968).
Syklisering: det oppnådde tioamidet blir deretter underkastet betingelsene rapportert av Hitosuyanagi et al. (Hitotsuyanagi Y. et al., J. Org. Chem.2002, 67: 3266-3271) som ble noe modifisert (5 eq. hydrazid og 1,1 eq. kvikksølv(II)acetat i acetonitril).
Syklisering til triazoler ble generelt oppnådd i løpet av tre timer. Når hydrazidet ikke var kommersielt tilgjengelig ble det fremstilt ved kjente fremgangsmåter fra deres syre eller metylesterforløpere.
Avbeskyttelse av tert-butyloksykarbonylgruppen (Boc) ble utført ved romtemperatur i surt medium slik det vanligvis er beskrevet.
For R5 = -CO-alkyl, -CO-sykloalkyl, -CO-sykloalkylalkyl, -CO-aryl, -CO-arylalkyl, -CO-heteroaryl, -CO-heteroarylalkyl, -CO-heterosyklyl, -CO-heterosyklylalkyl, -CO-C*(R9R10)-NH2, -CO-CH2-C*(R9R10)-NH2, -CO-C*(R9R10)-CH2-NH2(R):
For R5 = alkyl, sykloalkyl, sykloalkylalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterosyklyl, heterosyklylalkyl (R):
For R5 = alkyl-SO2-, aryl-SO2-, arylalkyl-SO2- (R = alkyl, aryl, arylalkyl):
Forbindelsene ifølge oppfinnelsen, forbindelser 1 til 190, ble navngitt fra den tegnede formelen ved anvendelse av Chem Draw Ultra 8 software (CambridgeSoft Corporation, Cambridge, USA).
Figurene 1-13 viser de målte konkurreringsverdiene i GHS-R 1a-reseptorligandbindingsundersøkelsen for<125>I-His<9>-ghrelin og valgte forbindelser 9, 31, 39, 45, 50, 62, 64, 71, 73, 74, 79, 81 og 90 slik det er beskrevet i II) i eksempeldelen.
Figurene 14-40 viser beregnede dose-responsverdier i den in vitro-intracellulære kalsiumfrigivelsesundersøkelsen med humane GHS-R 1a-transfekterte CHO-celler til valgte forbindelser 1, 9, 12, 20, 22, 31, 39, 41, 42, 45, 46, 47, 48, 49, 50, 51, 55, 62, 64, 67, 71, 73, 74, 79, 81, 90 og ghrelin slik det er beskrevet i III) i eksempeldelen så vel som EC50og KI-verdier for GHS-reseptoragonister og IC50og Kb-verdier for GHS-reseptorantagonister.
Figurene 41 - 46 viser effektene av valgte forbindelser 9, 38, 50, 64, 74, 81 på isoprorerenolindusert lipolyseinhiberingskurven til ikke-acylert ghrelin (UAG) i primære adipocytter fra mus under diettindusert fedme slik det er beskrevet i (VIII) i eksempeldelen.
Innholdet i alle siterte referanser og patenter er herved innbefattet ved referanse.
Oppfinnelsen er forklart i mer detalj ved hjelp av følgende eksempler uten imidlertid å være begrenset dertil.
Eksempler
I) Syntese av forbindelser ifølge oppfinnelsen
Eksempel 1
(R)-N-(1-(5-(2-(1H-indol-3-yl)etyl)-4-(2,4-dimetoksybenzyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid (forbindelse 1)
Forbindelse 1 ble oppnådd fra Boc-(D)-Trp (10 mmol), (2,4-dimetoksyfenyl)metanamin, 3-(1H-indol-3-yl)propanhydrazid og Boc-2-amino-2-metylpropansyre i henhold til de generelle synteseskjemaene med et totalt utbytte etter rensing med HPLC på 35 %.
<1>H NMR (400 MHz, 300 °K, DMSO-d<6>):
δ1,32 (3H, s, CH3Aib), 1,36 (3H, s, CH3Aib), 2,93 (2H, m, CH2-CH2-indol), 2,97 (2H, m, CH2-CH2-indol), 3,31 (1H, dd, J = 14,5, J = 6,1, 1H CH2δTrp), 3,38 (1H, dd, J = 14,5, J = 9,1, 1H CH2δTrp), 3,66 (3H, s, o-OCH3), 3,72 (3H, s, p-OCH3), 4,93 (1H, d, J = 16,9, 1H CH2o,p-dimetoksybenzyl), 5,10 (1H, d, J = 16,9, 1H CH2o,p-dimetoksybenzyl), 5,23 (1H, m, C αH Trp), 6,31 (1H, dd, J = 8,5, J = 1,7, H5o,p-dimetoksybenzyl), 6,45 (1H, d, J = 8,5, H6o,p-dimetoksybenzyl), 6,59 (1H, d, J = 1,7, H3o,pdimetoksybenzyl), 6,88 (1H, t, J = 7,5, H5Trp), 6,94 (1H, t, J = 7,5, H5-indol), 7,04 (1H, t, H6Trp), 7,06 (1H, t, H6indol), 7,08 (1H, s, H2indol), 7,11 (1H, s, H2Trp), 7,18 (1H, d, J = 7,9, H4Trp), 7,33 (3H, H4, H7indol, H7Trp), 8,05 (2H, s, NH2Aib), 8,95 (1H, d, J = 7,9, NH Trp), 10,80 (1H, s, NH indol), 10,82 (1H, s, NH indol Trp).
<13>C NMR (400 MHz, DMSO-d<6>):
δ22,4 (CH2-CH2indol), 23,2 (CH3Aib), 23,3 (CH3Aib), 25,4 (CH2-CH2indol), 28,7 (C β Trp), 41,3 (CH2- o,p-dimetoksybenzyl), 45,3 (C α Trp), 55,2 (p-OCH3), 55,4 (o-OCH3), 56,3 (Cq Aib), 98,6 (C3o,p-dimetoksybenzyl), 104,7 (C5o,p-dimetoksybenzyl), 109,5 (C3Trp), 111,3 (C7Trp, C7indol), 112,9 (C3indol), 115,2 (C1o,p-dimetoksybenzyl), 117,8 (C4-indol), 117,9 (C4Trp), 118,2 (C5Trp, C5indol), 120,9 (C6Trp, C6indol), 122,4 (C2indol), 124,3 (C2Trp), 126,8 (C9indol), 126,9 (C9Trp), 127,5 (C6o,p dimetoksybenzyl), 136,0 (C8Trp), 136,2 (C8indol), 154,6 (2Cq triazol), 157,3 (C2 o,pdimetoksybenzyl), 160,4 (C4 o,p-dimetoksybenzyl), 171,3 (CO Aib).
ESI-MS: funnet: m/z 606,3 [M+H]<+>/ beregnet: 604,3 g/mol
Eksempel 2
(R)-N-(1-(5-benzyl-4-(naftalen-1-ylmetyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)-etyl)-2-amino-2-metylpropanamid (forbindelse 4)
Forbindelse 4 ble oppnådd fra Boc-(D)-Trp (10 mmol), naftalen-1-yl-metanamin, 2-fenylacetohydrazid og Boc-2-amino-2-metylpropansyre i henhold til de generelle synteseskjemaene med et totalt utbytte etter rensing med HPLC på 42 %.
<1>H NMR (300 MHz, DMSO-d<6>, 300 °K):
δ (ppm) 1,18 (3H, s, CH3Aib), 1,24 (3H, s, CH3Aib), 3,17 (1H, dd, J = 14 Hz og 5 Hz, CH2βTrp), 3,36 (1H, dd, J = 14 og 9 Hz, CH2βTrp), 4,05 (2H, m, CH2-benzyl), 4,90 (1H, m, CH αTrp), 5,65 (1H, d, J = 18 Hz, CH2-naftyl), 5,81 (1H, d, J = 18 Hz, CH2-naftyl), 6,12 (1H, d, Jo= 7 Hz, H2naftyl), 6,38 (1H, t, Jo= 7 Hz, H5Trp), 6,47 (1H, d, Jo= 8 Hz, H4Trp), 6,85 (1H, t, Jo= 8 Hz, H6Trp), 7,03 (1H, d, Jm= 2 Hz, H2Trp), 7,05-7,12 (5H, m, CHar benzyl), 7,15 (1H, d, Jo= 8 Hz, H7Trp), 7,19 (1H, d, Jo= 8 Hz, H3naftyl), 7,58 (2H, m, H6og H7naftyl), 7,81 (1H, d, Jo= 8 Hz, H4naftyl), 7,89-8,01 (5H, m, NH2Aib, H5og H8naftyl), 8,92 (1H, d, J = 8 Hz, NH amid), 10,73 (1H, s, NH indol Trp).
<13>C NMR (75 MHz, DMSO-d<6>, 300°K):
δ (ppm) 23,5 (CH3Aib), 23,6 (CH3Aib), 29,2 (CH2βTrp), 30,5 (CH2-benzyl), 44,0 (CH2-naftyl), 45,6 (CH αTrp), 56,6 (Cq Aib), 109,7 (C3Trp), 111,7 (C7Trp), 117,9 (C4Trp), 118,4 (C5Trp), 121,1 (C6Trp), 122,1 (C2naftyl), 122,8 (C8naftyl), 124,9 (C2Trp), 125,7 (C3naftyl), 126,7 (C6naftyl), 126,9 (C9Trp), 127,0 (C7naftyl), 128,2 (C4benzyl), 128,7-129,1 (C2, C3, C5og C6benzyl, C4og C5naftyl), 129,9 (C9naftyl), 131,5 (C1naftyl), 133,5 (C10naftyl), 136,2 (C1benzyl), 136,4 (C8Trp), 154,2 (Cq triazol), 155,7 (Cq triazol), 171,9 (CO Aib).
ESI-MS: funnet: m/z 543,4 [M+H]<+>/ beregnet: 542,2 g/mol.
Eksempel 3
(R)-N-(1-(5-(2-(1H-indol-3-yl)etyl)-4-(naftalen-1-ylmetyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid (forbindelse 5)
Forbindelse 5 ble oppnådd fra Boc-(D)-Trp (10 mmol), naftalen-1-yl-metanamin, 3-(1H-indol-3-yl)propanhydrazid og Boc-2-amino-2-metylpropansyre i henhold til de generelle synteseskjemaene med et totalt utbytte etter rensing med HPLC på 33 %.
<1>H NMR (400 MHz, DMSO-d<6>, 300°K):
δ (ppm) 1,25 (3H, s, CH3Aib), 1,28 (3H, s, CH3Aib), 2,93 (2H, m, CH2-CH2-indol), 3,01 (2H, m, CH2-CH2-indol), 3,30 (1H, dd,<3>J = 14,3 og 5,8 Hz, CH2βTrp), 3,40 (1H, dd,<3>J = 14,3 og 8,8 Hz, CH2βTrp), 5,03 (1H, m, CH αTrp), 5,62 (1H, d, J = 18,0 Hz, CH2-naftyl), 5,76 (1H, J = 18,0 Hz, CH2-naftyl), 3,36 (1H, d, Jo= 7,2 Hz, H2naftyl), 6,51 (1H, t, J, = 7,4 Hz, H5Trp), 6,72 (1H, d, Jo= 7,9 Hz, H4Trp), 6,76 (1H, t, Jo= 7,5 Hz, H5indol), 6,92 (1H, t, Jo= 7,5 Hz, H6Trp), 7,0 (1H, t, Jo= 7,5 Hz, H6indol), 7,02 (1H, d, J = 2,0 Hz, H2indol), 7,09 (1H, d, J = 2,0 Hz, H2Trp), 7,13 (1H, d, Jo= 7,9 Hz, H4indol), 7,26 (1H, Jo= 7,9 Hz, H7Trp), 7,27 (1H, t, Jo= 8,2 Hz, H3naftyl), 7,29 (1H, d, H7indol), 7,58-7,64 (2, m, H6og H7naftyl), 7,88 (1H, d, Jo= 8,2 Hz, H4naftyl), 7,93 (1H, d, Jo= 7,9 Hz, H8naftyl), 7,98 (3H, brs, NH2Aib), 8,03 (1H, d, Jo= 8,2 Hz, H5naftyl), 8,96 (1H, d, Jo= 7,9 Hz, NH Trp), 10,75 (1H, brs, NH indol), 10,77 (1H, brs, NH indol Trp).
<13>C NMR (100 MHz, DMSO-d<6>, 300°K):
δ (ppm) 22,6 (CH2-CH2-indol), 23,1 (CH3Aib), 23,2 (CH3Aib), 25,3 (CH2-CH2-indol), 28,8 (CH2βTrp), 43,3 (CH2-naftyl), 45,3 (CH αTrp), 56,2 (Cq Aib), 109,4 (C3Trp), 111,2 (C7indol og C7Trp), 112,9 (C3indol), 117,5 (C4Trp), 117,8 (C4indol), 118,0 (C5Trp), 118,1 (C5indol), 120,7 (C6Trp), 120,8 (C6indol), 121,6 (C2naftyl), 122,5 (C2indol og C8naftyl), 124,4 (C2Trp), 125,4 (C3naftyl), 126,3 (C6naftyl), 126,6 (C9indol, C9Trp og C7naftyl), 127,9 (C4naftyl), 128,6 (C5naftyl), 129,5 (C9naftyl), 131,4 (C1naftyl), 133,1 (C10naftyl), 135,9 (C8Trp), 136,1 (C8indol), 154,7 (2 Cq triazol), 171,4 (CO Aib).
ESI-MS: funnet: m/z 596,4 [M+H]<+>/ beregnet: 595,3 g/mol.
Eksempel 4
(R)-N-(1-(5-(2-(1H-indol-3-yl)etyl)-4-(3-metoksybenzyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid (forbindelse 6)
Forbindelse 6 ble oppnådd fra Boc-(D)-Trp (10 mmol), (3-metoksyfenyl)metanamin, 3-(1H-indol-3-yl)propanhydrazid og Boc-2-amino-2-metylpropansyre i henhold til de generelle synteseskjemaene med et totalutbytte etter rensing med HPLC på 25 %.
<1>H NMR (400 MHz, DMSO-d<6>):
δ (ppm) 1,28 (3H, s, CH3Aib), 1,30 (3H, s, CH3Aib), 2,92 (2H, m, CH2-CH2-indol), 2,98 (2H, m, CH2-CH2-indol), 3,33 (1H, dd, J = 14,5, J = 6,2, 1H CH2βTrp), 3,40 (1H, dd, J = 14,5, J = 8,8, 1H CH2βTrp), 3,66 (3H, s, OCH3), 5,09 (2H, m, CH2m-metoksybenzyl), 5,22 (1H, m, C αH Trp), 6,38 (1H, d, J = 7,5, H6m-metoksybenzyl), 6,59 (1H, s, H2m-metoksybenzyl), 6,86 (1H, t, H5Trp), 6,87 (1H, d, H4m-metoksybenzyl), 6,92 (1H, t, J = 7,5, H5indol), 7,03 (1H, t, J = 7,9, H6Trp), 7,05 (1H, t, H6indol), 7,07 (1H, s, H2indol), 7,11 (1H, s, H2Trp), 7,18 (1H, t, H5m-metoksybenzyl), 7,19 (1H, d, H4Trp), 7,31 (1H, H4indol), 7,32 (2H, H7Trp, H7indol), 8,00 (2H, s, NH2Aib), 8,96 (1H, d, J = 8,1, NH Trp), 10,78 (1H, s, NH indol), 10,80 (1H, s, NH indol Trp).
<13>C NMR (400 MHz, DMSO-d<6>):
δ (ppm) 22,4 (CH2-CH2indol), 23,1 (CH3Aib), 23,3 (CH3Aib), 25,4 (CH2-CH2indol), 28,7 (C β Trp), 45,3 (CH2m-metoksybenzyl), 45,4 (C α Trp), 55,0 (OCH3), 56,3 (Cq Aib), 109,5 (C3Trp), 111,3 (C7Trp, C7indol), 112,0 (C2m-metoksybenzyl), 113,0 (C4m-metoksybenzyl, C3indol), 117,8 (C4Trp, C6m-metoksybenzyl), 118,0 (C4indol), 118,2 (C5indol), 118,3 (C5Trp), 120,8 (C6indol), 120,9 (C6Trp), 122,4 (C2indol), 124,3 (C2Trp), 126,7 (C9indol), 126,9 (C9Trp), 130,0 (C5m-metoksybenzyl), 136,0 (C8indol), 136,1 (C8Trp), 137,2 (C1m-metoksybenzyl), 154,3 (2 Cq triazol), 159,6 (C3m-metoksybenzyl), 171,4 (CO Aib).
ESI-MS: funnet: m/z 576,6 [M+H]<+>/ beregnet: 575,3 g/mol.
Eksempel 5
(R)-N-(1-(4-(3-metoksybenzyl)-5-benzyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)-etyl)-2-amino-2-metylpropanamid (forbindelse 7)
Forbindelse 7 ble oppnådd fra Boc-(D)-Trp (10 mmol), (3-metoksyfenyl)metanamin, 2-fenylacetohydrazid og Boc-2-amino-2-metylpropansyre i henhold til de generelle synteseskjemaene med et totalutbytte etter rensing med HPLC på 30 %.
<1>H NMR (400 MHz, DMSO-d<6>):
δ (ppm) 1,25 (3H, s, CH3Aib), 1,29 (3H, s, CH3Aib), 3,24 (1H, dd, J = 14,3, J = 5,8, 1H CH2βTrp), 3,38 (1H, dd, J = 14,3, J = 9,1, 1H CH2βTrp), 3,61 (3H, s, m-OCH3), 4,04 (2H, m, CH2benzyl), 5,07 (1H, d, J = 17,4, 1H CH2m-metoksybenzyl), 5,13 (1H, d, J = 17,4, 1H CH2m-metoksybenzyl), 5,14 (1H, m, C αH Trp), 6,32 (1H, d, J = 7,8, H6m-metoksybenzyl), 6,40 (1H, m, H2m-metoksybenzyl), 6,82 (1H, t, H5Trp), 6,83 (1H, d, J = 7,8, H4m-metoksybenzyl), 7,01 (1H, t, J = 8,2, H6Trp), 7,04 (1H, d, J = 8,2, H4Trp), 7,06 (1H, d, J = 2,0, H2Trp), 7,12 (2H, m, H2, H6benzyl), 7,13 (1H, t, J = 7,9, H5m-metoksybenzyl), 7,20 (1H, m, H4benzyl), 7,24 (2H, m, H3, H5benzyl), 7,29 (1H, d, J = 8,2, H7Trp), 7,99 (2H, s, NH2Aib), 8,92 (1H, d, J = 8,2, NH Trp), 10,77 (1H, s, NH indol Trp).
<13>C NMR (400 MHz, DMSO-d<6>):
δ (ppm) 23,0 (CH3Aib), 23,3 (CH3Aib), 28,6 (C β Trp), 30,1 (CH2benzyl), 45,2 (C α Trp), 45,6 (CH2- m-metoksybenzyl), 54,9 (m-OCH3), 56,2 (Cq Aib), 109,4 (C3Trp), 111,2 (C7Trp), 111,7 (C2m-metoksybenzyl), 113,1 (C4m-metoksybenzyl), 117,9 (C4Trp, C6m-metoksybenzyl), 118,2 (C5Trp), 120,8 (C6Trp), 124,3 (C2Trp), 126,6 (C4benzyl), 126,8 (C9Trp), 128,3 (C3, C5benzyl), 128,4 (C2, C6benzyl), 129,9 (C5mmetoksybenzyl), 135,9 (C1benzyl, C8Trp), 137,0 (C1m-metoksybenzyl), 153,5 (Cq triazol), 154,8 (Cq triazol), 159,5 (C3m-metoksybenzyl), 171,3 (CO Aib).
ESI-MS: funnet: m/z 523,3 [M+H]<+>/ beregnet: 522,3 g/mol.
Eksempel 6
(R)-N-(1-(5-(2-(1H-indol-3-yl)etyl)-4-benzyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid (forbindelse 8)
Forbindelse 8 ble oppnådd fra Boc-(D)-Trp (10 mmol), fenylmetanamin, 3-(1H-indol-3-yl)propanhydrazid og Boc-2-amino-2-metylpropansyre i henhold til de generelle synteseskjemaene med et totalutbytte etter rensing med HPLC på 45 %.
<1>H NMR (400 MHz, DMSO-d<6>):
δ (ppm) 1,29 (3H, s, CH3Aib), 1,30 (3H, s, CH3Aib), 2,88 (2H, m, CH2CH2-indol), 2,97 (2H, m, CH2-CH2-indol), 3,37 (2H, m, CH2βTrp), 5,11 (2H, s, CH2benzyl), 5,21 (1H, m, C αH Trp), 6,86 (1H, t, J = 7,4, H5Trp), 6,88 (2H, H2, H6benzyl), 6,92 (1H, t, J = 7,6, H5indol), 7,03 (1H, t, J = 7,6, H6Trp), 7,05 (2H, H6indol, H2indol), 7,09 (1H, d, J = 1,8, H2Trp), 7,17 (1H, d, J = 7,9, H4Trp), 7,26 (2H, H3, H5benzyl), 7,27 (1H, H4benzyl), 7,30 (1H, H4indol), 7,32 (2H, H7Trp, H7indol), 8,03 (2H, brs, NH2Aib), 8,95 (1H, d, J = 8,1, NH Trp), 10,77 (1H, s, NH indol), 10,81 (1H, s, NH indol Trp).
<13>C NMR (400 MHz, DMSO-d<6>):
δ (ppm) 22,4 (CH2-CH2indol), 23,1 (CH3Aib), 23,3 (CH3Aib), 25,4 (CH2-CH2indol), 28,7 (C β Trp), 45,3 (C α Trp, CH2-benzyl), 56,3 (Cq Aib), 109,5 (C3Trp), 111,3 (C7Trp, C7indol), 113,0 (C3indol), 117,8 (C4Trp), 118,0 (C4indol), 118,2 (C5indol), 118,3 (C5Trp), 120,9 (C6Trp, C6indol), 122,4 (C2indol), 124,3 (C2Trp), 125,9 (C2, C6benzyl), 126,7 (C9indol), 126,9 (C9Trp), 127,6 (C4benzyl), 128,8 (C3, C5benzyl), 135,7 (C1benzyl), 136,0 (C8Trp), 136,1 (C8indol), 154,3 (Cq triazol), 154,5 (Cq triazol), 171,4 (CO Aib).
ESI-MS: funnet: m/z 546,3 [M+H]<+>/beregnet: 545,3 g/mol.
Eksempel 7
(R)-N-(1-(5-(3-(1H-indol-3-yl)propyl)-4-benzyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid (forbindelse 9)
Forbindelse 9 ble oppnådd fra Boc-(D)-Trp (10 mmol), fenylmetanamin, 4-(1H-indol-3-yl)butanhydrazid og Boc-2-amino-2-metylpropansyre i henhold til de generelle synteseskjemaene med et totalutbytte etter rensing med HPLC på 38 %.
<1>H NMR (400 MHz, DMSO-d<6>):
δ (ppm) 1,29 (3H, s, CH3Aib), 1,31 (3H, s, CH3Aib), 1,90 (2H, m, CH2-CH2-CH2-indol), 2,61 (2H, m, CH2-CH2-CH2-indol), 2,69 (2H, m, CH2-CH2-CH2-indol), 3,37 (2H, m, CH2βTrp), 5,09 (2H, s, CH2benzyl), 5,20 (1H, m, C αH Trp), 6,85 (3H, m, H2, H6benzyl, H5Trp), 6,94 (1H, t, J = 7,5, H5indol), 7,01 (1H, s, H2indol), 7,02 (1H, t, J = 7,8, H6Trp), 7,05 (1H, t, J = 8, H6indol), 7,08 (1H, d, J = 2,0, H2Trp), 7,14 (1H, d, J = 8,0, H4Trp), 7,25 (3H, m, H3, H4, H5benzyl), 7,31 (1H, d, J = 8,0, H7Trp), 7,32 (1H, d, J = 8,0, H7indol), 7,42 (1H, d, J = 7,8, H4indol), 8,03 (2H, s, NH2Aib), 8,95 (1H, d, J = 8,1, NH Trp), 10,73 (1H, s, NH indol), 10,80 (1H, d, J = 2,0, NH indol Trp).
<13>C NMR (400 MHz, DMSO-d<6>):
δ (ppm) 23,1 (CH3Aib), 23,3 (CH3Aib), 23,8 (CH2-CH2-CH2-indol), 24,1 (CH2-CH2-CH2-indol), 27,2 (CH2-CH2-CH2-indol), 28,7 (C β Trp), 45,4 (C α Trp), 45,5 (CH2benzyl), 56,3 (Cq Aib), 109,4 (C3Trp), 111,3 (C7Trp, C7indol), 113,6 (C3indol), 117,8 (C4Trp), 118,0 (C5indol), 118,2 (C4indol), 118,3 (C5Trp), 120,8 (C6indol, C6Trp), 122,2 (C2indol), 124,3 (C2Trp), 125,9 (C2, C6benzyl), 126,8 (C9Trp), 127,0 (C9indol), 127,7 (C4benzyl), 128,7 (C3, C5benzyl), 135,5 (C1benzyl), 136,0 (C8Trp), 136,2 (C8indol), 154,3 (Cq triazol), 154,7 (Cq triazol), 171,4 (CO Aib).
ESI-MS: funnet: m/z 560,4 [M+H]<+>/ beregnet: 559,3 g/mol.
Eksempel 8
(R)-N-(1-(5-(3-(1H-indol-3-yl)propyl)-4-(3-metoksybenzyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid (forbindelse 10)
Forbindelse 10 ble oppnådd fra Boc-(D)-Trp (10 mmol), (3-metoksyfenyl)metanamin, 4-(1H-indol-3-yl)butanhydrazid og Boc-2-amino-2-metylpropansyre i henhold til de generelle synteseskjemaene med et totalutbytte etter rensing med HPLC på 25 %.
<1>H NMR (400 MHz, DMSO-d<6>):
δ (ppm) 1,27 (3H, s, CH3Aib), 1,30 (3H, s, CH3Aib), 1,92 (2H, m, CH2-CH2-CH2-indol), 2,62 (2H, m, CH2-CH2-CH2-indol), 2,68 (2H, m, CH2-CH2-CH2-indol), 3,24 (1H, dd, J = 14,5, J = 5,8, 1H CH2βTrp), 3,39 (1H, dd, J = 14,5, J = 9,0, 1H CH2βTrp), 3,66 (3H, s, m-OCH3), 5,07 (2H, s, CH2m-metoksybenzyl), 5,18 (1H, m, C αH Trp), 6,35 (1H, d, J = 7,5, H6m-metoksybenzyl), 6,54 (1H, bs, H2m-metoksybenzyl), 6,84 (1H, t, J = 7,5, H5Trp), 6,87 (1H, dd, J = 8,0, J = 2,1, H4m-metoksybenzyl), 6,94 (1H, t, J = 7,3, H5indol), 7,02 (1H, t, H6Trp), 7,02 (1H, s, H2indol), 7,05 (1H, t, J = 7,8, H6indol), 7,08 (1H, d, J = 2,1, H2Trp), 7,13 (1H, d, J = 8,1, H4Trp), 7,17 (1H, t, J = 8,1, H5m-metoksybenzyl), 7,30 (1H, d, H7Trp), 7,32 (1H, d, J = 8, H7indol), 7,42 (1H, d, J = 7,6, H4indol), 7,98 (2H, s, NH2Aib), 8,93 (1H, d, J = 8,2, NH Trp), 10,71 (1H, s, NH indol), 10,77 (1H, s, NH indol Trp).
<13>C NMR (430 MHz, DMSO-d<6>):
δ (ppm) 23,1 (CH3Aib), 23,3 (CH3Aib), 23,9 (CH2-CH2-CH2-indol), 24,3 (CH2-CH2-CH2-indol), 27,4 (CH2-CH2-CH2indol), 28,8 (C β Trp), 45,2 (CH2- m-metoksybenzyl), 45,4 (C α Trp), 55,1 (m-OCH3), 56,3 (Cq Aib), 109,5 (C3Trp), 111,3 (C7Trp, C7indol), 111,8 (C2m-metoksybenzyl), 113,0 (C4m-metoksybenzyl), 113,8 (C3indol), 117,8 (C6m-metoksybenzyl), 117,9 (C4Trp), 118,1 (C5indol), 118,2 (C5Trp, C4indol), 120,8 (C6Trp), 120,9 (C6indol), 122,2 (C2indol), 124,3 (C2Trp), 126,8 (C9Trp), 127,0 (C9indol), 130,0 (C5m-metoksybenzyl), 136,0 (C8Trp), 136,2 (C8indol), 137,4 (C1mmetoksybenzyl), 154,3 (Cq triazol), 154,6 (Cq triazol), 159,7 (C3m-metoksybenzyl), 171,4 (CO Aib).
ESI-MS: funnet: m/z 590,3 [M+H]<+>/ beregnet: 589,3 g/mol.
Eksempel 9
(R)-N-(1-(5-(3-(1H-indol-3-yl)propyl)-4-(naftalen-1-ylmetyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid (forbindelse 11)
Forbindelse 11 ble oppnådd fra Boc-(D)-Trp (10 mmol), naftalen-1-ylmetanamin, 4-(1H-indol-3-yl)butanhydrazid og Boc-2-amino-2-metylpropansyre i henhold til de generelle synteseskjemaene med et totalutbytte etter rensing med HPLC på 22 %.
<1>H NMR (300 MHz, DMSO-d<6>, 300°K):
δ (ppm) 1,20 (3H, s, CH3Aib), 1,25 (3H, s, CH3Aib), 1,93 (2H, m, CH2-CH2-CH2-indol), 2,66 (4H, m, CH2-CH2-CH2-indol), 3,25 (1H, dd, J = 14 Hz og 5 Hz, CH2βTrp), 3,40 (1H, dd, J = 14 Hz og 9 Hz, CH2βTrp), 4,95 (1H, m, CH αTrp), 5,66 (1H, d, J = 18 Hz, CH2-naftyl), 5,81 (1H, d, J = 18 Hz, CH2-naftyl), 6,37 (1H, d, Jo= 7 Hz, H2naftyl), 6,43 (1H, t, Jo= 7 Hz, H5Trp), 6,59 (1H, d, Jo= 8 Hz, H4Trp), 6,86 (3H, m, H5og H6indol, H6Trp), 6,95 (1H, d, J = 2 Hz, H2indol), 7,00 (1H, d, Jo= 8 Hz, H4indol), 7,06 (1H, d, J = 2 Hz, H2Trp), 7,20-7,33 (4H, m, H4og H7indol, H7Trp, H3naftyl), 7,60 (2H, m, H6og H7naftyl), 7,87 (1H, d, Jo= 8 Hz, H4naftyl), 7,99 (5H, m, NH2Aib, H5og H8 naftyl), 8,95 (1H, d, J = 8 Hz, NH amid), 10,70 (1H, s, NH indol), 10,77 (1H, s, NH indol Trp).
<13>C NMR (75 MHz, DMSO-d<6>, 300°K):
δ (ppm) 23,5 (CH3Aib), 23,6 (CH3Aib), 24,1 (CH2-CH2-CH2-indol), 24,5 (CH2-CH2-CH2-indol), 27,6 (CH2-CH2-CH2-indol), 29,1 (CH2βTrp), 44,1 (CH2-naftyl), 45,7 (CH αTrp), 56,7 (Cq Aib), 109,7 (C3Trp), 111,7 (C7indol og C7Trp), 113,9 (C3indol), 117,9 (C4Trp), 118,5 (C4indol, C5Trp), 118,6 (C5indol), 121,1 (C6Trp), 121,2 (C6indol), 122,1 (C2naftyl), 122,7 (C2indol), 122,9 (C8naftyl), 125,0 (C2Trp), 125,9 (C3naftyl), 126,8 (C6naftyl), 127,0 (C9indol), 127,1 (C7naftyl), 127,4 (C9Trp) 128,5 (C4naftyl), 129,2 (C5naftyl), 129,9 (C9naftyl), 131,6 (C1naftyl), 133,6 (C10naftyl), 136,4 (C8Trp), 136,7 (C8indol), 155,4 (Cq-er triazol), 171,9 (CO Aib).
ESI-MS: funnet: m/z 610,3 [M+H]<+>/ beregnet: 609,3 g/mol.
Eksempel 10
(R)-N-(1-(5-(2-(1H-indol-3-yl)etyl)-4-(4-metoksybenzyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid (forbindelse 12)
Forbindelse 12 ble oppnådd fra Boc-(D)-Trp (10 mmol), (4-metoksyfenyl)metanamin, 3-(1H-indol-3-yl)propanhydrazid og Boc-2-amino-2-metylpropansyre i henhold til de generelle synteseskjemaene med et totalutbytte etter rensing med HPLC på 28 %.
<1>H NMR (400 MHz, DMSO-d<6>):
δ (ppm) 1,30 (3H, s, CH3Aib), 1,33 (3H, s, CH3Aib), 2,91 (2H, m, CH2-CH2-indol), 2,97 (2H, m, CH2-CH2-indol), 3,37 (2H, d, CH2βTrp), 3,71(3H, s, OCH3), 5,02 (2H, s, CH2p-metoksybenzyl), 5,23 (1H, m, C αH Trp), 6,78 (4H, m, CHar p-metoksybenzyl), 6,87 (1H, t, J = 7,5, H5Trp), 6,93 (1H, t, J = 7,5, H5indol), 7,03 (1H, t, H6Trp), 7,05 (1H, t, H6indol), 7,07 (1H, s, H2indol), 7,09 (1H, s, H2Trp), 7,21 (1H, d, J = 8, H4Trp), 7,32 (3H, H4indol, H7Trp, H7indol), 8,02 (2H, s, NH2Aib), 8,97 (1H, d, J = 8,1, NH Trp), 10,77 (1H, s, NH indol), 10,80 (1H, s, NH indol Trp).
<13>C NMR (400 MHz, DMSO-d<6>):
δ (ppm) 22,4 (CH2-CH2indol), 23,1 (CH3Aib), 23,4 (CH3Aib), 25,5 (CH2-CH2indol), 28,9 (C β Trp), 44,9 (CH2p-metoksybenzyl), 45,3 (C α Trp), 55,0 (OCH3), 56,3 (Cq Aib), 109,5 (C3Trp), 111,3 (C7Trp, C7indol), 113,0 (C3indol), 114,1 (C3, C5pmetoksybenzyl), 117,9 (C4Trp), 118,0 (C4indol), 118,2 (C5indol), 118,3 (C5Trp), 120,9 (C6indol, C6Trp), 122,0 (C2indol), 124,4 (C2Trp), 126,7 (C9indol), 126,9 (C9Trp), 127,3 (C2, C6p-metoksybenzyl), 127,4 (C1p-metoksybenzyl), 135,9 (C8Trp), 136,1 (C8indol), 154,2 (Cq triazol), 154,5 (Cq triazol), 158,4 C4p-metoksybenzyl), 171,4 (CO Aib).
ESI-MS: funnet: m/z 576,3 [M+H]<+>/ beregnet: 575,3 g/mol.
Eksempel 11
(R)-N-(1-(4-(4-metoksybenzyl)-5-benzyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid (forbindelse 13)
Forbindelse 13 ble oppnådd fra Boc-(D)-Trp (10 mmol), (4-metoksyfenyl)metanamin, 2-fenylacetohydrazid og Boc-2-amino-2-metylpropansyre i henhold til de generelle synteseskjemaene med et totalutbytte etter rensing med HPLC på 37 %.
<1>H NMR (300 MHz, DMSO-d<6>, 300°K):
δ (ppm) 1,24 (3H, s, CH3Aib), 1,28 (3H, s, CH3Aib), 3,26 (1H, dd,<3>J = 14 Hz og 6 Hz, CH2βTrp), 3,31 (1H, dd,<3>J = 14 Hz og 9 Hz, CH2βTrp), 3,67 (3H, s, OCH3), 3,99 (2H, s, CH2-benzyl), 4,99 (2H, s, CH2-p-metoksybenzyl), 5,12 (1H, m, CH αTrp), 6,67 (4H, m, CHar p-metoksybenzyl), 6,80 (1H, t, Jo= 8 Hz, H5Trp), 6,98 (1H, t, Jo= 8 Hz, H6Trp), 7,02-7,06 (4H, m, H2og H6benzyl, H2og H4Trp), 7,12-7,25 (3H, m, H3, H4og H5benzyl), 7,26 (1H, d, Jo= 8 Hz, H7Trp), 8,01 (3H, brs, NH2Aib), 8,92 (1H, d, J = 8 Hz, NH Trp), 10,77 (1H, s, NH indol Trp).
<13>C NMR (75 MHz, DMSO-d<6>, 300°K):
δ (ppm) 23,5 (CH3Aib), 23,7 (CH3Aib), 29,1 (CH2βTrp), 30,6 (CH2-benzyl), 45,7 (CH2-p-metoksybenzyl), 45,7 (CH αTrp), 55,5 (OCH3), 56,7 (Cq Aib), 109,8 (C3Trp), 111,7 (C7Trp), 114,5 (C3og C5p-metoksybenzyl), 118,3 (C4Trp), 118,7 (C5Trp), 121,3 (C6Trp), 124,8 (C2Trp), 127,1 (C2og C6benzyl), 127,3 (C9Trp), 127,6 (C1pmetoksybenzyl), 127,8 (C2og C6p-metoksybenzyl), 128,8 (C3, C4og C5p-metoksybenzyl), 136,3 (C1benzyl), 136,4 (C8Trp), 153,8 (Cq triazol), 155,2 (Cq triazol), 159,1 (C4p-metoksybenzyl), 171,9 (CO Aib).
ESI-MS: funnet: m/z 524,1 [M+H]<+>/ beregnet: 522,3 g/mol.
Eksempel 12
(R)-N-(1-(5-(2-(1H-indol-3-yl)etyl)-4-heksyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid (forbindelse 15)
Forbindelse 15 ble oppnådd fra Boc-(D)-Trp (10 mmol), heksan-1-amin, 3-(1H-indol-3-yl)propanhydrazid og Boc-2-amino-2-metylpropansyre i henhold til de generelle synteseskjemaene med et totalutbytte etter rensing med HPLC på 28 %.
<1>H NMR (400 MHz, DMSO-d<6>):
δ (ppm) 0,77 (3H, t, J = 7,2 (CH2)5-CH3), 1,01 (4H, m, 2CH2), 1,11 (2H, m, CH2-CH3), 1,14 (1H, m, 1H N-CH2-CH2), 1,33 (1H, m, 1H N-CH2-CH2), 1,40 (3H, s, CH3Aib), 1,42 (3H, s, CH3Aib), 3,05 (2H, m, CH2-CH2-indol), 3,10 (2H, m, CH2-CH2-indol), 3,37 (1H, dd, J = 14,2, J = 7,6, 1H CH2βTrp), 3,44 (1H, dd, J = 14,2, J = 7,6, 1H CH2βTrp), 3,58 (1H, m, 1H N-CH2), 3,71 (1H, m, 1H N-CH2), 5,21 (1H, m, C αH Trp), 6,96 (1H, H5Trp), 6,97 (1H, H5indol), 7,06 (2H, H6Trp, H6indol), 7,09 (1H, s, H2Trp), 7,13 (1H, s, H2indol), 7,34 (2H, H7Trp, H7indol), 7,48 (1H, d, H4indol), 7,50 (1H, H4Trp), 8,14 (2H, s, NH2Aib), 9,08 (1H, d, J = 7,8, NH Trp), 10,84 (1H, s, NH indol), 10,88 (1H, s, NH indol Trp).
<13>C NMR (400 MHz, DMSO-d<6>):
δ (ppm) 13,7 (CH2)5-CH<3>), 21,7 (CH2-CH3), 22,4 (CH2-CHn-indol), 23,1 (CH3Aib), 23,3 (CH3Aib), 25,1 (CH2-CHn-indol), 25,5 (CH3-CH2-CH2-CH2), 29,1 (C β Trp), 29,3 (N-CH2-CH2), 30,4 (CH3CH2-CH2), 42,6 (N-CH2-CH2), 45,6 (C α Trp), 56,3 (Cq Aib), 109,2 (C3Trp), 111,4-111,5 (C7Trp, C7indol), 112,8 (C3indol), 117,7 (C4Trp), 118,0 (C5indol), 118,2 (C4indol), 118,4 (C5Trp), 120,9 (C6indol, C6Trp), 122,6 (C2indol), 124,3 (C2Trp), 126,8 (C9Trp), 126,9 (C9indol), 136,0 (C8Trp), 136,2 (C8indol), 154,0 (Cq triazol), 154,1 (Cq triazol), 171,4 (CO Aib).
ESI-MS: funnet: m/z 540,3 [M+H]<+>/ beregnet: 539,3 g/mol.
Eksempel 13
(S)-N-(1-(5-(2-(1H-indol-3-yl)etyl)-4-(2,4-dimetoksybenzyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid (forbindelse 18)
Forbindelse 18 ble oppnådd fra Boc-(L)-Trp (10 mmol), (2,4-dimetoksyfenyl)metanamin, 3-(1H-indol-3-yl)propanhydrazid og Boc-2-amino-2-metylpropansyre i henhold til de generelle synteseskjemaene med et totalutbytte etter rensing med HPLC på 30 %.
<1>H NMR (300 MHz, DMSO-d<6>, 300°K):
δ (ppm) 1,27 (3H, s, CH3Aib), 1,31 (3H, s, CH3Aib), 2,89 (2H, m, CH2CH2-indol), 2,93 (2H, m, CH2CH2-indol), 3,27 (2H, m, CH2βTrp), 3,62 (3H, s, o-OCH3), 3,68 (3H, s, p-OCH3), 4,89 (1H, d,<3>J = 17 Hz, CH2-o,p-dimetoksybenzyl), 5,06 (1H, d,<3>J = 17 Hz, CH2-o,p-dimetoksybenzyl), 5,18 (1H, m, CH αTrp), 6,27 (1H, dd, Jo= 8 Hz og Jp= 2 Hz, H5o,p-dimetoksybenzyl), 6,40 (1H, d, 8 Hz, H6o,p-dimetoksybenzyl), 6,56 (1H, d, Jp= 2 Hz, H3o,p-dirnetoksybenzyl), 6,83 (1H, t, J = 7 Hz, H5Trp), 6,90 (1H, t, Jo= 7 Hz, H5indol), 7,02 (1H, t, H6Trp), 7,04 (1H, t, H6indol), 7,07 (1H s, H2indol), 7,08 (1H, s, H2Trp), 7,12 (1H, d, Jo= 8 Hz, H4Trp), 7,29 (3H, H4og H7indol, H7Trp), 8,00 (3H, brs, NH2Aib), 8,93 (1H, d, J = 8 Hz, NH amid), 10,76 (1H, s, NH indol), 10,79 (1H, s, NH indol Trp).
<13>C NMR (75 MHz, DMSO-d<6>, 300°K):
δ (ppm) 22,9 (CH2CH2-indol), 23,6 (CH3Aib), 23,7 (CH3Aib), 25,8 (CH2CH2-indol), 29,2 (CH2βTrp), 41,4 (CH2-o,p-dimetoksybenzyl), 45,7 (C αTrp), 55,7 (p-OCH3), 55,9 (o-OCH3), 56,7 (Cq Aib), 99,0 (C3o,p-dimetoksybenzyl), 105,1 (C5o,p-dimetoksybenzyl), 109,9 (C3Trp), 111,8 (C7Trp, C7indol), 113,4 (C3indol), 115,6 (C1o,p-dimetoksybenzyl), 118,3 (C4indol), 118,4 (C4Trp), 118,6 (C5Trp, C5indol), 121,3 (C6Trp, C6indol), 122,6 (C2indol), 124,4 (C2Trp), 127,2 (C9indol), 127,3 (C9Trp), 128,0 (C6o,p-dimetoksybenzyl), 136,4 (C8Trp), 136,6 (C8indol), 155,0 (2 Cq triazol), 157,7 (C2o,p-dimetoksybenzyl), 160,9 (C4o,p-dimetoksybenzyl), 171,6 (CO Aib).
ESI-MS: funnet: m/z 606,2 [M+H]<+>/ beregnet: 605,3 g/mol.
Eksempel 14
(R)-N-(1-(5-(3-(1H-indol-3-yl)propyl)-4-(4-metoksybenzyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid (forbindelse 23)
Forbindelse 23 ble oppnådd fra Boc-(D)-Trp (10 mmol), (4-metoksyfenyl)metanamin, 4-(1H-indol-3-yl)butanhydrazid og Boc-2-amino-2-metylpropansyre i henhold til de generelle synteseskjemaene med et totalutbytte etter rensing med HPLC på 25 %.
<1>H NMR (300 MHz, DMSO-d<6>, 300°K):
δ (ppm) 1,27 (3H, s, CH3Aib), 1,30 (3H, s, CH3Aib), 1,84 (2H, m, CH2CH2-CH2-indol), 2,58 (2H, m, CH2CH2CH2-indol), 2,65 (2H, m, CH2CH2CH2-indol), 3,34 (2H, d,<3>J = 7 Hz, CH2βTrp), 3,67 (3H, s, OCH3), 4,96 (2H, s, CH2-p-metoksybenzyl), 5,19 (1H, m, CH αTrp), 6,71 (4H, s, CH ar p-metoksybenzyl), 6,89 (1H, t, Jo= 7 Hz, H5Trp), 6,92 (1H, t, Jo= 7 Hz, H5indol), 7,02 (1H, s, H2indol), 7,05 (1H, s, H2Trp), 7,14 (1H, d, Jo= 8 Hz, H4Trp), 7,33 (3H, H4indol, H7Trp, H7indol), 8,02 (3H, brs, NH2Aib), 7,90 (1H, d, J = 8 Hz, NH amid), 10,73 (1H, s, NH indol), 10,79 (1H, s, NH indol Trp).
<13>C NMR (75 MHz, DMSO-d<6>, 300°K):
δ (ppm) 23,6 (CH3Aib), 23,8 (CH3Aib), 24,3 (CH2CH2CH2-indol), 24,8 (CH2CH2CH2-indol), 27,7 (CH2CH2CH2-indol), 29,1 (C β Trp), 45,5 (N-CH2-p-metoksybenzyl), 45,8 (C α Trp), 55,5 (OCH3), 56,8 (Cq Aib), 109,8 (C3Trp), 111,7 (C7Trp, C7indol), 114,0 (C3indol), 114,5 (C3, C5p-metoksybenzyl), 118,3 (C4indol, C4Trp), 118,5 (C5indol), 118,8 (C5Trp), 121,3 (C6indol, C6Trp), 127,3 (C9indol), 127,4 (C9Trp), 127,6 (C1pmetoksybenzyl), 127,9 (C2, C6p-metoksybenzyl, C2Trp, C2indol), 136,1 (C8indol), 136,4 (C8Trp), 154,7 (Cq triazol), 155,1 (Cq triazol), 159,2 (C4p-metoksybenzyl), 171,9 (CO Aib).
ESI-MS: funnet: m/z 590,0 [M+H]<+>/ beregnet: 589,3 g/mol.
Eksempel 15
(R)-N-(1-(5-(2-(1H-indol-3-yl)etyl)-4-(2-metoksy)benzyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid (forbindelse 25)
Forbindelse 25 ble oppnådd fra Boc-(D)-Trp (10 mmol), (2-metoksyfenyl)metanamin, 3-(1H-indol-3-yl)propanhydrazid og Boc-2-amino-2-metylpropansyre i henhold til de generelle synteseskjemaene med et totalutbytte etter rensing med HPLC på 28 %.
<1>H NMR (300 MHz, DMSO-d<6>, 300°K):
δ (ppm) 1,27 (3H, s, CH3Aib), 1,29 (3H, s, CH3Aib), 2,90 (2H, m, CH2-CH2-indol), 2,96 (2H, m, CH2-CH2-indol), 3,29 (2H, m, CH2βTrp), 3,65 (3H, s, OCH3), 5,09 (3H, m, CH2-o-metoksybenzyl og CH αTrp), 6,49 (1H, d, Jo= 8 Hz, H3o-metoksybenzyl), 6,76 (1H, t, Jo= 8 Hz, H5Trp), 6,81 (1H, t, Jo= 8 Hz, H5indol), 6,89 (1H, t, J, = 7 Hz, H6Trp), 6,96 (1H, t, Jo= 8 Hz, H6indol), 6,98 (1H, s, H2indol), 7,02 (3H, m, H4, H5og H6o-metoksybenzyl), 7,07 (1H, d, Jo= 6 Hz, H4Trp), 7,18 (1H, m, H4indol), 7,29 (2H, m, H7indol og H7Trp), 8,07 (3H, brs, NH2Aib), 8,97 (1H, d, J = 8 Hz, NH amid), 10,80 (1H, s, NH indol), 10,82 (1H, s, NH indol Trp).
<13>C NMR (75 MHz, DMSO-d<6>, 300°K):
δ (ppm) 22,8 (CH2-CH2-indol), 23,6 (CH3Aib), 23,7 (CH3Aib), 25,8 (CH2-CH2-indol), 29,1 (CH2βTrp), 42,3 (CH2-o- metoksybenzyl), 45,7 (CH αTrp), 55,8 (OCH3), 56,7 (Cq Aib), 109,8 (C3Trp), 111,5 (C3o-metoksybenzyl), 111,8 (C7indol og C7Trp), 113,2 (C3indol), 118,2 (C4Trp), 118,4 (C4indol), 118,7 (C5indol og C5Trp), 121,0 (C6indol), 121,3 (C6Trp), 121,4 (C5o-metoksybenzyl), 123,0 (C2indol og C2Trp), 123,3 (C1o-metoksybenzyl), 127,0 (C4o-metoksybenzyl), 127,1 (C9indol), 127,3 (C9Trp), 129,8 (C6o-metoksybenzyl), 136,4 (C8indol), 136,6 (C8Trp), 155,2 (Cq triazol), 171,9 (CO Aib).
ESI-MS: funnet: m/z 576,1 [M+H]<+>/ beregnet: 575,3 g/mol.
Data for ytterligere eksempler på utførelsesformer som ble syntetisert i henhold til de generelle synteseskjemaene, er angitt nedenfor (referanse også til tabell 1):
(R)-N-(1-(5-(3-(1H-indol-3-yl)propyl)-4-fenetyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid (forbindelse 3):
<1>H NMR (300 MHz, DMSO-d<6>, 300°K):
δ (ppm) 1,32 (s, 3H, CH3Aib), 1,37 (s, 3H, CH3Aib), 1,86 (2H, m, CH2-CH2-CH2-indol), 2,38 (2H, m, CH2-CH2-CH2-indol), 2,65 (4H, m, CH2-CH2-CH2-indol og CH2-CH2-fenyl), 3,38 (2H, m, CH2-CH2-fenyl), 3,74 (1H, m, CH2βTrp), 3,92 (1H, m, CH2βTrp), 5,23 (1H, m, CH αTrp), 6,78 (2H, m, H5indol og H5Trp), 6,93 (1H, t, Jo= 8 Hz, H6Trp), 7,01 (3H, m, H6indol, H2og H6fenyl), 7,05 (1H, d, J = 2 Hz, H2Trp), 7,08 (1H, d, J = 2 Hz, H2indol), 7,15 (3H, m, H3, H4og H5fenyl), 7,29 (1H, d, Jo= 8 Hz, H4Trp), 7,31 (1H, d, Jo= 8 Hz, H7Trp), 7,44 (1H, d, Jo= 8 Hz, H7indol), 7,46 (1H, d, Jo= 8 Hz, H4indol), 8,06 (3H, brs, NH2Aib), 9,05 (1H, d, 8 Hz, NH amid), 10,76 (1H, s, NH indol), 10,85 (1H, d, J = 2 Hz, NH indol Trp).
<13>C NMR (75 MHz, DMSO-d<6>, 300°K):
δ (ppm) 23,5 (CH3Aib), 23,6 (CH2-CH2-CH2-indol), 23,9 (CH3Aib), 24,5 (CH2-CH2-CH2-indol), 27,3 (CH2-CH2-CH2-indol), 29,4 (CH2βTrp), 35,7 (CH2-CH2-fenyl), 44,5 (CH2-CH2-fenyl), 46,1 (CH αTrp), 56,8 (Cq Aib), 109,6 (C3Trp), 111,8 (C7indol), 111,9 (C7indol), 113,9 (C3indol), 118,3 (C4Trp), 118,6 (C5indol), 118,7 (C4indol), 118,9 (C5Trp), 121,3 (C6Trp), 121,4 (C6indol), 122,8 (C2indol og C2Trp), 127,1 (C4fenyl), 127,3 (C9Trp), 127,5 (C9indol), 128,8 (C2og C6fenyl), 129,1 (C3og C5fenyl), 136,5 (C1fenyl), 136,8 (C8Trp), 137,2 (C8indol), 154,7 (Cq triazol), 172,0 (CO Aib).
(R)-N-(1-(5-(3-(1H-indol-3-yl)propyl)-4-heksyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid (forbindelse 16):
<1>H NMR (300 MHz, DMSO-d<6>, 300°K):
δ (ppm) 0,74 (3H, t, J = 6 Hz, CH3-CH2-CH2-CH2-CH2-CH2), 0,95 (4H, brs, CH3-CH2-CH2-CH2-CH2-CH2), 1,06 (3H, m, CH3-CH2-CH2-CH2-CH2-CH2og 1H N-CH2-CH2), 1,38 (7H, s, CH3Aib og 1H N-CH2-CH2), 1,97 (2H, m, CH2-CH2-CH2-indol), 2,71 (4H, m, CH2-CH2-CH2-indol), 3,37 (2H, m, CH2βTrp), 3,56 (2H, m, N-CH2), 5,15 (1H, m, CH αTrp), 6,91 (2H, m, H5indol og H5Trp), 7,00 (2H, m, H6indol og H6Trp), 7,07 (2H, s, H2indol og H2Trp), 7,29 (2H, d, Jo= 8 Hz, H7indol og H7Trp), 7,45 (2H, d, Jo= 7 Hz, H4indol og H4Trp), 8,15 (3H, brs, NH2Aib), 9,10 (1H, d, J = 6 Hz, NH amid), 10,77 (1H, s, NH indol), 10,85 (1H, s, NH indol Trp).
<13>C NMR (75 MHz, DMSO-d<6>, 300°K):
δ (ppm) 14,2 (CH3-CH2-CH2-CH2-CH2-CH2), 22,2 (CH3-CH2-CH2-CH2-CH2-CH2og CH2-CH2-CH2-indol), 23,6 (CH3Aib), 23,7 (CH3Aib), 24,5 (CH2-CH2-CH2-indol), 25,9 (CH3-CH2-CH2-CH2-CH2-CH2), 27,5 (CH2βTrp og CH2-CH2-CH2-indol), 29,7 (N-CH2-CH2), 30,8 (CH3-CH2-CH2-CH2-CH2-CH2), 43,2 (N-CH2), 46,1 (CH αTrp), 56,8 (Cq Aib), 109,5 (C3Trp), 111,8 (C7Trp), 111,9 (C7indol), 113,9 (C3indol), 118,1 (C4Trp), 118,5 (C5indol), 118,6 (C4indol), 118,9 (C5Trp), 121,3 (C8indol og C6Trp), 122,8 (C2indol og C2Trp), 127,3 (C9Trp), 127,4 (C9indol), 136,5 (C8Trp), 136,8 (C8indol), 154,7 (Cq triazol), 172,0 (CO Aib).
(R)-N-(1-(4,5-bis(2-(1H-indol-3-yl)etyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid (forbindelse 17):
<1>H NMR (300 MHz, DMSO-d<6>, 300°K):
δ (ppm) 1,30 (3H, s, CH3Aib), 1,37 (3H, s, CH3Aib), 2,50 (2H, m, N-CH2-CH2-indol), 2,68 (2H, t, Jo= 8 Hz, C-CH2-CH2-indol), 2,91 (2H, t, Jo= 8 Hz, C-CH2-CH2-indol), 3,34 (2H, m, N-CH2-CH2-indol), 3,93 (2H, m, CH2βTrp), 5,25 (1H, m, CH αTrp), 6,72-6,94 (4H, m, H5og H6Trp, H5indol fra C-CH2-CH2-indol og H5indol fra N-CH2-CH2-indol), 6,98-7,04 (4H, m, H2Trp, H6indol fra C-CH2-CH2-indol, H2og H6indol fra N-CH2-CH2-indol), 7,11 (1H, s, H2indol fra C-CH2-CH2-indol), 7,19 (1H, d, Jo= 8 Hz, H4indol fra N-CH2-CH2-indol), 7,28 (3H, m, H4og H7Trp, H7indol fra N-CH2-CH2-indol), 7,40 (1H, d, Jo= 8 Hz, H7indol fra C-CH2-CH2-indol), 7,44 (1H, d, Jo= 8 Hz, H4indol fra C-CH2-CH2-indol), 8,04 (3H, brs, NH2Aib), 9,69 (1H, d, J = 8 Hz, NH amid), 10,73 (1H, s, NH indol fra C-CH2-CH2-indol), 10,82 (1H, d, J = 2 Hz, NH indol Trp), 10,84 (1H, s, NH indol fra N-CH2-CH2-indol).
<13>C NMR (75 MHz, DMSO-d<6>, 300°K):
δ (ppm) 22,7 (C-CH2-CH2-indol), 23,6 (CH3Aib), 23,8 (CH3Aib), 25,4 (C-CH2-CH2-indol), 26,0 (N-CH2-CH2-indol), 29,6 (CH2βTrp), 43,9 (N-CH2-CH2-indol), 46,0 (CH αTrp), 56,8 (Cq Aib), 109,5 (C3indol fra N-CH2-CH2-indol), 109,9 (C3Trp), 111,7 (C7Trp), 111,9 (C7indol fra N-CH2-CH2-indol og C7indol fra C-CH2-CH2-indol), 113,5 (C3indol fra C-CH2-CH2-indol), 118,3 (C4indol fra N-CH2-CH2-indol), 118,4 (C4Trp), 118,5 (C5indol fra C-CH2-CH2-indol), 118,7 (C4indol fra C-CH2-CH2-indol), 118,9 (C5Trp), 119,0 (C5indol fra N-CH2-CH2-indol), 121,3 (C6Trp), 121,5 (C6indol fra C-CH2-CH2-indol og C6indol fra N-CH2-CH2-indol), 122,8 (C2Trp, C2indol fra C-CH2-CH2-indol og indol fra N-CH2-CH2-indol), 127,1 (C9Trp), 127,2 (C9indol fra C-CH2-CH2-indol), 127,4 (C9indol fra N-CH2-CH2-indol), 136,5 (C8Trp og C8indol fra C-CH2-CH2-indol), 136,6 (C8indol fra N-CH2-CH2-indol), 154,5 (Cq triazol), 154,8 (Cq triazol), 171,8 (CO amid).
(R)-N-(1-(4-(3-metoksybenzyl)-5-fenetyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)-etyl)-2-amino-2-metylpropanamid (forbindelse 19):
<1>H NMR (300 MHz, DMSO-d<6>, 300°K):
δ (ppm) 1,24 (3H, s, CH3Aib), 1,27 (3H, s, CH3Aib), 2,82 (4H, m, CH2-CH2-fenyl), 3,32 (2H, m, CH2βTrp), 3,63 (3H, s, OCH3), 5,08 (2H, m, CH2-m-metoksybenzyl), 5,18 (1H, m, CH αTrp), 6,35 (1H, d, Jo= 8 Hz, H6m-metoksybenzyl), 6,57 (1H, s, H2m-metoksybenzyl), 6,82 (1H, t, Jo= 8 Hz, H5Trp), 6,84 (1H, d, Jo= 8 Hz, H4mmetoksybenzyl), 6,99 (1H, t, Jo= 8 Hz, H6Trp), 7,08 (1H, m, H4fenyl), 7,11-7,16 (5H, m, H2og H4Trp, H2og H6fenyl, H5m-metoksybenzyl), 7,20 (2H, m, H3og H5fenyl), 7,27 (1H, d, Jo= 8 Hz, H7Trp), 8,01 (3H, brs, NH2Aib), 8,96 (1H, d, J = 8 Hz, NH amid), 10,81 (1H, d, J = 2 Hz, NH indol).
<13>C NMR (75 MHz, DMSO-d<6>, 300°K):
δ (ppm) 23,5 (CH3Aib), 23,8 (CH3Aib), 26,4 (CH2-CH2-fenyl), 29,1 (CH2βTrp), 32,7 (CH2-CH2-fenyl), 45,7 (CH αTrp), 45,8 (CH2-m-metoksybenzyl), 55,5 (OCH3), 56,7 (Cq Aib), 109,8 (C3Trp), 111,8 (C7Trp), 112,5 (C2m-metoksybenzyl), 113,5 (C4mmetoksybenzyl), 118,2 (C4Trp), 118,4 (C6m-metoksybenzyl), 118,7 (C5Trp), 121,3 (C6Trp), 124,8 (C2Trp), 126,5 (C4fenyl), 127,3 (C9Trp), 128,7 (C2, C3, C5og C6fenyl), 130,5 (C5m-metoksybenzyl), 136,4 (C8Trp), 137,7 (C1m-metoksybenzyl), 170,9 (C1fenyl), 154,6 (Cq triazol), 154,9 (Cq triazol), 160,1 (C3m-metoksybenzyl), 171,9 (CO amid).
(R)-N-(1-(4-(4-metoksybenzyl)-5-fenetyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)-etyl)-2-amino-2-metylpropanamid (forbindelse 20):
<1>H NMR (300 MHz, DMSO-d<6>, 300°K):
δ (ppm) 1,28 (3H, s, CH3Aib), 1,32 (3H, s, CH3Aib), 2,46 (2H, m, CH2-CH2-fenyl), 2,82 (2H, m, CH2-CH2-fenyl), 3,35 (2H, d, J = 7 Hz, CH2βTrp), 3,68 (3H, s, OCH3), 5,02 (2H, s, CH2-p-metoksybenzyl), 5,22 (1H, m, CH αTrp), 6,73-6,81 (4H, m, CHar pmetoksybenzyl), 6,84 (1H, t, Jo= 7 Hz, H5Trp), 7,00 (1H, t, Jo= 7 Hz, H6Trp), 7,05-7,11 (4H, m, H2og H6fenyl, H2og H4Trp), 7,14-7,22 (3H, m, H3, H4og H5fenyl), 7,29 (1H, d, Jo= 8 Hz, H7Trp), 8,09 (3H, brs, NH2Aib), 8,99 (1H, d, J = 8 Hz, NH amid), 10,83 (1H, s, NH indol Trp).
<13>C NMR (75 MHz, DMSO-d<6>, 300°K):
δ (ppm) 23,5 (CH3Aib), 23,8 (CH3Aib), 26,5 (CH2-CH2-fenyl), 29,1 (CH2βTrp), 32,6 (CH2-CH2-fenyl), 45,5 (CH2-p-metoksybenzyl), 45,7 (CH αTrp), 55,5 (OCH3), 56,8 (Cq Aib), 109,7 (C3Trp), 111,8 (C7Trp), 114,6 (C3og C5p-metoksybenzyl), 118,3 (C4Trp), 118,7 (C5Trp), 121,3 (C6Trp), 124,9 (C2Trp), 126,6 (C2og C6fenyl), 127,3 (C9Trp), 127,6 (C1p-metoksybenzyl), 128,0 (C2og C6p-metoksybenzyl), 128,7 (C3, C4og C5fenyl), 136,4 (C8Trp), 140,8 (C1fenyl), 154,5 (Cq triazol), 154,8 (Cq triazol), 159,2 (C4p-metoksybenzyl), 172,0 (CO Aib).
(R)-N-(1-(4-(4-metoksybenzyl)-5-(3-fenylpropyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid (forbindelse 22):
<1>H NMR (300 MHz, DMSO-d<6>, 300°K):
δ (ppm) 1,27 (3H, s, CH3Aib), 1,31 (3H, s, CH3Aib), 1,73 (2H, m, CH2-CH2-CH2-fenyl), 2,47 (2H, m, CH2-CH2-CH2-fenyl), 2,52 (2H, t,<3>J = 7 Hz, CH2-CH2-CH2-fenyl), 3,35 (2H, d, J = 7 Hz, CH2βTrp), 3,68 (3H, s, OCH3), 4,98 (2H, s, CH2-p-metoksybenzyl), 5,20 (1H, m, CH αTrp), 6,75 (4H, m, CHar p-metoksybenzyl), 6,82 (1H, t, Jo= 7 Hz, H5Trp), 6,99 (1H, t, Jo= 7 Hz, H6Trp), 7,04-7,07 (4H, m, H2og H6fenyl, H2og H4Trp), 7,13-7,24 (3H, m, H3, H4og H5fenyl), 7,29 (1H, d, Jo= 8 Hz, H7Trp), 8,03 (3H, brs, NH2Aib), 8,96 (1H, d, J = 8 Hz, NH amid), 10,80 (1H, d, J = 2 Hz, NH indol Trp).
<13>C NMR (75 MHz, DMSO-d<6>, 300°K):
δ (ppm) 23,6 (CH3Aib), 23,6 (CH3Aib), 24,06 (CH2-CH2-CH2-fenyl), 28,5 (CH2-CH2-CH2-fenyl), 29,2 (CH2βTrp), 34,7 (CH2-CH2-CH2-fenyl), 45,5 (CH2-p-metoksybenzyl), 45,8 (CH αTrp), 55,5 (OCH3), 56,8 (Cq Aib), 109,8 (C3Trp), 111,8 (C7Trp), 114,6 (C3og C5p-metoksybenzyl), 118,3 (C4Trp), 118,7 (C5Trp), 121,3 (C6Trp), 124,9 (C2Trp), 126,2 (C2og C6fenyl), 127,3 (C9Trp), 127,8 (C1p-metoksybenzyl), 127,9 (C2og C6pmetoksybenzyl), 128,7 (C3, C4og C5fenyl), 136,4 (C8Trp), 141,7 (C1fenyl), 154,8 (Cq triazol), 159,2 (C4p-metoksybenzyl), 171,9 (CO Aib).
(R)-N-(1-(4-(2-(1H-indol-3-yl)etyl)-5-(3-(1H-indol-3-yl)propyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid (forbindelse 24):
<1>H NMR (300 MHz, DMSO-d<6>, 300°K):
δ (ppm) 1,29 (3H, s, CH3Aib), 1,35 (3H, s, CH3Aib), 1,78 (2H, m, CH2-CH2-CH2-indol), 2,34 (2H, m, CH2-CH2-CH2-indol), 2,48 (2H, m, N-CH2-CH2-indol), 2,80 (2H, m, CH2-CH2-CH2-indol), 3,34 (2H, m, N-CH2-CH2-indol), 3,94 (2H, m, CH2βTrp), 5,27 (1H, m, CH αTrp), 6,73-6,94 (4H, m, H5og H6Trp, H5indol fra N-CH2-CH2-indol og H5indol fra CH2-CH2-CH2-indol), 6,99-7,04 (5H, m, H2Trp, H2og H6indol fra N-CH2-CH2-indol, H2og H6indol fra CH2-CH2-CH2-indol), 7,20 (1H, d, Jo= 8 Hz, H4indol fra N-CH2-CH2-indol), 7,29 (3H, m, H4og H7Trp, H7indol fra N-CH2-CH2-indol), 7,40 (1H, d, Jo= 8 Hz, H7indol fra CH2-CH2-CH2-indol), 7,44 (1H, d, Jo= 8 Hz, H4indol fra CH2-CH2-CH2-indol), 8,05 (3H, brs, NH2Aib), 9,07 (1H, d, J = 8 Hz, NH amid), 10,75 (1H, s, NH indol fra CH2-CH2-CH2-indol), 10,86 (1H, s, NH indol Trp), 10,90 (1H, s, NH indol fra N-CH2-CH2-indol).
<13>C NMR (75 MHz, DMSO-d<6>, 300°K):
δ (ppm) 23,6 (CH3Aib), 23,8 (CH3Aib), 24,5 (CH2-CH2-CH2-indol), 25,8 (CH2-CH2-CH2-indol), 27,2 (CH2-CH2-CH2-indol), 29,4 (CH2βTrp), 44,1 (N-CH2-CH2-indol), 46,0 (CH αTrp), 52,9 (N-CH2-CH2-indol), 56,8 (Cq Aib), 109,7 (C3Trp og C3indol fra N-CH2-CH2-indol), 111,8 (C7Trp), 111,9 (C7indol fra N-CH2-CH2-indol og C7indol fra CH2-CH2-CH2-indol), 114,0 (C3indol fra CH2-CH2-CH2-indol), 118,2 (C4indol fra N-CH2-CH2-indol), 118,3 (C4Trp), 118,5 (C5indol fra CH2-CH2-CH2-indol), 118,6 (C4indol fra CH2-CH2-CH2-indol), 118,9 (C5Trp), 119,0 (C5indol fra N-CH2-CH2-indol), 121,3 (C6Trp), 121,4 (C6indol fra CH2-CH2-CH2-indol), 121,6 (C6indol fra N-CH2-CH2-indol), 122,7 (C2Trp, C2indol fra N-CH2-CH2-indol og C2indol fra CH2-CH2-CH2-indol), 127,1 (C9Trp), 127,4 (C9indol fra N-CH2-CH2-indol og C9indol fra CH2-CH2-CH2-indol), 136,4 (C8Trp), 136,5 (C8indol fra CH2-CH2-CH2-indol), 136,7 (C8indol fra N-CH2-CH2-indol), 154,7 (2 Cq triazol), 171,9 (CO amid).
(R)-N-(1-(4-(2-metoksybenzyl)-5-fenetyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)-etyl)-2-amino-2-metylpropanamid (forbindelse 26):
<1>H NMR (300 MHz, DMSO-d<6>, 300°K):
δ (ppm) 1,26 (3H, s, CH3Aib), 1,29 (3H, s, CH3Aib), 2,78-2,92 (4H, m, CH2-CH2-fenyl), 3,29 (2H, m, CH2βTrp), 3,65 (3H, s, OCH3), 4,97-5,21 (3H, m, CH αTrp og CH2-o-metoksybenzyl), 6,52 (1H, d, Jo= 7 Hz, H3o-metoksybenzyl), 6,78 (1H, t, Jo= 7 Hz, H5Trp), 6,82 (1H, t, Jo= 8 Hz, H6Trp), 6,84-7,04 (3H, m, H4, H5og H6o-metoksybenzyl), 7,15 (1H, d, J0= 7 Hz, H4Trp), 7,19-7,29 (4H, m, H3, H4og H5fenyl, H7Trp), 8,03 (3H, brs, NH2Aib), 8,94 (1H, d, J = 8 Hz, NH amid), 10,82 (1H, s, NH indol Trp).
<13>C NMR (75 MHz, DMSO-d<6>, 300°K):
δ (ppm) 23,6 (CH3Aib), 23,7 (CH3Aib), 26,3 (CH2-CH2-fenyl), 29,0 (CH2βTrp), 32,5 (CH2-CH2-fenyl), 42,3 (CH2-o- metoksybenzyl), 45,7 (CH αTrp), 55,8 (OCH3), 56,7 (Cq Aib), 109,7 (C3Trp), 111,5 (C7Trp), 111,8 (C3o-metoksybenzyl), 118,2 (C4Trp), 118,7 (C5Trp), 121,0 (C6Trp), 121,3 (C5o-metoksybenzyl), 123,2 (C1o-metoksybenzyl), 124,9 (C2Trp), 126,6 (C2og C6fenyl), 127,2 (C9Trp og C4o-metoksybenzyl), 128,7 (C3, C4og C5fenyl), 129,9 (C6o-metoksybenzyl), 136,4 (C8Trp), 140,6 (C1fenyl), 154,8 (Cq triazol), 155,2 (Cq triazol), 156,7 (C2o-metoksybenzyl), 171,9 (CO Aib).
(R)-N-(2-(1H-indol-3-yl)-1-(4-(naftalen-1-ylmetyl)-5-fenetyl-4H-1,2,4-triazol-3-yl)etyl)-2-amino-2-metylpropanamid (forbindelse 27):
<1>H NMR (300 MHz, DMSO-d<6>, 300°K):
δ (ppm) 1,21 (3H, s, CH3Aib), 1,25 (3H, s, CH3Aib), 2,46 (2H, m, CH2-CH2-fenyl), 2,88 (2H, m, CH2-CH2-fenyl), 3,26 (2H, dd,<3>J = 14 Hz og 6 Hz, CH2βTrp), 3,36 (2H, dd,<3>J = 14 Hz og 9 Hz, CH2βTrp), 4,99 (1H, m, CH αTrp), 5,65 (1H, d,<3>J = 18 Hz, CH2-naftyl), 5,78 (1H, d,<3>J = 18 Hz, CH2-naftyl), 6,29 (1H, d, Jo= 7 Hz, H2naftyl), 6,45 (1H, t, Jo= 7 Hz, H5Trp), 6,62 (1H, d, Jo= 8 Hz, H4Trp), 6,88 (1H, t, Jo= 8 Hz, H6Trp), 7,04-7,06 (4H, m, H2og H7Trp, H2og H6fenyl), 7,07-7,25 (H3naftyl, H3, H4og H5fenyl), 7,57-7,60 (2H, m, H6og H7naftyl), 7,86 (1H, d, Jo= 8 Hz, H4naftyl), 7,98-8,00 (4H, m, H5og H8naftyl, NH2Aib), 8,96 (1H, d, J = 8 Hz, NH amid), 10,77 (1H, s, NH indol Trp).
<13>C NMR (75 MHz, DMSO-d<6>, 300°K):
δ (ppm) 23,5 (CH3Aib), 23,6 (CH3Aib), 26,3 (CH2CH2-fenyl), 29,2 (CH2βTrp), 32,6 (CH2-CH2-fenyl), 43,8 (CH2-naftyl), 45,6 (CH αTrp), 56,7 (Cq Aib), 109,7 (C3Trp), 111,7 (C7Trp), 117,9 (C4Trp), 118,4 (C5Trp), 121,1 (C6Trp), 122,1 (C2naftyl), 123,0 (C8naftyl), 124,9 (C2Trp), 125,9 (C3naftyl), 126,5 (C6naftyl), 126,9 (C2og C6fenyl), 127,0 (C9Trp og C7naftyl), 127,1 (C4naftyl), 128,4 (C5naftyl), 128,7 (C3, C4og C5fenyl), 130,0 (C9naftyl), 131,7 (C1naftyl), 133,6 (C10naftyl), 136,4 (C8Trp), 140,8 (C1fenyl), 154,8 (Cq triazol), 155,3 (Cq triazol), 171,9 (CO Aib).
(R)-N-(1-(5-(2-(1H-indol-3-yl)etyl)-4-(3,4-diklorbenzyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid (forbindelse 28):
<1>H NMR (300 MHz, DMSO-d<6>, 300°K):
δ (ppm) 1,26 (6H, s, CH3Aib), 2,87 (2H, m, CH2-CH2-indol), 2,96 (2H, m, CH2-CH2-indol), 3,32 (2H, m, CH2βTrp), 5,13 (3H, m, CH αTrp og CH2-m,p-diklorbenzyl), 6,58 (1H, d, Jo= 8 Hz, H6m,p-diklorbenzyl), 6,85 (1H, t, Jo= 7 Hz, H5Trp), 6,96 (1H, t, Jo= 7 Hz, H5indol), 7,01 (2H, m, H6indol og H6Trp), 7,04 (1H, s, H2Trp), 7,08 (1H, s, H2indol), 7,13 (1H, d, Jo= 8 Hz, H5m,p-diklorbenzyl), 7,20-7,30 (4H, m, H4og H7indol, H7Trp og H2m,p-diklorbenzyl), 7,36 (1H, d, Jo= 8 Hz, H4Trp), 8,08 (3H, brs, NH2Aib), 8,98 (1H, d, J = 8 Hz, NH amid), 10,80 (1H, s, NH indol), 10,82 (1H, s, NH indol Trp).
<13>C NMR (75 MHz, DMSO-d<6>, 300°K):
δ (ppm) 22,8 (CH2-CH2-indol), 23,4 (CH3Aib), 23,8 (CH3Aib), 25,8 (CH2-CH2-indol), 29,0 (CH2βTrp), 44,8 (CH2-m,p-diklorbenzyl), 45,6 (CH αTrp), 56,8 (Cq Aib), 109,7 (C3indol), 111,8 (C7indol og C7Trp), 118,1 (C4Trp), 118,4 (C5indol), 118,6 (C4indol og C5Trp), 121,3 (C6indol og C6Trp), 123,0 (C2indol og C2Trp), 126,4 (C6m,pdiklorbenzyl), 127,1 (C9Trp), 127,3 (C9indol), 128,6 (C2m,p-diklorbenzyl), 130,9 (C4m,p-diklorbenzyl), 131,3 (C5m,p-diklorbenzyl), 132,0 (C3m,p-diklorbenzyl), 136,4 (C8Trp), 136,6 (C8indol), 137,2 (C1m,p-diklorbenzyl), 154,7 (Cq triazol), 155,1 (Cq triazol), 172,0 (CO Aib).
(R)-N-(1-(4-(4-fluorbenzyl)-5-benzyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid (forbindelse 30):
<1>H NMR (300 MHz, DMSO-d<6>, 300°K):
δ (ppm) 1,27 (3H, s, CH3Aib), 1,29 (3H, s, CH3Aib), 3,33 (2H, m, CH2βTrp), 4,02 (2H, s, CH2-benzyl), 5,10 (3H, m, CH2-p-fluorbenzyl og CH αTrp), 6,71 (2H, m, H3og H5p-fluorbenzyl), 6,80 (1H, t, Jo= 8 Hz, H5Trp), 6,90 (2H, d, Jo= 8 Hz, H2og H6pfluorbenzyl), 6,94 (1H, t, Jo= 8 Hz, H6Trp), 6,99-7,10 (4H, m, H2og H4Trp, H2og H6benzyl), 7,20 (3H, m, H3, H4og H5benzyl), 7,27 (1H, d, Jo= 8 Hz, H7Trp), 8,09 (3H, brs, NH2Aib), 8,97 (1H, d, J = 8 Hz, NH amid), 10,79 (1H, s, NH indol Trp).
<13>C NMR (75 MHz, DMSO-d<6>, 300°K):
δ (ppm) 23,5 (CH3Aib), 23,8 (CH3Aib), 29,0 (CH2βTrp), 31,1 (CH2-benzyl), 45,7 (CH2- p-fluorbenzyl), 45,8 (CH αTrp), 56,8 (Cq Aib), 109,6 (C3Trp), 111,8 (C7Trp), 115,6 og 115,9 (C3og C5p-fluorbenzyl), 118,2 (C4Trp), 118,7 (C5Trp), 121,3 (C6Trp), 124,8 (C2Trp), 127,1 (C4benzyl), 127,2 (C9Trp), 128,8 og 128,9 (C2og C6pfluorbenzyl), 129,4 (C2, C3, C5og C6p-fluorbenzyl), 131,6 (C1p-fluorbenzyl), 135,9 (C1benzyl), 136,4 (C8Trp), 154,0 (C4p-fluorbenzyl), 155,3 (Cq triazol), 172,0 (CO amid).
(R)-N-(1-(4-(4-metylbenzyl)-5-(3-fenylpropyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid (forbindelse 33):
<1>H NMR (300 MHz, DMSO-d<6>, 300°K):
δ (ppm) 1,25 (3H, s, CH3Aib), 1,28 (3H, s, CH3Aib), 1,73 (2H, m, CH2-CH2-CH2-fenyl), 2,23 (3H, s, CH3p-metylbenzyl), 2,49-2,54 (4H, m, CH2-CH2-CH2-fenyl), 3,33 (2H, m, CH2βTrp), 5,04 (2H, s, CH2-p-metylbenzyl), 5,16 (1H, m, CH αTrp), 6,74 (2H, d, Jo= 8 Hz, H3og H5p-metylbenzyl), 6,80 (1H, t, Jo= 7 Hz, H5Trp), 6,98 (1H, t, Jo= 7 Hz, H6Trp), 7,03 (1H, d, J = 2 Hz, H2Trp), 7,06 (5H, m, CHar fenyl), 7,14 (1H, d, Jo= 7 Hz, H4Trp), 7,20 (2H, d, Jo= 7 Hz, H2og H6p-metylbenzyl), 7,27 (1H, d, Jo= 8 Hz, H7Trp), 8,01 (3H, brs, NH2Aib), 8,95 (1H, d, J = 8 Hz, NH amid), 10,80 (1H, d, J = 2 Hz, NH indol Trp).
<13>C NMR (75 MHz, DMSO-d<6>, 300°K):
δ (ppm) 21,0 (CH3p-metylbenzyl), 23,5 (CH3Aib), 23,8 (CH3Aib), 24,0 (CH2-CH2-CH2-fenyl), 28,5 (CH2-CH2-CH2-fenyl), 29,1 (CH2βTrp), 34,7 (CH2-CH2-CH2-fenyl), 45,7 (CH αTrp), 45,8 (CH2-p-metylbenzyl), 56,8 (Cq Aib), 109,8 (C3Trp), 111,8 (C7Trp), 118,3 (C4Trp), 118,7 (C5Trp), 121,3 (C6Trp), 124,9 (C2Trp), 126,2 (C4fenyl), 126,4 (C3og C5p-metylbenzyl), 127,3 (C9Trp), 128,7 (C2, C3, C5og C6fenyl), 129,8 (C2og C6p-metylbenzyl), 133,0 (C1p-metylbenzyl), 136,4 (C8Trp), 137,5 (C4p-metylbenzyl), 141,7 (C1fenyl), 154,8 (Cq triazol), 171,9 (CO Aib).
(R)-N-(1-(5-(2-(1H-indol-3-yl)etyl)-4-(4-metylbenzyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid (forbindelse 34):
<1>H NMR (300 MHz, DMSO-d<6>, 300°K):
δ (ppm) 1,25 (3H, s, CH3Aib), 1,28 (3H, s, CH3Aib), 2,23 (3H, s, CH3-p-metylbenzyl), 2,84-2,97 (4H, m, CH2-CH2-indol), 3,32 (2H, m, CH2βTrp), 5,04 (2H, s, CH2- p-metylbenzyl), 5,16 (1H, m, CH αTrp), 6,79-6,86 (4H, m, CH ar p-metylbenzyl), 6,99-7,05 (4H, m, H5og H6indol, H5og H6Trp), 7,08 (3H, m, H2indol, H2og H4Trp), 7,25-7,30 (3H, m, H4og H7indol, H7Trp), 8,00 (3H, brs, NH2Aib), 8,94 (1H, d, J = 8 Hz, NH amid), 10,76 (1H, s, NH indol), 10,78 (1H, s, NH indol Trp).
<13>C NMR (75 MHz, DMSO-d<6>, 300°K):
δ (ppm) 21,0 (CH3-p-metylbenzyl), 22,8 (CH2-CH2-indol), 23,8 (CH3Aib), 23,9 (CH3Aib), 25,9 (CH2-CH2-indol), 28,5 (CH2βTrp), 45,7 (CH2- p-metylbenzyl og CH αTrp), 56,7 (Cq Aib), 109,9 (C3Trp), 111,8 (C7indol og C7Trp), 113,4 (C3indol), 118,1 (C4Trp), 118,3 (C4indol), 118,5 (C5indol), 118,7 (C5Trp), 120,9 (C8indol og C6Trp), 121,3 (C2indol og C2Trp), 126,3 (C3og C5p-metylbenzyl), 127,2 (C9indol), 127,3 (C9Trp), 129,8 (C2og C6p-metylbenzyl), 133,1 (C1p-metylbenzyl), 135,8 (C8indol, C8Trp), 136,4 (C4p-meetylbenzyl), 154,8 (Cq triazol), 155,0 (Cq triazol), 171,9 (CO Aib).
(R)-N-(1-(4-(4-metylbenzyl)-5-fenetyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid (forbindelse 37):
<1>H NMR (300 MHz, DMSO-d<6>, 300°K):
δ (ppm) 1,25 (3H, s, CH3Aib), 1,28 (3H, s, CH3Aib), 2,23 (3H, s, CH3p-metylbenzyl), 2,83 (4H, m, CH2-CH2-fenyl), 3,32 (2H, m, CH2βTrp), 5,05 (2H, s, CH2-p-metylbenzyl), 5,18 (1H, m, CH αTrp), 6,75 (2H, d, Jo= 8 Hz, H3og H5p-metylbenzyl), 6,82 (1H, t, Jo= 8 Hz, H5Trp), 6,99 (1H, t, Jo= 8 Hz, H6Trp), 7,02-7,11 (6H, m, H2Trp og CHar fenyl), 7,15 (1H, d, Jo= 7 Hz, H4Trp), 7,20 (2H, d, Jo= 7 Hz, H2og H6p-metylbenzyl), 7,28 (1H, d, Jo= 8 Hz, H7Trp), 8,01 (3H, brs, NH2Aib), 8,93 (1H, d, J = 8 Hz, NH amid), 10,77 (1H, s, NH indol Trp).
<13>C NMR (75 MHz, DMSO-d<6>, 300°K):
δ (ppm) 21,0 (CH3p-metylbenzyl), 23,6 (CH3Aib), 23,8 (CH3Aib), 26,5 (CH2-CH2-fenyl), 29,1 (CH2βTrp), 32,7 (CH2-CH2-fenyl), 45,7 (CH αTrp og CH2-p-metylbenzyl), 56,8 (Cq Aib), 109,8 (C3Trp), 111,8 (C7Trp), 118,3 (C4Trp), 118,7 (C5Trp), 121,3 (C6Trp), 124,8 (C2Trp), 126,4 (C3og C5p-metylbenzyl), 126,6 (C4fenyl), 127,3 (C9Trp), 128,7 (C2, C3, C5og C6fenyl), 129,8 (C2og C6p-metylbenzyl), 133,0 (C1p-metylbenzyl), 136,4 (C8Trp), 137,5 (C4p-metylbenzyl), 140,9 (C1fenyl), 154,5 (Cq triazol), 154,9 (Cq triazol), 171,9 (CO amid).
(R)-N-(1-(5-benzyl-4-(pyridin-2-ylmetyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)-etyl)-2-amino-2-metylpropanamid (forbindelse 39):
<1>H NMR (300 MHz, DMSO-d<6>, 300°K):
δ (ppm) 1,23 (3H, s, CH3Aib), 1,27 (3H, s, CH3Aib), 3,34 (1H, dd, J = 14 Hz og 6 Hz, CH2βTrp), 3,43 (1H, dd, J = 14 Hz og 9 Hz, CH2βTrp), 4,13 (2H, s, CH2-benzyl), 5,22 (1H, s, CH αTrp), 5,35 (2H, s, CH2-o-pyridyl), 6,80 (1H, t, Jo= 8 Hz, H5Trp), 6,92 (1H, t, Jo= 8 Hz, H5pyridyl), 6,97 (1H, t, Jo= 8 Hz, H6Trp), 7,04 (1H, d, Jo= 8 Hz, H4Trp), 7,07 (1H, d, J = 2 Hz, H2Trp), 7,10-7,16 (5H, m, CHar benzyl), 7,19 (1H, s, H3opyridyl), 7,26 (1H, d, Jo= 8 Hz, H7Trp), 7,57 (1H, t, Jo= 9 Hz, H4o-pyridyl), 8,16 (3H, brs, NH2Aib), 8,36 (1H, d, J α β = 5 Hz, H6o-pyridyl), 9,01 (1H, d, J = 8 Hz, NH amid), 10,85 (1H, s, NH indol Trp).
<13>C NMR (75 MHz, DMSO-d<6>, 300°K):
δ (ppm) 23,4 (CH3Aib), 23,7 (CH3Aib), 28,6 (CH2βTrp), 30,4 (CH2-benzyl), 45,7 (CH αTrp), 47,7 (CH2- o-pyridyl), 56,7 (Cq Aib), 109,8 (C3Trp), 111,8 (C7Trp), 118,3 (C4Trp), 118,6 (C5Trp), 121,2 (C6Trp), 121,7 (C3o-pyridyl), 123,3 (C5o-pyridyl), 124,8 (C2Trp), 127,1 (C4benzyl), 127,3 (C9Trp), 128,8 (C2og C6benzyl), 129,0 (C3og C5benzyl), 135,6 (C1benzyl), 136,4 (C8Trp), 137,5 (C4o-pyridyl), 149,5 (C6opyridyl), 154,1 (Cq triazol), 154,2 (Cq triazol), 155,7 (C2o-pyridyl), 172,0 (CO amid).
(R)-N-(1-(4-(4-etylbenzyl)-5-fenetyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid (forbindelse 43):
<1>H NMR (300 MHz, DMSO-d<6>, 300°K):
δ (ppm) 1,10 (3H, t, J = 8 Hz, CH3-CH2p-etylbenzyl), 1,25 (3H, s, CH3Aib), 1,28 (3H, s, CH3Aib), 2,53 (2H, q, J = 8 Hz, CH3-CH2p-etylbenzyl), 2,83 (4H, m, CH2-CH2-fenyl), 3,34 (2H, m, CH2βTrp), 5,07 (2H, s, CH2-p-etylbenzyl), 5,19 (1H, m, CH αTrp), 6,77 (2H, d, Jo= 8 Hz, H3og H5p-etylbenzyl), 6,81 (1H, t, Jo= 7 Hz, H5Trp), 6,99 (1H, t, Jo= 8 Hz, H6Trp), 7,05-7,10 (7H, m, CHar fenyl, H2og H6p-etylbenzyl), 7,13 (1H, d, J = 2 Hz, H2Trp), 7,20 (1H, d, Jo= 7 Hz, H4Trp), 7,28 (1H, d, Jo= 8 Hz, H7Trp), 8,03 (3H, brs, NH2Aib), 8,94 (1H, d, J = 8 Hz, NH amid), 10,79 (1H, s NH indol Trp).
<13>C NMR (75 MHz, DMSO-d8<6>, 300°K):
δ (ppm) 15,9 (CH3-CH2p-etylbenzyl), 23,5 (CH3Aib), 23,8 (CH3Aib), 26,5 (CH2-CH2-fenyl), 28,1 (CH3-CH2p-etylbenzyl), 29,1 (CH2βTrp), 32,7 (CH2-CH2-fenyl), 45,7 (CH αTrp), 45,8 (CH2-p-etylbenzyl), 56,8 (Cq Aib), 109,8 (C3Trp), 111,8 (C7Trp), 118,3 (C4Trp), 118,7 (C5Trp), 121,3 (C6Trp), 124,9 (C2Trp), 126,5 (C3og C5p-etylbenzyl), 126,6 (C4fenyl), 127,3 (C9Trp), 128,6 (C2og C6p-etylbenzyl, C2, C3, C5og C6fenyl), 133,1 (C1p-etylbenzyl), 136,5 (C8Trp), 140,8 (C1fenyl), 143,8 (C4p-etylbenzyl), 154,6 (Cq triazol), 154,9 (Cq triazol), 171,9 (CO amid).
(R)-N-(1-(4-(4-metoksybenzyl)-5-fenetyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)-etyl)piperidin-4-karboksamid (forbindelse 44):
<1>H NMR (300 MHz, DMSO d<6>, 300°K):
δ (ppm) 1,42 (m, 2H, H3og H5piperidyl), 1,55 (m, 1H, H5piperidyl ), 2,23 (m, 1H, H4piperidyl), 2,75 (m, 5H, H2piperidyl og CH2-CH2-fenyl), 3,04 (m, 1H, H6piperidyl), 3,13 (m, 1H, H2piperidyl), 3,32 (m, 2H, CH2βTrp), 3,66 (s, 3H, OCH3), 4,97 (m, 2H, CH2-p-metoksybenzyl), 5,23 (m, 1H, CH αTrp), 6,70 (s, 4H, CHar p-metoksybenzyl), 6,87 (t, 1H, Jo= 8 Hz, H5Trp), 7,00 (m, 2H, H2og H6Trp), 7,07 (d, 2H, Jo= 8 Hz, H2og H6fenyl), 7,14 (d, 1H, Jo= 7 Hz, H4Trp), 7,18-7,30 (m, 4H, H7Trp, H3, H4og H5fenyl), 8,16 og 8,46 (2 m, 2H, NH piperidyl TFA-salt), 8,66 (d, 1H, J = 8 Hz, NH amid), 10,75 (1H, s, NH indol Trp).
<13>C NMR (75 MHz, DMSO d<6>, 300°K):
δ (ppm) 24,9 (C3piperidyl), 25,4 (C5piperidyl), 26,5 (CH2-CH2-fenyl), 29,2 (CH2βTrp), 32,7 (CH2-CH2-fenyl), 38,7 (C4piperidyl), 42,7 (C2og C6piperidyl), 44,7 (CH Trp), 45,3 (CH2-p-metoksybenzyl), 55,5 (OCH3), 110,2 (C3Trp), 111,7 (C7Trp), 114,4 (C3og C5p-metoksybenzyl), 118,5 (C4Trp), 118,7 (C5Trp), 121,3 (C6Trp), 124,4 (C2Trp), 126,5 (C2og C6fenyl), 127,5 (C9Trp), 127,8 (C1, C2og C6p-metoksybenzyl), 128,7 (C3, C4og C5fenyl), 136,4 (C8Trp), 140,8 (C1fenyl), 155,3 (Cq triazol), 155,4 (Cq triazol), 159,1 (C4p-metoksybenzyl), 173,1 (CO amid).
(R)-N-(1-(5-(2-(1H-indol-3-yl)etyl)-4-(4-metoksybenzyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)piperidin-4-karboksamid (forbindelse 45):
<1>H NMR (300 MHz, DMSO d<6>, 300°K):
δ (ppm) 1,41 (m, 2H, H3og H5piperidyl), 1,54 (dd, 1H, J = 13 Hz og 2 Hz, H5piperidyl), 2,23 (m, 1H, H4piperidyl), 2,72 (m, 2H, H2og H6piperidyl), 2,77-2,93 (m, 4H, CH2-CH2-indol), 3,06 (m, 2H, H2og H6piperidyl), 3,32 (m, 2H, CH2βTrp), 3,65 (s, 3H, OCH3), 4,94 (s, 2H, CH2-p-metoksybenzyl), 5,22 (m, 1H, CH αTrp), 6,68 (s, 4H, CHar p-metoksybenzyl), 6,87 (m, 3H, H5og H6Trp, H5indol), 6,98 (m, 4H, H2og H6indol, H2og H4Trp), 7,20-7,33 (m, 3H, H4og H7indol, H7Trp), 8,15 og 8,46 (2 m, 2H, NH piperidyl TFA-salt), 8,64 (d, 1H, J = 8 Hz, NH amid), 10,74 (s, 2H, NH indol og NH indol Trp).
<13>C NMR (75 MHz, DMSO d<6>, 300°K):
δ (ppm) 22,9 (CH2-CH2-indol), 24,9 (C3piperidyl), 25,4 (C5piperidyl), 26,0 (CH2-CH2indol), 29,3 (CH2βTrp), 39,1 (C4piperidyl), 42,7 (C2og C6piperidyl), 44,7 (CH αTrp), 45,3 (CH2-p-metoksybenzyl), 55,5 (OCH3), 109,5 (C3Trp), 111,7 (C7indol og C7Trp), 113,5 (C3indol), 114,4 (C3og C5p-metoksybenzyl), 118,5 (C4indol og C4Trp), 118,6 (C5indol og C5Trp), 121,2 (C6indol), 121,3 (C6Trp), 122,9 (C2indol og C2Trp), 127,2 (C9indol), 127,6 (C9Trp, C2og C6p-metoksybenzyl), 127,9 (C1p-metoksybenzyl), 136,4 (C8Trp), 136,6 (C8indol), 154,9 (Cq triazol), 155,2 (Cq triazol), 159,0 (C4p-metoksybenzyl), 173,0 (CO amid).
(R)-N-(1-(4-(4-metoksybenzyl)-5-fenetyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)-etyl)-2-aminoacetamid (forbindelse 50):
<1>H NMR (300 MHz, DMSO d<6>, 300°K):
δ (ppm) 2,78 (m, 4H, CH2-CH2-fenyl), 3,26 (1H, dd, J = 14 Hz og 7 Hz, CH2βTrp), 3,39 (m, 3H, CH2βTrp og CH2-NH2), 3,65 (s, 3H, OCH3), 4,95 (m, 2H, CH2-pmetoksybenzyl), 5,20 (m, 1H, CH αTrp), 6,63 (s, 4H, CHar p-metoksybenzyl), 6,86 (t, 1H, Jo= 7 Hz, H5Trp), 6,99 (s, 1H, H2Trp), 7,02 (t, 1H, Jo= 7 Hz, H6Trp), 7,10 (m, 2H, H2og H6fenyl), 7,15 (d, 1H, Jo= 7 Hz, H4Trp), 7,23 (m, 3H, H3, H4og H5Trp), 7,31 (d, 1H, Jo= 8 Hz, H7Trp), 7,95 (brs, 3H, NH2Gly, TFA-salt), 9,20 (d, 1H, J = 8 Hz, NH amid), 10,82 (s, 1H, NH indol Trp).
<13>C NMR (75 MHz, DMSO d<6>, 300ºK):
δ (ppm) 26,5 (CH2-CH2-fenyl), 29,8 (CH2βTrp), 32,7 (CH2-CH2-fenyl), 39,0 (CH2NH2), 45,3 (CH2- p-metoksybenzyl), 45,4 (CH αTrp), 55,4 (OCH3), 109,7 (C3Trp), 111,8 (C7Trp), 114,5 (C3og C5p-metoksybenzyl), 118,3 (C4Trp), 118,9 (C5Trp), 121,4 (C6Trp), 124,6 (C2Trp), 126,5 (C2og C6fenyl), 127,3 (C9Trp), 127,7 (C1pmetoksybenzyl), 127,8 (C2og C6p-metoksybenzyl), 128,7 (C3, C4og C5fenyl), 136,4 (C8Trp), 140,9 (C1fenyl), 154,3 (Cq triazol), 154,8 (Cq triazol), 159,0 (C4p-metoksybenzyl), 166,1 (CO amid).
(R)-N-(1-(4-(4-metoksybenzyl)-5-fenetyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)-etyl)-2-(pyridin-2-yl)acetamid (forbindelse 51):
<1>H NMR (300 MHz, DMSO d<6>, 300°K):
δ (ppm) 2,77-2,88 (m, 4H, CH2-CH2-fenyl), 3,37 (m, 2H, CH2βTrp), 3,64 (s, 3H, OCH3), 3,74 (m, 2H, CH2-o-pyridyl), 5,03 (m, 2H, CH2-p-metoksybenzyl), 5,24 (m, 1H, CH αTrp), 6,65 (s, 4H, CHar p-metoksybenzyl), 6,85 (t, 1H, Jo= 7 Hz, H5Trp), 7,01 (m, 2H, H2og H6Trp), 7,08 (d, 2H, Jo= 7 Hz, H2og H6fenyl), 7,15 (d, 1H, Jo= 7 Hz, H4Trp), 7,21 (m, 3H, H3, H4og H5fenyl), 7,27-7,36 (m, 2H, H7Trp og H3o-pyridyl), 7,58 (t, 1H, J = 6 Hz, H5o-pyridyl), 8,04 (t, 1H, Jo= 8 Hz, H4o-pyridyl), 8,62 (d, 1H, J α β = 5 Hz, H6o-pyridyl), 9,17 (d, 1H, J = 8 Hz, NH amid), 10,81 (s, 1H, NH indol Trp).
<13>C NMR (75 MHz, DMSO d<6>, 300°K):
δ (ppm) 26,4 (CH2-CH2-fenyl), 29,2 (CH2βTrp), 32,4 (CH2-CH2-fenyl), 41,7 (CH2-opyridyl), 45,3 (CH αTrp), 45,7 (CH2-p-metoksybenzyl), 55,5 (OCH3), 109,7 (C3Trp), 111,8 (C7Trp), 114,4 (C3og C5p-metoksybenzyl), 118,4 (C4Trp), 118,8 (C5Trp), 121,4 (C6Trp), 124,1 (C3o-pyridyl), 124,6 (C2Trp), 126,4 (C5o-pyridyl), 126,6 (C2og C6fenyl), 127,2 (C9Trp), 127,4 (C1p-metoksybenzyl), 127,9 (C2og C6p-metoksybenzyl), 128,7 (C3, C4og C5fenyl), 136,4 (C8Trp), 140,5 (C1fenyl), 142,1 (C4opyridyl), 145,3 (C6o-pyridy), 153,0 (C2o-pyridyl), 154,5 (Cq triazol), 155,3 (Cq triazol), 159,1 (C4p-metoksybenzyl), 167,9 (CO amid).
(R)-N-(1-(4-(2,4-dimetoksybenzyl)-5-fenetyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)pikolinamid (forbindelse 64):
<1>H NMR (300 MHz, DMSO d<6>, 300°K):
δ (ppm) 2,83 (m, 2H, CH2-CH2-fenyl), 2,90 (m, 2H, CH2-CH2-fenyl), 3,48 (m, 2H, CH2βTrp), 3,57 (s, 3H, OCH3), 3,61 (s, 3H, OCH3), 4,97 (d, 1H, J = 17 Hz, CH2-o,pdimetoksybenzyl), 5,09 (d, 1H, J = 17 Hz, CH2-o,p-dimetoksybenzyl), 5,56 (m, 1H, CH αTrp), 6,18 (dd, 1H, Jo= 8 Hz og Jm= 2 Hz, H5o,p-dimetoksybenzyl), 6,41 (d, 1H, Jm= 2 Hz, H3o,p-dimetoksybenzyl), 6,55 (d, 1H, Jo= 8 Hz, H6o,p-dimetoksybenzyl), 6,87 (t, 1H, Jo= 8 Hz, H5Trp), 7,01 (t, 1H, Jo= 8 Hz, H6Trp), 7,08 (m, 3H, H2Trp, H2og H6fenyl), 7,14 (d, 1H, Jo= 7 Hz, H4Trp), 7,19-7,31 (m, 4H, H7Trp, H3, H4og H5fenyl), 7,56 (t, 1H, J = 8 Hz, NH amid), 7,91 (m, 2H, H4og H5o-pyridyl), 8,57 (d, 1H, J α β = 5 Hz, H6o-pyridyl), 9,16 (d, 1H, Jo= 8 Hz, H3o-pyridyl), 10,80 (s, 1H, NH indol Trp).
<13>C NMR (75 MHz, DMSO d<6>, 300°K):
δ (ppm) 26,2 (CH2-CH2-fenyl), 28,8 (CH2βTrp), 32,1 (CH2-CH2-fenyl), 43,0 (CH2-o,pdimetoksybenzyl), 45,5 (CH αTrp), 55,6 (OCH3), 55,8 (OCH3), 98,9 (C3o,p-dimetoksybenzyl), 105,0 (C5o,p-dimetoksybenzyl), 109,5 (C3Trp), 111,8 (C7Trp), 114,4 (C1o,pdimetoksybenzyl), 118,4 (C4Trp), 118,8 (C5Trp), 121,4 (C6Trp), 122,4 (C3o-pyridyl), 124,4 (C2Trp), 126,7 (C6o,p-dimetoksybenzyl), 127,2 (C5o-pyridyl), 127,5 (C9Trp), 128,6-128,8 (C2, C3, C4, C5og C6fenyl), 136,4 (C8Trp), 138,1 (C4o-pyridyl), 140,2 (C1fenyl), 148,8 (C6o-pyridyl), 149,3 (C2o-pyridyl), 155,2 (Cq triazol), 155,4 (Cq triazol), 157,9 (C2o,p-dimetoksybenzyl), 161,0 (C4o,p-dimetoksybenzyl), 163,9 (CO amid).
(R)-N-(1-(4-(2,4-dimetoksybenzyl)-5-fenetyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)pyrazin-2-karboksamid (forbindelse 66):
<1>H NMR (300 MHz, DMSO d6, 300°K):
δ (ppm) 2,87 (m, 4H, CH2-CH2-fenyl), 3,51 (m, 2H, CH2βTrp), 3,58 (s, 3H, OCH3), 3,59 (s, 3H, OCH3), 4,97 (d, 1H, J = 17 Hz, CH2-o,p-dimetoksybenzyl), 5,08 (d, 1H, J = 17 Hz, CH2-o,p-dimetoksybenzyl), 5,56 (s, 1H, CH αTrp), 6,10 (dd, 1H, Jo= 8 Hz og Jm= 2 Hz, H5o,p-dimetoksybenzyl), 6,36 (d, 1H, Jm= 2 Hz, H3o,p-dimetoksybenzyl), 6,40 (d, 1H, Jo= 8 Hz, H6o,p-dimetoksybenzyl), 6,87 (t, 1H, Jo= 8 Hz, H5Trp), 7,00 (t, 1H, Jo= 7 Hz, H6Trp), 7,09 (m, 3H, H2Trp, H2og H6fenyl), 7,15 (d, 1H, Jo= 7 Hz, H4Trp), 7,19-7,28 (m, 3H, H3, H4og H5fenyl), 7,36 (d, 1H, Jo= 8 Hz, H7Trp), 8,61 (t, 1H, J = 2 Hz, H3o-pyrazinyl), 8,78 (d, 1H, J = 2 Hz, H5o-pyrazinyl), 8,94 (d, 1H, J = 1 Hz, H6o-pyrazinyl), 9,26 (d, 1H, J = 8 Hz, NH amid), 10,78 (s, 1H, NH indol Trp).
<13>C NMR (75 MHz, DMSO d<6>, 300°K):
δ (ppm) 26,1 (CH2-CH2-fenyl), 28,4 (CH2βTrp), 32,1 (CH2-CH2-fenyl), 42,9 (CH2-o,pdimetoksybenzyl), 45,5 (CH αTrp), 55,5 (OCH3), 55,8 (OCH3), 98,7 (C3o,p-dimetoksybenzyl), 104,9 (C5o,p-dimetoksybenzyl), 109,7 (C3o,p-dimetoksybenzyl), 111,8 (C7Trp), 114,5 (C1o,p-dimetoksybenzyl), 118,5 (C4Trp), 118,8 (C5Trp), 121,4 (C6Trp), 124,4 (C2Trp), 126,7 (C6o,p-dimetoksybenzyl), 127,5 (C9Trp), 128,1 (C4fenyl), 128,7-128,8 (C2, C3, C5og C6fenyl), 136,4 (C8Trp), 140,3 (C1fenyl), 141,2 (C6o,pdimetoksybenzyl), 144,2 (C2o-pyrazinyl), 144,3 (C3o-pyrazinyl), 146,8 (C5opyrazinyl), 155,2 (Cqs triazol), 157,7 (C2o,p-dimetoksybenzyl), 160,7 (CO amid), 162,9 (C4o,p-dimetoksybenzyl).
(S)-N-((R)-1-(5-(2-(1H-indol-3-yl)etyl)-4-(2,4-dimetoksybenzyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)pyrrolidin-2-karboksamid (forbindelse 70):
<1>H NMR (300 MHz, DMSO d<6>, 300°K):
δ (ppm) 1,40 (m, 1H, H3Pro), 1,53 (m, 1H, H4Pro), 1,71 (m, 1H, H4Pro), 2,09 (m, 1H, H3Pro), 2,90 (m, 4H, CH2-CH2-indol), 3,06 (t, 2H, J = 6 Hz, H5Pro), 3,28 (m, 2H, CH2βTrp), 3,40 (s, 3H, OCH3), 3,80 (s, 3H, OCH3), 3,80(m, 1H, CH αPro), 4,80 (d, 1H, J = 17 Hz, CH2-o,p-dimetoksybenzyl), 5,4 (d, 1H, J = 17 Hz, CH2-o,p-dimetoksybenzyl), 5,1 (m, 1H, CH αTrp), 6,26 (dd, 1H, Jo= 8 Hz og Jm= 2 Hz, H5o,p-dimetoksybenzyl), 6,38 (d, 1H, Jo= 8 Hz, H6o,p-dimetoksybenzyl), 6,53 (d, 1H, Jm= 2 Hz, H3o,p-dimetoksybenzyl), 6,84 (t, 1H, H5indol), 6,91 (t, 1H, Jo= 8 Hz, H5Trp), 6,93-7,07 (m, 4H, H2og H6indol, H2og H6Trp), 7,16 (d, 1H, Jo= 8 Hz, H4Trp), 7,29 (m, 3H, H4og H7indol, H7Trp), 8,39 og 9,10 (2 m, 2H, NH Pro TFA-salt), 9,22 (d, 1H, J = 8 Hz, NH amid), 10,76 (s, 1H, NH indol), 10,80 (s, 1H, NH indol Trp).
<13>C NMR (75 MHz, DMSO d<6>, 300°K):
δ (ppm) 22,9 (CH2-CH2-indol), 23,5 (C4Pro), 25,8 (CH2-CH2-indol), 29,6 (CH2βTrp), 29,8 (C3Pro), 41,9 (CH2-o,p-dimetoksybenzyl), 45,2 (CH αTrp), 46,0 (C5Pro), 55,7 (OCH3), 55,9 (OCH3), 59,3 (CH αPro), 99,0 (C3o,p-dimetoksybenzyl), 105,1 (C5o,pdimetoksybenzyl), 109,7 (C3Trp), 111,8 (C7indol og C7Trp), 113,4 (C3indol), 115,6 (C1o,p-dimetoksybenzyl), 118,4 (C4indol og C4Trp), 118,7 (C5indol og C5Trp), 121,4 (C6indol og C6Trp), 123,0 (C2indol og C2Trp), 127,2 (C9indol), 127,3 (C9Trp), 128,1 (C6o,p-dimetoksybenzyl), 136,5 (C8Trp), 136,6 (C8indol), 155,0 (Cq triazol), 157,8 (C2o,p-dimetoksybenzyl), 160,9 (C4o,p-dimetoksybenzyl), 168,1 (CO amid).
(R)-N-(1-(5-(2-(1H-indol-3-yl)etyl)-4-(2,4-dimetoksybenzyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)pyrazin-2-karboksamid (forbindelse 71):
<1>H NMR (300 MHz, DMSO d<6>, 300°K):
δ (ppm) 3,01 (m, 2H, CH2-CH2-indol) 3,10 (m, 2H, CH2-CH2-indol), 3,51 (m, 2H, CH2βTrp), 3,55 (s, 3H, OCH3), 3,57 (s, 3H, OCH3), 5,15 (d, 2H, J = 7 Hz, CH2-o,p-dimetoksybenzyl), 5,63 (m, 1H, CH αTrp), 6,08 (dd, 1H, Jo= 8 Hz og Jm= 2 Hz, H5o,pdimetoksybenzyl), 6,35 (d, 1H, Jm= 2 Hz, H3o,p-dimetoksybenzyl), 6,53 (d, 1H, Jo= 8 Hz, H6o,p-dimetoksybenzyl), 6,89 (m, 2H, H5indol og H5Trp), 6,99 (m, 2H, H6indol og H6Trp), 7,08 (m, 2H, H2indol og H2Trp), 7,29 (m, 3H, H4Trp, H4og H7indol), 7,41 (d, 1H, Jo= 8 Hz, H7Trp), 8,61 (t, 1H, J = 2 Hz, H3o-pyrazin), 8,79 (d, 1H, J = 2 Hz, H5o-pyrazin), 8,94 (d, 1H, J = 1 Hz, H6o-pyrazin), 9,43 (d, 1H, J = 8 Hz, NH amid), 10,84 (s, 2H, NH indol og NH indol Trp).
<13>C NMR (75 MHz, DMSO d<6>, 300°K):
δ (ppm) 22,0 (CH2-CH2-indol), 25,3 (CH2-CH2-indol), 27,9 (CH2βTrp), 44,1 (CH2-o,pdimetoksybenzyl), 45,5 (CH αTrp), 55,5 (OCH3), 55,8 (OCH3), 98,8 (C3o,p-dimetoksybenzyl), 104,9 (C5o,p-dimetoksybenzyl), 109,3 (C3Trp), 111,8 (C7indol og C7Trp), 112,1 (C3indol), 113,4 (C1o,p-dimetoksybenzyl), 118,4 (C4indol), 118,5 (C4Trp), 118,8 (C5indol og C5Trp), 121,5 (C6indol og C6Trp), 127,0 (C9indol), 127,4 (C9Trp), 136,4 (C8Trp), 136,6 (C8indol), 141,2 (C6o-pyrazin), 144,1 (C2o-pyrazin), 144,3 (C3o-pyrazin), 146,8 (C5o-pyrazin), 155,4 (Cq triazol), 156,0 (Cq triazol), 157,8 (C2o,pdimetoksybenzyl), 161,0 (CO amid), 163,2 (C4o,p-dimetoksybenzyl).
(R)-N-(1-(5-(2-(1H-indol-3-yl)etyl)-4-(2,4-dimetoksybenzyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)pikolinamid (forbindelse 73):
<1>H NMR (300 MHz, DMSO d<6>, 300°K):
δ (ppm) 2,94 (m, 4H, CH2-CH2-indol), 3,47 (m, 2H, CH2βTrp), 3,57 (s, 3H, OCH3), 3,60 (s, 3H, OCH3), 5,05 (m, 2H, CH2-o,p-dimetoksybenzyl), 5,56 (m, 1H, CH αTrp), 6,14 (dd, 1H, Jo= 8 Hz og Jm= 2 Hz, H5o,p-dimetoksybenzyl), 6,41 (d, 1H, Jm= 2 Hz, H3o,p-dimetoksybenzyl), 6,52 (d, 1H, Jo= 8 Hz, H6o,p-dimetoksybenzyl), 6,88 (t, 2H, Jo= 7 Hz, H5indol og H5Trp), 6,99 (t, 1H, Jo= 8 Hz, H6Trp), 7,01 (t, 1H, Jo= 8 Hz, H6indol), 7,04 (d, 1H, J = 2 Hz, H2Trp), 7,07 (d, 1H, J = 2 Hz, H2indol), 7,27-7,33 (m, 4H, H4og H7Trp, H4og H7indol), 7,55 (m, 1H, NH amid), 7,90 (m, 2H, H4og H5opyridyl), 8,57 (d, 1H, J α β = 4 Hz, H6o-pyridyl), 9,15 (d, 1H, J = 8 Hz, H3o-pyridyl), 10,78 (brs, 2H NH indol og NH indol Trp).
<13>C NMR (75 MHz, DMSO d<6>, 300°K):
δ (ppm) 22,3 (CH2-CH2-indol), 25,6 (CH2-CH2-indol), 28,9 (CH2βTrp), 43,1 (CH2-o,pdimetoksybenzyl), 45,5 (CH αTrp), 55,5 (OCH3), 55,8 (OCH3), 98,9 (C3o,p-dimetoksybenzyl), 105,0 (C5o,p-dimetoksybenzyl), 109,5 (C3Trp), 111,8 (C7indol og C7Trp), 112,8 (C3indol), 114,4 (C1o,p-dimetoksybenzyl), 118,4 (C4indol og C4Trp), 118,7 (C5indol), 118,8 (C5Trp), 121,4 (C6indol og C6Trp), 122,5 (C2indol og C3o-pyridyl), 123,1 (C2Trp), 127,1 (C5o-pyridyl), 127,2 (C9indol), 127,5 (C9Trp), 128,6 (C6o,pdimetoksybenzyl), 136,4 (C8Trp), 136,6 (C8indol), 139,1 (C4o-pyridyl), 146,6 (C6opyridyl), 150,6 (C2o-pyridyl), 155,5 (Cq triazol), 155,6 (Cq triazol), 157,8 (C2o,pdimetoksybenzyl), 161,0 (C4o,p-dimetoksybenzyl), 163,9 (CO amid).
(R)-1-(5-(2-(1H-indol-3-yl)etyl)-4-(2,4-dimetoksybenzyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etanamin (forbindelse 74):
<1>H NMR (300 MHz, DMSO d<6>, 300°K):
δ (ppm) 2,79 (m, 2H, CH2-CH2-indol), 2,86 (m, 2H, CH2-CH2-indol), 3,30 (dd, 1H,<3>J = 14 Hz og 5 Hz, CH2βTrp), 3,38 (dd, 1H,<3>J = 14 Hz og 6 Hz, CH2βTrp), 3,62 (s, 3H, OCH3), 3,63 (s, 3H, OCH3), 4,47 (d, 1H,<3>J = 17 Hz, CH2-o,p-dimetoksybenzyl), 4,59 (d, 1H,<3>J = 17 Hz, CH2-o,p-dimetoksybenzyl), 6,11 (dd, 1H, Jo= 8 Hz og Jm= 2 Hz, H5o,p-dimetoksybenzyl), 6,20 (d, 1H, Jo= 8 Hz, H6o,p-dimetoksybenzyl), 6,45 (d, 1H, Jm= 2 Hz, H3o,p-dimetoksybenzyl), 6,87 (t, 1H, J = 8 Hz, H5Trp), 6,91 (t, 1H, Jo= 8 Hz, H5indol), 7,00-7,04 (m, 2H, H6indol og H6Trp), 7,07 (s, 1H, H2indol), 7,09 (s, 1H, H2Trp), 7,17-7,35 (m, 4H, H4og H7indol, H4og H7Trp), 8,75 (brs, 3H, NH2TFA-salt), 10,78 (s, 1H, NH indol), 11,00 (s, 1H, NH indol Trp).
<13>C NMR (75 MHz, DMSO d<6>, 300°K):
δ (ppm) 22,9 (CH2-CH2-indol), 25,7 (CH2-CH2-indol), 29,9 (CH2βTrp), 41,5 (CH2-o,pdimetoksybenzyl), 46,5 (CH αTrp), 55,6 (OCH3), 55,9 (OCH3), 98,8 (C3o,p-dimetoksybenzyl), 105,0 (C5o,p-dimetoksybenzyl), 107,4 (C3Trp), 111,8 (C7indol og C7Trp), 113,4 (C3indol), 115,1 (C1o,p-dimetoksybenzyl), 118,0 (C4indol), 118,4 (C4Trp), 118,6 (C5Trp), 119,0 (C5indol), 121,3 (C6Trp), 121,6 (C6indol), 122,9 (C2indol), 125,4 (C2Trp), 127,1 (C9indol og C9Trp), 128,5 (C6o,p-dimetoksybenzyl), 136,5 (C8Trp), 136,6 (C8indol), 152,3 (Cq triazol), 155,6 (Cq triazol), 157,6 (C2o,p-dimetoksybenzyl), 160,8 (C4o,p-dimetoksybenzyl).
(R)-N-(1-(4-(4-metoksybenzyl)-5-fenetyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)pikolinamid (forbindelse 79):
<1>H NMR (300 MHz, DMSO d<6>, 300°K):
δ (ppm) 2,85 (m, 4H, CH2-CH2-fenyl), 3,51 (m, 2H, CH2βTrp), 3,59 (s, 3H, OCH3), 5,11 (d, 1H, J = 17 Hz, CH2-p-metoksybenzyl), 5,23 (d, 1H, J = 17 Hz, CH2- pmetoksybenzyl), 5,51 (m, 1H, CH αTrp), 6,59 (d, 2H, Jo= 8 Hz, H3og H5p-metoksybenzyl), 6,73 (d, 2H, Jo= 8 Hz, H2og H6p-metoksybenzyl), 6,87 (t, 1H, Jo= 8 Hz, H5Trp), 7,01 (t, 1H, Jo= 8 Hz, H6Trp), 7,06 (m, 2H, H2og H6fenyl), 7,10 (d, 1H, J = 2 Hz, H2Trp), 7,14 (d, 1H, Jo= 7 Hz, H4Trp), 7,24 (m, 3H, H3, H4og H5fenyl), 7,34 (d, 1H, Jo= 8 Hz, H7Trp), 7,55 (m, 1H, NH amid), 7,88 (m, 2H, H4og H5o-pyridyl), 8,56 (d, 1H, J α β = 4 Hz, H6o-pyridyl), 9,20 (d, 1H, Jo= 8 Hz, H3o-pyridyl), 10,80 (s, 1H, NH indol Trp).
<13>C NMR (75 MHz, DMSO d<6>, 300°K):
δ (ppm) 26,2 (CH2-CH2-fenyl), 28,6 (CH2βTrp), 32,1 (CH2-CH2-fenyl), 45,5 (CH αTrp), 46,2 (CH2-p-metoksybenzyl), 55,4 (OCH3), 109,6 (C3Trp), 111,8 (C7Trp), 114,3 (C3og C5p-metoksybenzyl), 118,5 (C4Trp), 118,8 (C5Trp), 121,4 (C6Trp), 122,5 (C3o-pyridyl), 124,5 (C2Trp), 127,2 (C2og C6fenyl), 127,4 (C9Trp og C1pmetoksybenzyl), 127,8 (C5o-pyridyl), 128,7 (C2og C6p-metoksybenzyl), 128,8 (C3, C4og C5fenyl), 136,4 (C8Trp), 138,1 (C4o-pyridyl), 140,3 (C1fenyl), 148,7 (C6opyridyl), 149,3 (C2o-pyridyl), 155,0 (Cq triazol), 155,3 (Cq triazol), 159,0 (C4pmetoksybenzyl), 164,1 (CO amid).
(R)-N-(1-(5-(2-(1H-indol-3-yl)etyl)-4-(4-metoksybenzyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)pikolinamid (forbindelse 80):
<1>H NMR (300 MHz, DMSO d<6>, 300°K):
δ (ppm) 2,95 (m, 4H, CH2-CH2-indol), 3,48 (m, 2H, CH2βTrp), 3,58 (s, 3H, OCH3), 5,16 (m, 2H, CH2-p-metoksybenzyl), 5,50 (m, 1H, CH αTrp), 6,57 (d, 2H, Jo= 8 Hz, H3og H5p-metoksybenzyl), 6,72 (d, 2H, Jo= 8 Hz, H2og H6p-metoksybenzyl), 6,87 (t, 2H, Jo= 8 Hz, H5Trp og H5indol), 6,96-7,07 (m, 5H, H2og H6indol, H2, H4og H6Trp), 7,27-7,34 (m, 3H, H4og H7indol, H7Trp), 7,55 (m, 1H, NH amid), 7,88 (m, 2H, H4og H5o-pyridyl), 8,56 (d, 1H, J α β = 4 Hz, H6o-pyridyl), 9,18 (d, 1H, Jo= 8 Hz, H3o-pyridyl), 10,77 (brs, 2H, NH indol Trp og NH indol).
<13>C NMR (75 MHz, DMSO d<6>, 300°K):
δ (ppm) 22,4 (CH2-CH2-indol), 25,7 (CH2-CH2-indol), 28,9 (CH2βTrp), 45,5 (CH αTrp), 46,2 (CH2-p-metoksybenzyl), 55,4 (OCH3), 109,7 (C3Trp), 111,8 (C7Trp og C7indol), 112,6 (C3indol), 114,3 (C3og C5p-metoksybenzyl), 118,4 (C4Trp og C4indol), 118,7 (C5indol), 118,8 (C5Trp), 121,4 (C6Trp og Ca indol), 122,4 (C3o-pyridyl og C2indol), 124,5 (C2Trp), 126,7 (C9indol), 127,1 (C9Trp), 127,2 (C5o-pyridyl), 127,5 (C1p-metoksybenzyl), 127,7 (C2og C6p-metoksybenzyl), 136,4 (C8Trp), 136,6 (C8indol), 138,1 (C4o-pyridyl), 148,7 (C6o-pyridyl), 149,3 (C2o-pyridyl), 155,3 (Cq triazol), 159,0 (C4p-metoksybenzyl), 164,0 (CO amid).
(R)-N-1-(5-(2-(1H-indol-3-yl)etyl)-4-(4-metoksybenzyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)piperazin-2-karboksamid (forbindelse 81):
<1>H NMR (300 MHz, DMSO d<6>, 300°K):
δ (ppm) 2,18 (m, 2H, NH piperazin), 2,96 (m, 6H, H2, H5og H6piperazin), 3,34 (d, 2H, J = 7 Hz, CH2βTrp), 3,57 (m, 4H, CH2-CH2-indol), 3,61 (s, 3H, OMe), 3,64 (m, 1H, H3piperazin), 4,82 (m, 2H, CH2-p-metoksybenzyl), 5,40 (m, 1H, CH αTrp), 6,45 (d, 2H, Jo= 8 Hz, H3og H5p-metoksybenzyl), 6,51 (d, 2H, Jo= 8 Hz, H2og H6p-metoksybenzyl), 6,65-7,47 (m, 10H, CHar, indol og indol Trp), 8,95 (m, 1H, NH amid), 10,88 (d, 1H, J = 2 Hz, NH indol), 10,91 (s, 1H, NH indol Trp).
<13>C NMR (75 MHz, DMSO d<6>, 300°K):
δ (ppm) 22,5 (CH2-CH2-indol), 25,6 (CH2-CH2-indol), 31,3 (CH2βTrp), 41,9 (CH2-pmetoksybenzyl), 47,7 (CH αTrp, C5og C6piperazin), 55,5 (OCH3og C2piperazin), 61,1 (C3piperazin), 109,3 (C3Trp), 111,7 (C7indol og C7Trp), 114,0 (C3indol), 114,3 (C3og C5p-metoksybenzyl), 118,6 (C4indol), 118,7 (C4Trp), 118,9 (C5indol og C5Trp), 121,4 (C6indol), 121,5 (C6Trp), 123,9 (C2indol og C2Trp), 127,0 (C9indol), 127,2 (C9Trp), 127,7 (C1p-metoksybenzyl), 128,1 (C2og C6p-metoksybenzyl), 136,3 (C8Trp), 136,5 (C8indol), 155,5 (Cq triazol), 162,2 (C4p-metoksybenzyl), 171,1 (CO amid).
(S)-N-((R)-1-(5-(2-(1H-indol-3-yl)etyl)-4-(4-metoksybenzyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)pyrrolidin-2-karboksamid (forbindelse 89):
<1>H NMR (300 MHz, DMSO d<6>, 300°K):
δ (ppm) 1,42 (m, 1H, H3Pro), 1,52 (m, 1H, H4Pro), 1,72 (m, 1H, H4Pro), 2,07 (m, 1H, H3Pro), 2,94 (m, 4H, CH2-CH2-indol), 3,05 (t, 2H, J = 6 Hz, H5Pro), 3,30 (m, 2H, CH2βTrp), 3,67 (s, 3H, OCH3), 3,96 (m, 1H, CH αPro), 5,02 (s, 2H, CH2-p-metoksybenzyl), 5,19 (m, 1H, CH αTrp), 6,73 (s, 4H, CHar p-metoksybenzyl), 6,84 (t, 1H, Jo= 8 Hz, H5indol), 6,90 (t, 1H, Jo= 8 Hz, H5Trp), 6,93-7,06 (m, 4H, H2og H6indol, H2og H6Trp), 7,17 (d, 1H, Jo= 8 Hz, H4Trp), 7,29 (d, 3H, Jo= 8 Hz, H4og H7indol, H7Trp), 8,39 og 9,10 (2 m, 2H, NH Pro TFA-salt), 9,25 (d, 1H, J = 8 Hz, NH amid), 10,76 (s, 1H, NH indol), 10,80 (d, 1H, J = 2 Hz, NH indol Trp).
<13>C NMR (75 MHz, DMSO d<6>, 300°K):
δ (ppm) 22,8 (CH2-CH2-indol), 23,5 (C4Pro), 25,8 (CH2-CH2-indol), 29,4 (CH2βTrp), 29,8 (C3Pro), 45,2 (CH αTrp), 45,5 (CH2-p-metoksybenzyl), 46,0 (C5Pro), 55,5 (OCH3), 59,3 (CH αPro), 109,6 (C3Trp), 111,8 (C7indol og C7Trp), 113,4 (C3indol), 114,6 (C3og C5p-metoksybenzyl), 118,4 (C4indol), 118,5 (C4Trp), 118,7 (C5indol og C5Trp), 121,4 (C6indol og C6Trp), 123,0 (C2Trp), 124,7 (C2indol), 127,2 (C9indol), 127,3 (C9Trp), 127,7 (C1p-metoksybenzyl), 127,8 (C2og C6p-metoksybenzyl), 126,5 (C8Trp), 136,6 (C8indol), 154,8 (Cq triazol), 154,9 (Cq triazol), 159,2 (C4p-metoksybenzyl), 168,2 (CO amid).
(R)-N-((R)-1-(5-(2-(1H-indol-3-yl)etyl)-4-(4-metoksybenzyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)pyrrolidin-2-karboksamid (forbindelse 90):
<1>H NMR (300 MHz, DMSO d<6>, 300°K):
δ (ppm) 1,23 (m, 1H, H3Pro), 1,52 (m, 1H, H4Pro), 1,74 (m, 1H, H4Pro), 2,08 (m, 1H, H3Pro), 2,81 (m, 2H, H5Pro), 2,90-3,14 (m, 4H, CH2-CH2-indol), 3,31 (dd, 1H, J = 14 Hz og 7 Hz, CH2βTrp), 3,41 (dd, 1H, J = 14 Hz og 8 Hz, CH2βTrp), 3,63 (s, 3H, OCH3), 4,05 (m, 1H, CH αPro), 4,86 (s, 2H, CH2-p-metoksybenzyl), 5,21 (m, 1H, CH αTrp), 6,63 (s, 4H, CHar p-metoksybenzyl), 6,88 (t, 2H, Jo= 7 Hz, H5indol og H5Trp), 7,02 (m, 4H, H2og H5indol, H2og H6Trp), 7,26-7,34 (m, 4H, H4og H7indol, H4og H7Trp), 8,51 og 9,18 (2 m, 2H, NH Pro, TFA-salt), 9,27 (d, 1H, J = 8 Hz, NH amid), 10,73 (s, 1H, NH indol), 10,80 (s, 1H, NH indol Trp).
<13>C NMR (75 MHz, DMSO d<6>, 300°K):
δ (ppm) 22,8 (CH2-CH2-indol), 23,8 (C4Pro), 25,9 (CH2-CH2-indol), 29,7 (CH2βTrp og C3Pro), 45,4 (CH2-p-metoksybenzyl), 45,8 (CH αTrp), 46,1 (C5Pro), 55,5 (OCH3), 59,2 (CH αPro), 109,7 (C3Trp), 111,8 (C7Trp), 111,9 (C7indol), 113,4 (C3indol), 114,4 (C3og C5p-metoksybenzyl), 118,3 (C4indol), 118,5 (C4Trp), 118,6 (C5indol), 118,9 (C5Trp), 121,4 (C6indol og C6Trp), 122,9 (C2indol og C2Trp), 127,2 (C9indol), 127,4 (C9Trp), 127,6 (C1, C2og C6p-metoksybenzyl), 136,5 (C8Trp), 136,6 (C8indol), 154,4 (Cq triazol), 155,0 (Cq triazol), 159,1 (C4p-metoksybenzyl), 168,3 (CO amid).
(R)-N-(1-(5-(2-(1H-indol-3-yl)etyl)-4-(4-brombenzyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid (forbindelse 92):
<1>H NMR (400 MHz, DMSO-d<6>):
δ (ppm) 1,28 (3H, s, CH3Aib), 1,30 (3H, s, CH3Aib), 2,90 (2H, m, CH2-CH2-indol), 3,00 (2H, m, CH2-CH2-indol), 3,37 (2H, m, CH2βTrp), 5,10 (2H, s, CH24-brombenzyl), 5,13 (1H, m, C αH Trp), 6,75 (2H, d, J = 8,1, H2, H64-brombenzyl), 6,88 (1H, t, J = 7,3, H5Trp), 6,93 (1H, t, J = 7,5, H5indol), 7,03 (1H, t, J = 7,0, H6Trp), 7,05 (1H, H6indol), 7,07 (1H, d, J = 1,7, H2indol), 7,09 (1H, d, J = 1,8, H2Trp), 7,12 (1H, d, J = 8,2, H4Trp), 7,28 (1H, d, J = 7,9, H4indol), 7,32 (2H, d, J = 8,2, H7Trp, H7indol), 7,41 (2H, d, J = 8,1, H3, H54-brombenzyl), 8,01 (2H, s, NH2Aib), 8,95 (1H, d, J = 7,9, NH Trp), 10,77 (1H, brs, NH indol), 10,80 (1H, brs, NH indol Trp).
<13>C NMR (400 MHz, DMSO-d<6>):
δ (ppm) 22,4 (CH2-CH2-indol), 23,1 (CH3Aib), 23,4 (CH3Aib), 25,4 (CH2CH2-indol), 28,7 (Cp Trp), 44,8 (CH24-brombenzyl), 45,2 (C α Trp,), 56,3 (Cq Aib), 109,4 (C3Trp), 111,3 (C7Trp, C7indol), 113,0 (C3indol), 117,8 (C4Trp), 118,0 (C4indol), 118,2 (C5indol), 118,3 (C5Trp), 120,8 (C44-brombenzyl), 120,9 (C6Trp, C6indol), 122,5 (C2indol), 124,4 (C2Trp), 126,7 (C9indol), 126,8 (C9Trp), 128,0 (C2, C64-brombenzyl), 131,6 (C3, C54-brombenzyl), 135,1 (C14-brombenzyl), 136,1 (C8Trp, C8indol), 154,2 (Cq triazol), 154,5 (Cq triazol), 171,4 (CO Aib).
(R)-N-(1-(5-(2-(1H-indol-3-yl)etyl)-4-(4-metoksybenzyl)-4H-1,2,4-triazol-3-yl)-2-fenyletyl)-2-amino-2-metylpropanamid (forbindelse 93):
<1>H NMR (300 MHz, DMSO-d<6>, 300°K):
δ (ppm) 1,18 (3H, s, CH3Aib), 1,27 (3H, s, CH3Aib), 2,91 (4H, m, CH2-CH2-indol), 3,19 (2H, m, CH2βPhe), 3,69 (3H, s, OCH3), 5,05 (2H, m, CH2-p-metoksybenzyl), 5,20 (1H, m, CH αPhe), 6,82 (2H, d, Jo= 8 Hz, H3og H5p-metoksybenzyl), 6,88 (2H, d, Jo= 8 Hz, H2og H6p-metoksybenzyl), 6,92 (1H, t, Jo= 8 Hz, H5indol), 7,02 (1H, t, Jo= 7 Hz, H6indol), 7,03 (1H, d, J = 2 Hz, H2indol), 7,11-7,20 (5H, m, CHar Phe), 7,29 (2H, d, Jo= 8 Hz, H4og H7indol), 7,99 (3H, brs, NH2Aib), 8,93 (1H, d, J = 8 Hz, NH amid), 10,77 (1H, s, NH indol).
<13>C NMR (75 MHz, DMSO-d<6>, 300°K):
δ (ppm) 22,8 (CH2-CH2-indol), 23,5 (CH3Aib), 23,9 (CH3Aib), 25,9 (CH2-CH2-indol), 38,7 (CH2βPhe), 45,7 (CH2-p-metoksybenzyl), 46,4 (CH αPhe), 55,6 (OCH3), 56,8 (Cq Aib), 111,8 (C7indol), 113,4 (C3indol), 114,7 (C3og C5p-metoksybenzyl), 118,5 (C4Trp), 118,6 (C5Trp), 121,4 (C6Trp), 123,0 (C2Trp), 127,0 (C4fenyl), 127,2 (C9indol), 127,9 (C1p-metoksybenzyl), 128,1 (C2og C8fenyl), 128,5 (C3og C5fenyl), 129,8 (C2og C6p-metoksybenzyl), 136,6 (C8indol), 137,7 (C1fenyl), 155,2 (Cq triazol), 154,4 (Cq triazol), 159,3 (C4p-metoksybenzyl), 171,7 (CO Aib).
(R)-N-(1-(4-(2-(1H-indol-3-yl)etyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid (forbindelse 95):
<1>H NMR (400 MHz, DMSO-d<6>):
δ (ppm) 1,29 (3H, s, CH3Aib), 1,35 (3H, s, CH3Aib), 2,85 (1H, m, 1H N-CH2-CH2-In), 2,89 (1H, m, 1H, -N-CH2-CH2-In), 3,28 (1H, dd, J = 14,2, J = 6,8, 1H CH2β Trp), 3,40 (1H, dd, J = 14,2, J = 8,4, 1H CH2β Trp), 4,10 (2H, m, -N-CH2-CH2-In), 5,25 (1H, m, CH α Trp), 6,85 (1H, d, J = 2,0, H2indol), 6,90-6,98 (2H, m, H5indol), 7,01 (1H, d, J = 2,0, H2indol), 7,02-7,12 (2H, m, H6indol), 7,30 (1H, d, J = 8,2, H7indol), 7,33 (1H, d, J = 8,3, H7indol), 7,40 (1H, d, J = 7,9, H4indol), 7,47 (1H, d, J = 7,8, H4indol), 8,04 (2H, brs, NH2Aib), 8,42 (1H, s, H triazol), 9,01 (1H, d, J = 8,0, NH Trp), 10,81 (1H, s, NH indol), 10,90 (1H, s, NH indol).
(R)-N-(1-(5-((1H-indol-3-yl)metyl)-4-metyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)-etyl)-2-amino-2-metylpropanamid (forbindelse 96):
<1>H NMR (400 MHz, DMSO-d<6>):
δ (ppm) 1,20 (3H, s, CH3Aib), 1,28 (3H, s, CH3Aib), 3,32 (3H, d, N-CH3), 3,30-3,45 (2H, m, CH2β Trp), 4,22 (2H, s, -CH2-In), 5,30 (1H, m, CH α Trp), 6,91 (1H, t, J = 7,5, H5indol), 6,94 (1H, d, J = 7,5, H5indol), 7,02 (1H, t, J = 7,9, H6indol), 7,05 (1H, t, J = 7,9 H6indol), 7,08 (1H, d, J = 1,9, H2indol), 7,12 (1H, d, J = 1,9, H2indol), 7,29 (1H, d, J = 8,1, H7indol), 7,33 (1H, d, J = 8,2, H7indol), 7,48 (1H, d, J = 7,9, H4indol), 7,57 (1H, d, J = 7,9 H4indol), 8,00 (2H, brs, NH2Aib), 8,85 (1H, d, J = 8,2, NH Trp), 10,82 (1H, s, NH indol), 10,98 (1H, s, NH indol).
(R)-N-(1-(5-(2-(1H-indol-3-yl)etyl)-4-metyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid (forbindelse 97):
<1>H NMR (400 MHz, DMSO-d<6>):
δ (ppm) 1,30 (3H, s, CH3Aib), 1,40 (3H, s, CH3Aib), 3,00-3,20 (4H, m, -CH2-CH2-In), 3,36 (3H, s, N-CH3), 3,45-3,50 (2H, m, CH2β Trp), 5,30 (1H, m, CH α Trp), 6,95-7,04 (2H, t, H5indol), 7,06-7,13 (2H, m, H6indol), 7,18 (2H, brs, H2indol), 7,34 (1H, d, J = 8,0, H7indol), 7,36 (1H, d, J = 8,0, H7indol), 7,48 (1H, d, J = 7,8, H4indol), 7,58 (1H, d, J = 7,8, H4indol), 8,10 (2H, brs, NH2Aib), 8,95 (1H, d, J = 8,1, NH Trp), 10,95 (1H, s, NH indol), 10,96 (1H, s, NH indol).
<13>C NMR (100 MHz, DMSO-d<6>):
δ (ppm) 22,9 - 25,9 (-CH2-CH2-indol), 24,1 (CH3Aib), 24,3 (CH3Aib), 28,8 (CH2β Trp), 30,7 (-NCH3), 46,2 (CH α Trp), 57,2 (Cq Aib), 110,2 (C3indol), 112,3 (2C7indol), 113,5 (C3indol), 118,9-119,2 (2C5, 2C4indol), 121,9 (2C6indol), 123,6 (C2indol), 125,3 (C2indol), 127,7 (C9indol), 128,0 (C9indol), 136,9 (C8indol), 137,1 (C8indol), 155,3 (Cq triazol), 155,8 (Cq triazol), 172,2 (CO Aib).
(R)-N-(1-(5-((1H-indol-3-yl)metyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid (forbindelse 98):
<1>H NMR (400 MHz, DMSO-d<6>):
δ (ppm) 1,31 (3H, s, CH3Aib), 1,42 (3H, s, CH3Aib), 3,19 (1H, dd, J = 14,5, J = 9,6, 1H CH2βTrp), 3,35 (1H, dd, J = 14,5, J = 5,3, 1H CH2βTrp), 4,15 (2H, s, CH2indol), 5,26 (1H, m, C αH Trp), 6,95 (1H, t, H5Trp), 6,96 (1H, t, H5indol), 7,05 (1H, t, H6Trp), 7,06 (1H, s, H2Trp), 7,07 (1H, t, H6indol), 7,21 (1H, s, H2indol), 7,32 (1H, d, H7Trp), 7,37 (1H, d, H7indol), 7,51 (1H, d, J = 7,8, H4indol), 7,58 (1H, d, J = 7,8, H4Trp), 8,00 (2H, s, NH2Aib), 8,64 (1H, d, J = 8,7, NH Trp), 10,77 (1H, s, NH indol Trp), 10,92 (1H, s, NH indol).
<13>C NMR (400 MHz, DMSO-d<6>):
δ (ppm) 22,9 (CH2indol), 23,2 (CH3Aib), 23,3 (CH3Aib), 29,4 (C β Trp), 48,3 (C α Trp), 56,3 (Cq Aib), 109,7 (C3indol), 110,3 (C3Trp), 111,2 (C7Trp), 111,3 (C7indol), 118,1 (C4Trp, C5Trp), 118,3 (C4indol), 118,4 (C5indol), 120,7 (C6Trp), 121,0 (C6indol), 123,4 (C2indol), 123,6 (C2Trp), 126,8 (C9indol), 127,1 (C9Trp), 136,0 (C8Trp), 136,2 (C8indol), 157,5 (Cq triazol), 161,7 (Cq triazol), 170,8 (CO Aib).
(R)-N-(1-(5-((1H-indol-3-yl)metyl)-4-(2,4-dimetoksybenzyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid (forbindelse 99):
<1>H NMR (400 MHz, DMSO-d<6>):
δ (ppm) 1,27 (3H, s, CH3Aib), 1,29 (3H, s, CH3Aib), 3,25 (1H, dd, J = 14,3, J = 5,6, 1H CH2βTrp), 3,38 (1H, dd, J = 14,3, J = 9,1, 1H CH2βTrp), 3,68 (3H, s, OCH3), 3,72 (3H, s, OCH3), 4,10 (1H, d, J = 16,5, 1H CH2indol), 4,16 (1H, d, J = 16,5, 1H CH2indol), 4,96 (1H, d, J = 16,8, 1H CH2o,p-dimetoksybenzyl), 5,12 (1H, d, J = 16,8, 1H CH2o,p-dimetoksybenzyl), 5,16 (1H, m, C αH Trp), 6,21 (1H, dd, J = 8,5, J = 2,1, H5o,p-dimetoksybenzyl), 6,27 (1H, d, J = 8,5, H6o,p-dimetoksybenzyl), 6,57 (1H, d, J = 2,1, H3o,p-dimetoksybenzyl), 6,83 (1H, t, H5Trp), 6,94 (1H, t, H5indol), 7,02 (1H, t, H6Trp), 7,05 (1H, t, H2indol), 7,06 (1H, t, H6indol), 7,07 (1H, s, H2Trp), 7,07 (1H, t, H4Trp), 7,31 (1H, d, H7Trp), 7,33 (1H, d, H7indol), 7,36 (1H, d, J = 7,8, H4indol), 8,00 (2H, br s, NH2Aib), 8,92 (1H, d, J = 8,2, NH Trp), 10,79 (1H, s, NH indol Trp), 10,89 (1H, s, NH indol).
<13>C NMR (400 MHz, DMSO-d<6>):
δ (ppm) 21,2 (CH2-indol), 23,1 (CH3Aib), 23,2 (CH3Aib), 28,6 (C β Trp), 41,4 (N-CH2o,p-dimetoksybenzyl), 45,1 (C α Trp), 55,2 (OCH3), 55,4 (OCH3), 56,2 (Cq Aib), 98,5 (C3o,p-dimetoksybenzyl), 104,6 (C5o,p-dimetoksybenzyl), 107,9 (C3indol), 109,5 (C3Trp), 111,2 (C7Trp), 111,3 (C7indol), 115,1 (C1o,p-dimetoksybenzyl), 117,8 (C4Trp), 118,1 (C5Trp), 118,3 (C4indol), 118,4 (C5indol), 120,8 (C6Trp), 121,1 (C6indol), 123,5 (C2indol), 124,3 (C2Trp), 126,6 (C9indol), 126,8 (C9Trp), 127,2 (C6o,pdimetoksybenzyl), 136,0 (C8Trp), 136,2 (C8indol), 157,5 (Cq triazol), 154,9 (Cq triazol), 157,2 (C2o,p-dimetoksybenzyl), 160,3 (C4o,p-dimetoksybenzyl), 171,2 (CO Aib).
(R)-N-(1-(5-((1H-indol-3-yl)metyl)-4-(4-metoksybenzyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid (forbindelse 101):
<1>H NMR (300 MHz, DMSO-d<6>, 300°K):
δ (ppm) 1,22 (3H, s, CH3Aib), 1,25 (3H, s, CH3Aib), 3,22 (1H, dd, J = 14 Hz og 6 Hz, CH2βTrp), 3,34 (1H, dd, J = 14 Hz og 9 Hz, CH2βTrp), 3,68 (3H, s, OCH3), 4,11 (2H, m, CH2-indol), 5,09 (3H, m, CH αTrp og CH2-p-metoksybenzyl), 6,70 (4H, s, CHar pmetoksybenzyl), 6,78 (2H, m, H5indol og H5Trp), 6,93 (2H, m, H6indol og H6Trp), 7,01-7,06 (3H, m, H2indol, H2og H4Trp), 7,31 (3H, m, H4og H7indol, H7Trp), 7,98 (3H, brs, NH2Aib), 8,92 (1H, d, J = 8 Hz, NH amid), 10,77 (1H, s, NH indol), 10,89 (1H, s, NH indol Trp).
<13>C NMR (75 MHz, DMSO-d<6>, 300°K):
δ (ppm) 21,7 (CH2-indol), 23,5 (CH3Aib), 23,7 (CH3Aib), 28,9 (CH2βTrp), 45,6 (CH αTrp), 45,8 (CH2-p-metoksybenzyl), 55,5 (OCH3), 56,7 (Cq Aib), 108,1 (C3indol), 109,7 (C3Trp), 111,7 (C7Trp), 111,9 (C7indol), 114,5 (C3og C5p-metoksybenzyl), 118,3 (C4Trp), 118,7 (C4indol), 118,8 (C5indol), 118,9 (C5Trp), 121,3 (C6indol), 121,6 (C6Trp), 124,2 (C2indol), 125,3 (C2Trp), 127,1 (C9indol), 127,2 (C9Trp), 127,6 (C1p-metoksybenzyl), 127,8 (C2og C6p-metoksybenzyl), 136,4 (C8Trp), 136,7 (C8indol), 154,2 (Cq triazol), 155,2 (Cq triazol), 159,2 (C4p-metoksybenzyl), 171,9 (CO Aib).
(R)-N-(1-(4-(2,4-dimetoksybenzyl)-5-benzyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid (forbindelse 102):
<1>H NMR (400 MHz, DMSO-d<6>):
δ (ppm) 1,30 (3H, s, CH3Aib), 1,33 (3H, s, CH3Aib), 3,26 (1H, dd, J = 14,2, J = 5,9, 1H CH2βTrp), 3,38 (1H, dd, J = 14,2, J = 8,7, 1H CH2βTrp), 3,69 (3H, s, OCH3), 3,72 (3H, s, OCH3), 4,02 (2H, s, CH2benzyl), 4,87 (1H, d, J = 16,7, 1H CH2o,p-dimetoksybenzyl), 5,08 (1H, d, J = 16,7, 1H CH2o,p-dimetoksybenzyl), 5,17 (1H, m, C αH Trp), 6,24 (1H, dd, J = 8,4, J = 1,7, H5o,p-dimetoksybenzyl), 6,28 (1H, d, J = 8,4, H6o,pdimetoksybenzyl), 6,56 (1H, d, J = 1,7, H3o,p-dimetoksybenzyl), 6,85 (1H, t, J = 7,5, H5Trp), 7,02 (1H, t, H6Trp), 7,07 (2H, m, H2, H6benzyl), 7,08 (1H, s, H2Trp), 7,09 (1H, d, H4Trp), 7,16-7,29 (3H, m, H3, H4, H5benzyl), 7,31 (1H, d, J = 8,2, H7Trp), 8,01 (2H, s, NH2Aib), 8,92 (1H, d, J = 7,9, NH Trp), 11,79 (1H, s, NH indol Trp).
<13>C NMR (400 MHz, DMSO-d<6>):
δ (ppm) 23,2 (2CH3Aib), 28,7 (C β Trp), 30,2 (CH2-benzyl), 41,3 (CH2-o,p-dimetoksybenzyl), 45,2 (C α Trp), 55,2 (OCH3), 55,4 (OCH3), 56,2 (Cq Aib), 98,5 (C3o,p-dimetoksybenzyl), 104,7 (C5o,p-dimetoksybenzyl), 109,5 (C3Trp), 111,3 (C7Trp), 115,1 (C1o,p-dimetoksybenzyl), 117,8 (C4Trp), 118,2 (C5Trp), 120,8 (C6Trp), 124,3 (C2Trp), 126,5 (C2, C6benzyl), 126,8 (C9Trp), 127,3 (C6op-dimetoksybenzyl), 128,3 (C3, C4, C5benzyl), 135,8 (C1benzyl), 136,0 (C8Trp), 153,4 (Cq triazol), 155,0 (Cq triazol), 157,2 (C2o,p-dimetoksybenzyl), 160,3 (C4o,p-dimetoksybenzyl), 171,3 (CO Aib).
(R)-N-(1-(5-((1H-indol-3-yl)metyl)-4-fenetyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid (forbindelse 104):
<1>H NMR (300 MHz, DMSO-d<6>, 300°K):
δ (ppm) 1,27 (3H, s, CH3Aib), 1,29 (3H, s, CH3Aib), 2,39-2,53 (4H, m, CH2CH2-fenyl), 3,74 (1H, m, CH2βTrp), 3,92 (1H, m, CH2βTrp), 3,99 (2H, s, CH2-indol), 5,21 (1H, m, CH αTrp), 6,74 (2H, m, H5indol og H5Trp), 6,90 (1H, t, Jo= 8 Hz, H6Trp), 6,92 (1H, t, Jo= 8 Hz, H6indol), 7,01-7,06 (4H, m, H2og H6fenyl, H2indol og H2Trp), 7,16 (3H, m, H3, H4og H5fenyl), 7,27 (1H, d, Jo= 8 Hz, H4Trp), 7,32 (1H, d, Jo= 8 Hz, H7Trp), 7,36 (1H, d, Jo= 8 Hz, H7indol), 7,50 (1H, d, Jo= 8 Hz, H4indol), 7,99 (3H, brs, NH2Aib), 9,02 (1H, s, J = 8 Hz, NH amid), 10,79 (1H, s, NH indol Trp), 10,94 (1H, s, NH indol).
<13>C NMR (75 MHz, DMSO-d<6>, 300°K):
δ (ppm) 21,4 (CH2-indol), 23,5 (CH3Aib), 23,8 (CH3Aib), 29,5 (CH2βTrp), 35,8 (CH2-CH2-fenyl), 44,5 (CH2-CH2-fenyl), 45,8 (CH αTrp), 56,7 (Cq Aib), 108,5 (C3indol), 109,9 (C3Trp), 114,0 (C7indol og C7Trp), 118,4 (C4Trp), 118,8 (C4indol og C5Trp), 119,0 (C5indol), 121,4 (C6Trp), 121,7 (C6indol), 124,0 (C2indol og C2Trp), 127,1 (C4fenyl), 127,7 (C9indol og C9Trp), 128,8 (C2og C8fenyl), 129,1 (C3og C5fenyl), 136,5 (C8Trp), 136,6 (C8indol), 137,5 (C1fenyl), 153,6 (Cq triazol), 155,0 (Cq triazol), 171,8 (CO Aib).
(R)-N-(1-(5-benzyl-4-(2,2-difenyletyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid (forbindelse 106):
<1>H NMR (300 MHz, DMSO-d<6>, 300°K):
δ (ppm) 1,29 (3H, s, CH3Aib), 1,34 (3H, s, CH3Aib), 3,37 (4H, m, CH2βTrp og CH2-benzyl), 3,74 (1H, t, J = 7 Hz, CH2-CH(Phe)2), 4,21 (1H, dd, J = 14 Hz og 8 Hz, CH2CH(Phe)2), 4,51 (1H, dd, J = 14 Hz og 8 Hz, CH2-CH(Phe)2), 5,08 (1H, m, CH αTrp), 6,72 (2H, m, H2og H6benzyl), 6,86-6,93 (5H, m, H3, H4og H5benzyl, H5og H6Trp), 7,03 (1H, s, H2Trp), 7,06-7,25 (CHar fenyl fra CH(Phe)2), 7,33 (1H, d, Jo= 8 Hz, H4Trp), 7,47 (1H, d, Jo= 8 Hz, H7indol), 8,10 (3H, brs, NH2Aib), 8,98 (1H, d, J = 8 Hz, NH amid), 10,94 (1H, s, NH indol Trp).
<13>C NMR (75 MHz, DMSO-d<6>, 300°K):
δ (ppm) 23,5 (CH3Aib), 23,7 (CH3Aib), 29,4 (CH2βTrp), 30,1 (CH2-benzyl), 46,0 (CH αTrp), 47,7 (CH2-CH(Phe)2), 51,3 (CH(Phe)2), 56,8 (Cq Aib), 109,8 (C3Trp), 112,0 (C7Trp), 118,5 (C4Trp), 119,0 (C5Trp), 121,5 (C6Trp), 124,8 (C2Trp), 127,1 (C4fenyl fra CH(Phe)2), 127,4 (C9Trp, C2og C6benzyl), 128,3 (C2og C6fenyl fra CH(Phe)2), 128,8-129,1 (C3og C5fenyl fra CH(Phe)2, C3, C4og C5benzyl), 136,2 (C1benzyl), 136,5 (C8Trp), 141,0 (C1fenyl fra CH(Phe)2), 153,5 (Cq triazol), 155,1 (Cq triazol), 172,0 (CO Aib).
(R)-N-(1-(5-(2-(1H-indol-3-yl)etyl)-4-(2,2-difenyletyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid (forbindelse 107):
<1>H NMR (300 MHz, DMSO-d<6>, 300°K):
δ (ppm) 1,34 (3H, s, CH3Aib), 1,38 (3H, s, CH3Aib), 2,06 (1H, m, CH2-CH2-indol), 2,30 (1H, m, CH2-CH2-indol), 2,78 (2H, m, CH2-CH2-indol), 3,35 (1H, dd, J = 14 Hz og 7 Hz, CH2βTrp), 3,46 (1H, dd, J = 14 Hz og 9 Hz, CH2βTrp), 3,58 (1H, t, J = 7 Hz, CH2CH(Phe)2), 4,14 (1H, dd, J = 14 Hz og 8 Hz, CH2-CH(Phe)2), 4,39 (1H, dd, J = 14 Hz og 7 Hz, CH2-CH(Phe)2), 5,12 (1H, m, CH αTrp), 6,50 (2H, m, H5indol og H5Trp), 6,76 (2H, m, H6indol og H6Trp), 6,87 (2H, m, H2indol og H2Trp), 6,89-6,96 (2H, m, H4fenyl), 7,03-7,15 (8H, m, H2, H3, H5og H6fenyl), 7,33 (3H, m, H4indol, H4og H7Trp), 7,47 (1H, d, J = 8 Hz, H7indol), 8,11 (3H, brs, NH2Aib), 9,04 (1H, d, J = 8 Hz, NH amid), 10,76 (1H, s, NH indol), 10,96 (1H, s, NH indol Trp).
<13>C NMR (75 MHz, DMSO-d<6>, 300°K):
δ (ppm) 22,4 (CH2-CH2-indol), 23,6 (CH3Aib), 23,8 (CH3Aib), 24,9 (CH2-CH2-indol), 29,6 (CH2βTrp), 46,1 (CH αTrp), 47,5 (CH2-CH(Phe)2), 51,5 (CH2-CH(Phe)2), 56,8 (Cq Aib), 109,8 (C3Trp), 111,8 (C7Trp), 112,1 (C7indol), 113,5 (C3indol), 118,4 (C4Trp), 118,7 (C4og C5indol), 119,0 (C5Trp), 121,4 (C6indol og C6Trp), 122,8 (C2indol), 125,0 (C2Trp), 127,2 (C9indol og C9Trp), 127,3 (C4fenyl), 128,2 (C2og C6fenyl), 128,7 (C3og C5fenyl), 136,6 (C8indol og C8Trp), 141,0 (C1fenyl), 154,6 (2 Cq triazol), 172,0 (CO Aib).
(R)-N-(1-(4,5-dibenzyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid (forbindelse 109):
<1>H NMR (300 MHz, DMSO-d<6>, 300°K):
δ (ppm) 1,23 (3H, s, CH3Aib), 1,26 (3H, s, CH3Aib), 3,23 (1H, dd, J = 14 Hz og 6 Hz, CH2βTrp), 3,35 (1H, dd, J = 14 Hz og 9 Hz, CH2βTrp), 3,99 (2H, s, C-CH2-fenyl), 5,10 (3H, m, N-CH2-fenyl og CH αTrp), 6,77 (3H, m, H5Trp, H2og H6fenyl fra N-CH2-fenyl), 6,99 (2H, m, H2og H6Trp), 7,01-7,07 (3H, m, H4Trp, H2og H6fra C-CH2-fenyl), 7,15-7,23 (6H, m, H3, H4og H5fenyl fra N-CH2-fenyl og fra C-CH2-fenyl), 7,25 (1H, d, J = 8 Hz, H7Trp), 8,01 (3H, brs, NH2Aib), 8,91 (1H, d, J = 8 Hz, NH amid), 10,78 (1H, s, NH indol Trp).
<13>C NMR (75 MHz, DMSO-d<6>, 300°K):
δ (ppm) 23,5 (CH3Aib), 23,7 (CH3Aib), 29,0 (CH2βTrp), 30,6 (C-CH2-fenyl), 45,7 (CH αTrp), 46,1 (N-CH2-fenyl), 56,7 (Cq Aib), 109,8 (C3Trp), 111,7 (C7Trp), 118,3 (C4Trp), 118,7 (C5Trp), 121,2 (C6Trp), 124,8 (C2Trp), 126,3 (C2og C6fenyl fra N-CH2-fenyl), 127,0 (C2og C6fenyl fra C-CH2-fenyl), 127,2 (C9Trp), 128,0 (C4fenyl fra N-CH2-fenyl), 128,8 (C3, C4og C5fenyl fra C-CH2-fenyl), 128,9 (C3og C5fenyl fra N-CH2-fenyl), 135,8 (C1fenyl fra N-CH2-fenyl), 136,2 (C1fenyl fra C-CH2-fenyl), 136,4 (C8Trp), 153,9 (Cq triazol), 155,3 (Cq triazol), 171,9 (CO Aib).
(R)-N-(1-(5-benzyl-4-heksyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid (forbindelse 110):
<1>H NMR (300 MHz, DMSO-d<6>, 300°K):
δ (ppm) 0,71 (3H, t,<3>J = 7 Hz, (CH2)5-CH3), 0,87 (4H, m, 2 CH2), 0,95 (2H, m, CH2-CH3), 1,00 (2H, m, N-CH2-CH2), 1,36 (6H, s, CH3Aib), 3,36 (1H, dd,<3>J = 14 Hz og 7 Hz, CH2βTrp), 3,41 (1H, dd,<3>J = 14 Hz og 7 Hz, CH2βTrp), 3,50 (1H, m, N-CH2), 3,65 (1H, m, N-CH2), 4,11 (2H, s, CH2-benzyl), 5,14 (1H, m, CH αTrp), 6,90 (1H, t, Jo= 7 Hz, H5Trp), 7,01 (1H, t, Jo= 7 Hz, H6Trp), 7,04 (1H, s, H2Trp), 7,09 (2H, m, H2og H6benzyl), 7,17-7,29 (4H, m, H4Trp, H3, H4og H5benzyl), 7,47 (1H, d, Jo= 8 Hz, H7Trp), 8,10 (3H, brs, NH2Aib), 9,05 (1H, d, J = 7 Hz, NH amid), 10,84 (1H, s, NH indol Trp).
<13>C NMR (75 MHz, DMSO-d<6>, 300°K):
δ (ppm) 14,1 ((CH2)5-CH3), 22,1 (CH2-CH3), 23,8 (CH3Aib), 23,5 (CH3Aib), 25,8 (CH3-CH2-CH2-CH2), 29,5 (CH2βTrp), 30,3 (N-CH2-CH2), 30,8 (CH2-benzyl og CH3-CH2-CH2), 43,3 (N-CH2-CH2), 46,1 (CH αTrp), 56,8 (Cq Aib), 109,6 (C3Trp), 111,9 (C7Trp), 118,2 (C4Trp), 118,8 (C5Trp), 121,4 (C6Trp), 124,7 (C2Trp), 127,2 (C2og C6benzyl), 127,3 (C9Trp), 128,8 (C3, C4og C5benzyl), 136,2 (C1benzyl), 136,5 (C8Trp), 153,1 (Cq triazol), 155,1 (Cq triazol), 171,9 (CO Aib).
(R)-N-(1-(4-(2-(1H-indol-3-yl)etyl)-5-benzyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid (forbindelse 111):
<1>H NMR (400 MHz, DMSO-d<6>, 300°K):
δ (ppm) 1,31 (3H, s, CH3Aib), 1,35 (3H, s, CH3Aib), 2,51 (2H, m, CH2-CH2-indol), 3,37 (2H, m, CH2βTrp), 3,76-3,90 (4H, m, CH2-benzyl og CH2-CH2-indol), 5,25 (1H, m, CH αTrp), 6,88 (2H, t, Jo= 7 Hz, H5indol og H5Trp), 6,95 (2H, t, Jo= 7 Hz, H6indol og H6Trp), 7,03 (4H, m, H2Trp, H2indol, H2og H6benzyl), 7,16 (2H, d, Jo= 8 Hz, H4indol og H4Trp), 7,20-7,30 (4H, 3, H7indol, H3, H4og H5benzyl), 7,47 (1H, d, Jo= 8 Hz, H7, Trp), 8,05 (3H, brs, NH2Aib), 9,05 (1H, d, J = 8 Hz, NH amid), 10,83 (1H, s, NH indol), 10,88 (1H, s, NH indol Trp).
<13>C NMR (100 MHz, DMSO-d<6>, 300°K):
δ (ppm) 23,5 (CH3Aib), 23,7 (CH3Aib), 29,6 (CH2βTrp), 30,3 (CH2-benzyl og CH2CH2-indol), 44,1 (CH2-CH2-indol), 46,1 (CH αTrp), 56,8 (Cq Aib), 109,8 (C3Trp), 109,9 (C3indol), 111,9 (C7indol og C7Trp), 118,3 (C4Trp), 118,4 (C4indol), 118,9 (C5indol og C5Trp), 121,3 (C6Trp), 121,5 (C6indol), 123,7 (C2indol), 124,7 (C2Trp), 127,0 (C9indol), 127,2 (C2og C6benzyl), 127,4 (C9Trp), 128,8 (C3og C5benzyl), 129,0 (C4benzyl), 136,3 (C1benzyl), 136,4 (C8indol og C8Trp), 153,1 (Cq triazol), 155,3 (Cq triazol), 171,8 (CO Aib).
(S)-N-(1-(4-(2,4-dimetoksybenzyl)-5-benzyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid (forbindelse 112):
<1>H NMR (300 MHz, DMSO-d<6>, 300°K):
δ (ppm) 1,26 (3H, s, CH3Aib), 1,29 (3H, s, CH3Aib), 3,24 (1H, dd, J = 14 Hz og 6 Hz, CH2βTrp), 3,33 (1H, dd, J = 14 Hz og 9 Hz, CH2βTrp), 3,64 (3H, s, OCH3), 3,68 (3H, s, OCH3), 3,99 (2H, s, CH2fenyl), 4,84 (1H, d, J = 17 Hz, CH2-o,p-dimetoksybenzyl), 5,05 (1H, d, J = 17 Hz, CH2-o,p-dimetoksybenzyl), 5,13 (1H, m, CH αTrp), 6,24 (2H, m, H5og H6o,p-dimetoksybenzyl), 6,52 (1H, d, Jm= 2 Hz, H3o,p-dimetoksybenzyl), 6,83 (1H, t, Jo= 7 Hz, H5Trp), 7,01 (1H, t, Jo= 8 Hz, H6Trp), 7,04 (1H, s, H2Trp), 7,05-7,23 (6H, m, H4Trp og CHar fenyl), 7,27 (1H, d, Jo= 8 Hz, H7Trp), 8,01 (3H, brs, NH2Aib), 8,90 (1H, d, J = 8 Hz, NH amid), 10,77 (1H, d, J = 2 Hz, NH indol Trp).
<13>C NMR (75 MHz, DMSO-d<6>, 300°K):
δ (ppm) 23,6 (CH3Aib), 29,1 (CH2βTrp), 30,6 (CH2-fenyl), 41,9 (CH2-o,p-dimetoksybenzyl), 45,7 (CH αTrp), 55,7 (OCH3), 55,9 (OCH3), 56,7 (Cq Aib), 99,9 (C3o,pdimetoksybenzyl), 105,1 (C5o,p-dimetoksybenzyl), 109,9 (C3Trp), 111,7 (C7Trp), 115,5 (C1o,p-dimetoksybenzyl), 118,3 (C4Trp), 118,6 (C5Trp), 121,3 (C6Trp), 124,2 (C2Trp), 127,0 (C6o,p-dimetoksybenzyl), 127,3 (C9Trp), 127,8 (C4fenyl), 128,8 (C2, C3, C5og C6fenyl), 136,2 (C8Trp), 136,4 (C1fenyl), 153,9 (Cq triazol), 155,5 (Cq triazol), 157,6 (C2o,p-dimetoksybenzyl), 160,8 (C4o,p-dimetoksybenzyl), 171,8 (CO amid).
(R)-N-(1-(4-(3,5-dimetoksybenzyl)-5-fenetyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid (forbindelse 113):
<1>H NMR (300 MHz, DMSO-d<6>, 300°K):
δ (ppm) 1,24 (3H, s, CH3Aib), 1,27 (3H, s, CH3Aib), 2,83 (4H, s, CH2-CH2-fenyl), 3,32 (2H, m, CH2βTrp), 3,61 (6H, s, OCH3), 5,02 (2H, m, CH2-m-dimetoksybenzyl), 5,18 (1H, m, CH αTrp), 6,07 (2H, d, Jm= 2 Hz, H2og H6m-dimetoksybenzyl), 6,42 (1H, brs, H4m-dimetoksybenzyl), 6,83 (1H, t, Jo= 7 Hz, H5Trp), 6,99 (1H, t, Jo= 8 Hz, H6Trp), 7,08 (1H, d, J = 2 Hz, H2Trp), 7,13 (3H, t, Jo= 8 Hz, H3, H4og H5fenyl), 7,20 (3H, d, Jo= 7 Hz, H2og H6fenyl, H4Trp), 7,28 (1H, d, Jo= 8 Hz, H7Trp), 7,99 (3H, brs, NH2Aib), 8,92 (1H, d, J = 8 Hz, NH amid), 10,77 (1H, s, NH indol).
<13>C NMR (75 MHz, DMSO-d<6>, 300°K):
δ (ppm) 23,5 (CH3Aib), 23,8 (CH3Aib), 26,5 (CH2-CH2-fenyl), 29,2 (CH2βTrp), 32,7 (CH2-CH2-fenyl), 45,6 (CH αTrp), 45,8 (CH2- m-dimetoksybenzyl), 55,6 (OCH3), 56,8 (Cq Aib), 99,6 (C4m-dimetoksybenzyl), 104,6 (C2og C6m-dimetoksybenzyl), 109,9 (C3Trp), 111,8 (C7Trp), 118,2 (C4Trp), 118,7 (C5Trp), 121,3 (C6Trp), 124,8 (C2Trp), 126,5 (C4fenyl), 127,3 (C9Trp), 128,7 (C2, C3, C5og C6fenyl), 136,4 (C8Trp), 138,6 (C4m-dimetoksybenzyl), 140,9 (C1fenyl), 154,6 (Cq triazol), 154,8 (Cq triazol), 161,4 (C3og C5m-dimetoksybenzyl), 171,8 (CO amid).
(R)-N-(1-(4-(4-brombenzyl)-5-benzyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid (forbindelse 114):
<1>H NMR (300 MHz, DMSO-d<6>, 300°K):
δ (ppm) 1,23 (3H, s, CH3Aib), 1,25 (3H, s, CH3Aib), 3,26 (1H, dd,<3>J = 14 Hz og 6 Hz, CH2Trp), 3,34 (1H, dd,<3>J = 14 Hz og 9 Hz, CH2βTrp), 4,01 (2H, m, CH2-benzyl), 5,01 (1H, m, CH αTrp), 5,08 (2H, s, CH2-p-brombenzyl), 6,59 (2H, d, Jo= 8 Hz, H2og H6pbrombenzyl), 6,81 (1H, t, Jo= 7 Hz, H5Trp), 6,94 (1H, s, H2Trp), 6,98 (1H, t, Jo= 7 Hz, H6Trp), 7,06 (2H, m, H2og H6benzyl), 7,12 (1H, d, Jo= 7 Hz, H4Trp), 7,16-7,20 (3H, m, H3, H4og H5benzyl), 7,26 (1H, d, Jo= 8 Hz, H7Trp), 7,29 (2H, d, Jo= 8 Hz, H3og H5benzyl), 8,00 (3H, brs, NH2Aib), 8,92 (1H, d, J = 8 Hz, NH amid), 10,78 (1H, s, NH indol Trp).
<13>C NMR (75 MHz, DMSO-d<6>, 300°K):
δ (ppm) 23,5 (CH3Aib), 23,8 (CH3Aib), 29,0 (CH2βTrp), 30,5 (CH2-benzyl), 45,6 (CH2-p-brombenzyl), 45,7 (CH αTrp), 56,7 (Cq Aib), 109,7 (C3Trp), 111,8 (C7Trp), 118,2 (C4tryptofan), 118,7 (C5Trp), 121,2 (C4p-brombenzyl), 121,3 (C6Trp), 124,9 (C2typtofan), 127,0 (C2og C6benzyl), 127,2 (C9Trp), 128,4 (C2og C6p-brombenzyl), 128,9 (C3, C4og C5benzyl), 131,9 (C3og C5p-brombenzyl), 135,2 (C1p-brombenzyl), 136,2 (C8Trp), 136,4 (C1benzyl), 153,9 (Cq triazol), 155,3 (Cq triazol), 171,9 (CO Aib).
(R)-N-(1-(4-(2-metoksybenzyl)-5-benzyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid (forbindelse 115):
<1>H NMR (300 MHz, DMSO-d<6>, 300°K):
δ (ppm) 1,24 (3H, s, CH3Aib), 1,27 (3H, s, CH3Aib), 3,20 (1H, dd, J = 14 Hz og 5 Hz, CH2βTrp), 3,33 (1H, dd, J = 14 Hz og 9 Hz, CH2βTrp), 3,68 (3H, s, OCH3), 4,00 (2H, s, CH2-fenyl), 4,95 (1H, d, J = 1,7 Hz, CH2-o- metoksybenzyl), 5,07 (1H, m, CH αTrp), 5,18 (1H, d, J = 17 Hz, CH2-o- metoksybenzyl), 6,27 (1H, d, Jo= 8 Hz, H3o-metoksybenzyl), 6,67 (1H, t, Jo= 7 Hz, H5Trp), 6,77 (1H, t, Jo= 6 Hz, H6Trp), 6,92-7,05 (6H, m, H2Trp, H2og H6fenyl, H4, H5og H6o- metoksybenzyl), 7,14-7,26 (5H, m, H4og H7Trp, H3, H4og H5fenyl), 8,03 (3H, brs, NH2Aib), 8,91 (1H, d, J = 8 Hz, NH amid), 10,78 (1H, s, NH indol Trp).
<13>C NMR (75 MHz, DMSO-d<6>, 300°K):
δ (ppm) 23,5 (CH3Aib), 23,6 (CH3Aib), 29,1 (CH2βTrp), 30,5 (CH2-fenyl), 42,1 (CH2- o-metoksybenzyl), 45,7 (CH αTrp), 55,9 (OCH3), 56,7 (Cq Aib), 109,8 (C3Trp), 111,3 (C3o-metioksybenzyl), 111,7 (C7Trp), 118,2 (C4Trp), 118,7 (C5Trp), 120,9 (C5o-metoksybenzyl), 121,2 (C6Trp), 123,3 (C1o-metoksybenzyl), 124,8 (C2Trp), 126,6 (C2og C6fenyl), 127,1 (C4o-metoksybenzyl), 127,2 (C9Trp), 128,8 (C3, C4og C5fenyl), 129,5 (C6o-metoksybenzyl), 136,0 (C1fenyl), 136,4 (C8Trp), 154,0 (Cq triazol), 155,6 (Cq triazol), 156,5 (C2o-metoksybenzyl), 171,8 (CO Aib).
(S)-N-(1-(4-(2,4-dimetoksybenzyl)-5-fenetyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid (forbindelse 116):
<1>H NMR (300 MHz, DMSO-d<6>, 300°K):
δ (ppm) 1,28 (3H, s, CH3Aib), 1,32 (3H, s, CH3Aib), 2,81 (4H, m, CH2-CH2-fenyl), 3,30 (2H, t, CH2βTrp), 3,61 (3H, s, OCH3), 3,69 (3H, s, OCH3), 4,87 (1H, d, J = 17 Hz, CH2-o,p-dimetoksybenzyl), 5,03 (1H, d, J = 17 Hz, CH2-o,p-dimetoksybenzyl), 5,20 (1H, m, CH αTrp), 6,29 (1H, dd, Jo= 8 Hz og Jm = 2 Hz, H5o,p-dimetoksybenzyl), 6,43 (1H, d, Jo= 8 Hz, H6o,p-dimetoksybenzyl), 6,55 (1H, d, Jm= 2 Hz, H3o,p-dimetoksybenzyl), 6,83 (1H, t, Jo= 8 Hz, H5Trp), 6,99 (1H, t, Jo= 8 Hz, H6Trp), 7,06 (1H, d, J = 2 Hz, H2Trp), 7,09-7,25 (6H, m, H4Trp og CHar fenyl), 7,28 (1H, d, Jo= 8 Hz, H7Trp), 8,04 (3H, brs, NH2Aib), 8,92 (1H, d, J = 8 Hz, NH amid), 10,79 (1H, s, NH indol Trp).
<13>C NMR (75 MHz, DMSO-d<6>, 300°K):
δ (ppm) 23,6 (CH3Aib), 23,7 (CH3Aib), 26,5 (CH2-CH2-fenyl), 29,1 (CH2βTrp), 32,7 (CH2-CH2-fenyl), 41,8 (CH2-o,p-dimetoksybenzyl), 45,7 (CH αTrp), 55,7 (OCH3), 55,9 (OCH3), 56,8 (Cq Aib), 99,1 (C3o,p-dimetoksybenzyl), 105,2 (C5o,p-dimetoksybenzyl), 109,9 (C3Trp), 111,8 (C7Trp), 115,6 (C1o,p-dimetoksybenzyl), 118,3 (C4Trp), 118,7 (C5Trp), 121,3 (C6Trp), 124,4 (C2Trp), 126,6 (C4fenyl), 127,3 (C9Trp), 128,2 (C6o,p-dimetoksybenzyl), 128,7 (C2, C3, C5og C6fenyl), 136,4 (C8Trp), 140,9 (C1fenyl), 154,6 (Cq triazol), 155,0 (Cq triazol), 157,8 (C2o,p-dimetoksybenzyl), 160,9 (C4o,p-dimetoksybenzyl), 171,8 (CO Aib).
(R)-N-(1-(4,5-difenetyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid (forbindelse 117):
<1>H NMR (300 MHz, DMSO-d<6>, 300°K):
δ (ppm) 1,32 (3H, s, CH3Aib), 1,37 (3H, s, CH3Aib), 2,59 (4H, m, C-CH2-CH2-fenyl), 2,83 (2H, t, J = 8 Hz, N-CH2-CH2-fenyl), 3,38 (2H, m, N-CH2-CH2-fenyl), 3,84 (1H, m, CH2βTrp), 3,94 (1H, m, CH2βTrp), 5,23 (1H, m, CH αTrp), 6,84 (2H, m, H4fenyl fra C-CH2-CH2-fenyl og H4fenyl fra N-CH2-CH2-fenyl), 6,93 (1H, t, Jo= 8 Hz, H5Trp), 7,00 (1H, t, Jo= 8 Hz, H6Trp), 7,07 (1H, d, J = 2 Hz, H2Trp), 7,11-7,27 (9H, m, H2, H3, H5og H6fenyl fra C-CH2-CH2-fenyl, H2, H3, H5og H6fenyl fra N-CH2-CH2-fenyl og H4Trp), 7,50 (1H, d, Jo= 8 Hz, H7Trp), 8,07 (3H, brs, NH2Aib), 9,04 (1H, d, J = 8 Hz, NH amid), 10,85 (1H, s, NH indol Trp).
<13>C NMR (75 MHz, DMSO-d<6>, 300°K):
δ (ppm) 23,5 (CH3Aib), 23,8 (CH3Aib), 25,9 (C-CH2-CH2-fenyl), 29,5 (CH2βTrp), 32,4 (C-CH2-CH2-fenyl), 35,8 (N-CH2-CH2-fenyl), 44,2 (N-CH2-CH2-fenyl), 45,9 (CH αTrp), 56,8 (Cq Aib), 109,7 (C3Trp), 111,9 (C7Trp), 118,4 (C4Trp), 118,9 (C5Trp), 121,4 (C6Trp), 124,8 (C2Trp), 126,6 (C4fenyl fra C-CH2-CH2-fenyl), 127,2 (C4fenyl fra N-CH2-CH2-fenyl), 127,4 (C9Trp), 128,7 (C2og C6fenyl fra C-CH2-CH2-fenyl, C2og C6fenyl fra N-CH2-CH2-fenyl), 128,8 (C3og C5fenyl fra C-CH2-CH2-fenyl, C3og C5fenyl fra N-CH2-CH2-fenyl), 136,5 (C1fenyl fra N-CH2-CH2-fenyl), 137,5 (C1fenyl fra C-CH2-CH2-fenyl), 140,8 (C8Trp), 154,1 (Cq triazol), 154,7 (Cq triazol), 171,9 (CO Aib).
(R)-N-(1-(4-(3,4-diklorbenzyl)-5-benzyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid (forbindelse 118):
<1>H NMR (300 MHz, DMSO-d<6>, 300°K):
δ (ppm) 1,24 (3H, s, CH3Aib), 1,25 (3H, s, CH3Aib), 3,33 (2H, m, CH2βTrp), 4,04 (2H, s, CH2-benzyl), 5,05 (1H, m, CH αTrp), 5,12 (2H, s, CH2-m,p-diklorbenzyl), 6,49 (1H, dd, Jo= 8 Hz og Jm= 2 Hz, H6m,p-diklorbenzyl), 6,80 (1H, t, Jo= 8 Hz, H5Trp), 6,87 (1H, d, Jm= 2 Hz, H2Trp), 6,98 (1H, t, Jo= 7 Hz, H6Trp), 7,02-7,10 (3H, m, H2og H6benzyl, H5m,p-diklorbenzyl), 7,18 (3H, m, H3, H4og H5benzyl), 7,26 (2H, m, H4og H7Trp), 8,04 (3H, brs, NH2Aib), 8,94 (1H, d, J = 9 Hz, NH amid), 10,81 (1H, s, NH indol Trp).
<13>C NMR (75 MHz, DMSO-d<6>, 300°K):
δ (ppm) 23,4 (CH3Aib), 23,8 (CH3Aib), 29,0 (CH2βTrp), 30,4 (CH2-benzyl), 45,1 (CH2- m,p-diklorbenzyl), 45,6 (CH αTrp), 56,7 (Cq Aib), 109,6 (C3Trp), 111,8 (C7Trp), 118,1 (C4Trp), 118,6 (C5Trp), 121,3 (C6Trp), 124,9 (C2Trp), 126,4 (C6m,pdiklorbenzyl), 127,0 (C2m,p-diklorbenzyl), 127,2 (C9Trp), 128,4 (C2og C6benzyl), 130,7 (C4og C5m,p-diklorbenzyl), 131,8 (C3m,p-diklorbenzyl), 136,0 (C1benzyl), 136,4 (C8Trp), 136,7 (C1m,p-diklorbenzyl), 154,1 (Cq triazol), 155,2 (Cq triazol), 172,0 (CO Aib).
(R)-N-(1-(4-(4-metoksybenzyl)-5-benzyl-4H-1,2,4-triazol-3-yl)-2-fenyletyl)-2-amino-2-metylpropanamid (forbindelse 120):
<1>H NMR (300 MHz, DMSO-d<6>, 300°K):
δ (ppm) 1,18 (3H, s, CH3Aib), 1,26 (3H, s, CH3Aib), 3,09 (1H, dd, J = 14 Hz og 6 Hz, CH2βPhe), 3,18 (1H, dd, J = 14 Hz og 9 Hz, CH2βPhe), 3,99 (2H, d, J = 4 Hz, CH2-fenyl), 4,95 (1H, d, J = 16 Hz, CH2-p-metoksybenzyl), 5,06 (1H, d, J = 16 Hz, CH2-pmetoksybenzyl), 5,13 (1H, m, CH αPhe), 6,78 (4H, s, CHar p-metoksybenzyl), 7,02-7,08 (4H, m, H2og H6fenyl, H2og H6Phe), 7,12-7,25 (6H, m, H3, H4og H5fenyl, H3, H4og H5Phe), 7,99 (3H, brs, NH2Aib), 8,92 (1H, d, J = 8 Hz, NH amid).
<13>C NMR (75 MHz, DMSO-d<6>, 300°K):
δ (ppm) 23,4 (CH3Aib), 23,8 (CH3Aib), 30,7 (CH2-fenyl), 38,7 (CH2βPhe), 45,9 (CH2- p-metoksybenzyl), 46,4 (CH αPhe), 55,6 (OCH3), 56,7 (Cq Aib), 114,6 (C3og C5p-metoksybenzyl), 126,9 og 127,1 (C4fenyl og C4Phe), 127,7 (C1p-metoksybenzyl), 128,2 (C2og C6Phe), 128,5 (C3og C5Phe), 128,9 (C2, C3, C5og C6fenyl), 129,7 (C2og C6p-metoksybenzyl), 136,3 (C1fenyl), 137,6 (C1Phe), 154,0 (Cq triazol), 154,9 (Cq triazol), 159,2 (C4p-metoksybenzyl), 171,7 (CO amid).
(R)-N-(1-(4-(4-fluorbenzyl)-5-fenetyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid (forbindelse 121):
<1>H NMR (300 MHz, DMSO-d<6>, 300°K):
δ (ppm) 1,27 (3H, s, CH3Aib), 1,28 (3H, s, CH3Aib), 2,82 (4H, m, CH2-CH2-fenyl), 3,34 (2H, m, CH2βTrp), 5,06 (2H, s, CH2-p-fluorbenzyl), 5,16 (1H, m, CH αTrp), 6,85 (3H, m, H5Trp, H3og H5p-fluorbenzyl), 6,98-7,04 (4H, m, H2og H6Trp, H2og H6fenyl), 7,09-7,11 (2H, m, H2og H6p-fluorbenzyl), 7,15 (1H, d, Jo= 6 Hz, H4Trp), 7,19 (3H, t, Jo= 8 Hz, H3, H4og H5fenyl), 7,29 (1H, d, Jo= 8 Hz, H7Trp), 8,01 (3H, brs, NH2Aib), 8,94 (1H, d, J = 8 Hz, NH amid), 10,78 (1H, s, NH indol Trp).
<13>C NMR (75 MHz, DMSO-d<6>, 300°K):
δ (ppm) 23,5 (CH3Aib), 23,8 (CH3Aib), 26,5 (CH2-CH2-fenyl), 29,2 (CH2βTrp), 32,7 (CH2-CH2-fenyl), 45,4 (CH2-p-fluorbenzyl), 45,7 (CH αTrp), 56,8 (Cq Aib), 109,8 (C3Trp), 111,8 (C7Trp), 115,9 og 116,2 (C3og C5p-fluorbenzyl), 118,3 (C4Trp), 118,7 (C5Trp), 121,3 (C6Trp), 124,8 (C2Trp), 126,5 (C4fenyl), 127,3 (C9Trp), 128,5 (C2og C6p-fluorbenzyl), 128,7 (C2, C3, C5og C6fenyl), 132,2 (C1p-fluorbenzyl), 136,4 (C8Trp), 140,9 (C1fenyl), 154,5 (Cq triazol), 154,7 (Cq triazol), 160,3 (C4p-fluorbenzyl), 171,9 (CO amid).
NMR<19>F (282 MHz, DMSO-d<6>, 300°K):
δ (ppm) -114,9 (1F, m,p-fluorbenzyl).
(R)-N-(1-(4-(3,4-diklorbenzyl)-5-fenetyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl}-2-amino-2-metylpropanamid (forbindelse 122):
<1>H NMR (300 MHz, DMSO-d<6>, 300°K):
δ (ppm) 1,25 (3H, s, CH3Aib), 1,26 (3H, s, CH3Aib), 2,84 (4H, m, CH2-CH2-fenyl), 3,34 (2H, d, J = 7 Hz, CH2βTrp), 5,11 (3H, m, CH αTrp og CH2-m,p-diklorbenzyl), 6,63 (1H, dd, Jo= 8 Hz og Jm= 2 Hz, H6m,p-diklorbenzyl), 6,83 (1H, t, Jo= 8 Hz, H5Trp), 6,99 (1H, t, Jo= 8 Hz, H6Trp), 7,05 (1H, d, J = 2 Hz, H2Trp), 7,12 (5H, m, CHar fenyl), 7,17 (1H, d, Jo= 8 Hz, H4Trp), 7,21 (1H, s, H2m,p-diklorbenzyl), 7,27 (1H, d, Jo= 8 Hz, H5m,p-diklorbenzyl), 7,39 (1H, d, Jo= 8 Hz, H7Trp), 8,02 (3H, brs, NH2Aib), 8,94 (1H, d, J = 8 Hz, NH amid), 10,78 (1H, s, NH indol Trp).
<13>C NMR (75 MHz, DMSO-d<6>, 300°K):
δ (ppm) 23,5 (CH3Aib), 23,8 (CH3Aib), 26,4 (CH2-CH2-fenyl), 29,1 (CH2βTrp), 32,6 (CH2-CH2-fenyl), 44,7 (CH2-m,p-diklorbenzyl), 45,6 (CH αTrp), 56,7 (Cq Aib), 109,7 (C3Trp), 111,8 (C7Trp), 118,1 (C4Trp), 118,7 (C5Trp), 121,3 (C6Trp), 124,9 (C2Trp), 126,5 (C4fenyl og C6m,p-diklorbenzyl), 127,2 (C9Trp), 128,7 (C2, C3, C5og C6fenyl, C2m,p-diklorbenzyl), 130,9 (C4m,p-diklorbenzyl), 131,4 (C5m,p-diklorbenzyl), 132,0 (C3m,p-diklorbenzyl), 136,4 (C8Trp), 137,2 (C1m,p-diklorbenzyl), 140,8 (C1fenyl), 154,5 (Cq triazol), 154,7 (Cq triazol), 171,9 (CO amid).
(R)-N-(1-(4-(4-metylbenzyl)-5-benzyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid (forbindelse 124):
<1>H NMR (300 MHz, DMSO-d<6>, 300°K):
δ (ppm) 1,22 (3H, s, CH3Aib), 1,27 (3H, s, CH3Aib), 2,22 (3H, s, CH3p-metylbenzyl), 3,22 (1H, dd, J = 14 Hz og 6 Hz, CH2βTrp), 3,33 (1H, dd, J = 14 Hz og 9 Hz, CH2βTrp), 3,99 (2H, s, CH2-benzyl), 5,04 (2H, s, CH2-p-metylbenzyl), 5,09 (1H, m, CH αTrp), 6,64 (2H, d, Jo= 8 Hz, H3og H5p-metylbenzyl), 6,78 (1H, t, Jo= 7 Hz, H5Trp), 6,98 (4H, t, Jo= 7 Hz, H6Trp, H3, H4og H5benzyl), 7,01 (1H, d, J = 2 Hz, H2Trp), 7,07 (2H, d, Jo= 7 Hz, H2og H6p-metylbenzyl), 7,20 (3H, m, H4Trp, H2og H6benzyl), 7,26 (1H, d, Jo= 8 Hz, H7Trp), 7,98 (3H, brs, NH2Aib), 8,89 (1H, d, J = 8 Hz, NH amid), 10,74 (1H, s, NH indol Trp).
<13>C NMR (75 MHz, DMSO-d<6>, 300°K):
δ (ppm) 21,0 (CH3p-metylbenzyl), 23,5 (CH3Aib), 23,7 (CH3Aib), 29,1 (CH2βTrp), 30,6 (CH2-benzyl), 45,7 (CH αTrp), 46,0 (CH2-p-metylbenzyl), 56,7 (Cq Aib), 109,8 (C3Trp), 111,7 (C7Trp), 118,3 (C4Trp), 118,6 (C5Trp), 121,2 (C6Trp), 124,8 (C2Trp), 126,3 (C3og C5p-metylbenzyl), 127,0 (C4benzyl), 127,2 (C9Trp), 128,9 (C2, C3, C5og C6benzyl), 129,7 (C2og C6p-metylbenzyl), 132,9 (C1p-metylbenzyl), 136,3 (C4pmetylbenzyl), 136,4 (C8Trp), 137,4 (C1benzyl), 153,9 (Cq triazol), 155,3 (Cq triazol), 171,8 (CO amid).
(S)-N-(1-(4-(4-metoksybenzyl)-5-(3-fenylpropyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid (forbindelse 125):
<1>H NMR (300 MHz, DMSO-d<6>, 300°K):
δ (ppm) 1,27 (3H, s, CH3Aib), 1,31 (3H, s, CH3Aib), 1,74 (2H, m, (CH2-CH2-CH2-fenyl), 2,52 (4H, t, J = 7 Hz, CH2-CH2-CH2-fenyl), 3,35 (2H, d, J = 7 Hz, CH2βTrp), 3,68 (3H, s, OCH3), 4,98 (2H, s, CH2-p-metoksybenzyl), 5,20 (1H, m, CH αTrp), 6,75 (4H, s, CHar p-metoksybenzyl), 6,83 (1H, t, Jo= 8 Hz, H5Trp), 6,99 (1H, t, Jo= 7 Hz, H6Trp), 7,06 (3H, m, H2og H6fenyl, H2Trp), 7,14 (1H, d, J = 7 Hz, H4Trp), 7,19 (3H, t, Jo= 8 Hz, H3, H4og H5fenyl), 7,29 (1H, d, Jo= 8 Hz, H7Trp), 8,01 (3H, brs, NH2Aib), 8,94 (1H, d, J = 8 Hz, NH amid), 10,79 (1H, d, J = 2 Hz, NH indol Trp).
<13>C NMR (75 MHz, DMSO-d<6>, 300°K):
δ (ppm) 23,6 (CH3Aib), 23,8 (CH3Aib), 24,1 (CH2-CH2-CH2-fenyl), 28,5 (CH2-CH2CH2-fenyl), 29,2 (CH2βTrp), 34,7 (CH2-CH2-CH2-fenyl), 45,5 (CH2-p-metoksybenzyl), 45,8 (CH αTrp), 55,5 (OCH3), 56,8 (Cq Aib),109,8 (C3Trp), 111,8 (C7Trp), 114,6 (C3og C5p-metoksybenzyl), 118,3 (C4Trp), 118,7 (C5Trp), 121,3 (C6Trp), 124,9 (C2Trp), 126,2 (C4fenyl), 127,3 (C9Trp), 127,8 (C1p-metoksybenzyl), 127,9 (C3, C4og C5fenyl), 128,7 (C2og C6p-metoksybenzyl), 136,4 (C8Trp), 141,7 (C1fenyl), 154,7 (Cq triazol), 154,8 (Cq triazol), 159,2 (C1p-metoksybenzyl), 171,9 (CO amid).
(S)-N-(1-(4-(4-metoksybenzyl)-5-benzyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid (forbindelse 126):
<1>H NMR (300 MHz, DMSO-d<6>, 300°K):
δ (ppm) 1,25 (3H, s, CH3Aib), 1,28 (3H, s, CH3Aib), 3,26 (1H, dd, J = 14 Hz og 6 Hz, CH2βTrp), 3,34 (1H, dd, J = 14 Hz og 8 Hz, CH2βTrp), 3,99 (2H, s, CH2-fenyl), 4,98 (2H, s, CH2-p-metoksybenzyl), 5,13 (1H, m, CH αTrp), 6,68 (4H, s, CHar p-metoksybenzyl), 6,80 (1H, t, Jo= 8 Hz, H5Trp), 6,99 (1H, t, Jo= 8 Hz, H6Trp), 7,02-7,06 (4H, m, H2og H4Trp, H2og H6fenyl), 7,20 (3H, m, H3, H4og H5fenyl), 7,27 (1H, d, Jo= 8 Hz, H7Trp), 8,00 (3H, s, NH2Aib), 8,91 (1H, d, J = 8 Hz, NH amid), 10,76 (1H, s, NH indol Trp).
<13>C NMR (75 MHz, DMSO-d<6>, 300°K):
δ (ppm) 23,5 (CH3Aib), 23,7 (CH3Aib), 29,1 (CH2βTrp), 30,6 (CH2-fenyl), 45,7 (CH αTrp og CH2-p-metoksybenzyl), 55,5 (OCH3), 56,7 (Cq Aib), 109,8 (C3Trp), 111,7 (C7Trp), 114,5 (C3og C5p-metoksybenzyl), 118,3 (C4Trp), 118,7 (C5Trp), 121,3 (C6Trp), 124,8 (C2Trp), 127,1 (C4fenyl), 127,3 (C9Trp), 127,6 (C1p-metoksybenzyl), 127,8 (C2og C6p-metoksybenzyl), 128,8 (C2og C6fenyl), 128,9 (C3og C5fenyl), 136,3 (C8Trp), 136,4 (C1fenyl), 153,8 (Cq triazol), 155,2 (Cq triazol), 159,2 (C4p-metoksybenzyl), 171,9 (CO amid).
N-((R)-1-(4-(4-nitrobenzyl)-5-fenetyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid (forbindelse 128):
<1>H NMR (300 MHz, DMSO-d<6>, 300°K):
δ (ppm) 1,28 (3H, s, CH3Aib), 1,29 (3H, s, CH3Aib), 2,77-2,94 (4H, m, CH2-CH2-fenyl), 3,28 (1H, dd,<3>J = 14 Hz og 8 Hz, CH2βTrp), 3,43 (1H, dd,<3>J = 14 Hz og 7 Hz, CH2βTrp), 5,05 (1H, m, CH αTrp), 5,25 (2H, d, J = 7 Hz, CH2-p-nitrobenzyl), 6,72 (1H, t, Jo= 7 Hz, H5Trp), 6,89 (2H, d, Jo= 9 Hz, H2og H6p-nitrobenzyl), 6,92 (1H, t, Jo= 7 Hz, H6Trp), 7,00 (1H, d, Jm= 2 Hz, H2Trp), 7,08-7,15 (4H, m, H4og H7Trp, H2og H6fenyl), 7,17 (2H, Jo= 7 Hz, H3og H5fenyl), 7,24 (1H, t, Jo= 8 Hz, H4fenyl), 7,92 (2H, d, Jo= 9 Hz, H3og H5p-nitrobenzyl), 8,06 (3H, brs, NH2Aib), 8,98 (1H, d, J = 8 Hz, NH amid), 10,79 (1H, s, NH indol Trp).
<13>C NMR (75 MHz, DMSO-d<6>, 300°K):
δ (ppm) 23,5 (CH3Aib), 23,8 (CH3Aib), 26,4 (CH2-CH2-fenyl), 29,1 (CH2βTrp), 32,6 (CH2-CH2-fenyl), 45,3 (CH2-p-nitrobenzyl), 45,7 (CH αTrp), 56,8 (Cq Aib), 109,6 (C3Trp), 111,8 (C7Trp), 118,1 (C4Trp), 118,5 (C5Trp), 121,2 (C6Trp), 124,1 (C2og C5pnitrobenzyl), 124,8 (C2Trp), 126,5 (C2og C5fenyl), 127,2 (C9Trp, C1og C6p-nitrobenzyl), 128,7 (C3, C4og C5fenyl), 136,4 (C8Trp), 140,8 (C1fenyl), 143,5 (C1pnitrobenzyl), 154,5 (Cq triazol), 154,8 (Cq triazol), 172,0 (CO Aib).
(S)-N-(1-(4-(4-metoksybenzyl)-5-fenetyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)-etyl)-2-amino-2-metylpropanamid (forbindelse 129):
<1>H NMR (300 MHz, DMSO-d<6>, 300°K):
δ (ppm) 1,27 (3H, s, CH3Aib), 1,30 (3H, s, CH3Aib), 2,81 (4H, m, CH2-CH2-fenyl), 3,34 (2H, d, J = 7 Hz, CH2βTrp), 3,68 (3H, s, OCH3), 4,99 (2H, s, CH2-p-metoksybenzyl), 5,20 (1H, m, CH αTrp), 6,75 (4H, m, CHar p-metoksybenzyl), 6,83 (1H, t, Jo= 7 Hz, H5Trp), 7,03 (1H, t, Jo= 8 Hz, H6Trp), 7,04 (1H, d, J = 2 Hz, H2Trp), 7,10 (2H, d, Jo= 7 H, H2og H6fenyl), 7,13 (1H, d, Jo= 8 Hz, H4Trp), 7,19 (3H, t, Jo= 7 Hz, H3, H4og H5fenyl), 7,29 (1H, d, Jo= 8 Hz, H7Trp), 8,01 (3H, brs, NH2Aib), 8,94 (1H, d, J = 8 Hz, NH amid), 10,78 (1H, d, J = 2 Hz, NH indol Trp).
<13>C NMR (75 MHz, DMSO-d<6>, 300°K):
δ (ppm) 23,6 (CH3Aib), 23,8 (CH3Aib), 26,6 (CH2-CH2-fenyl), 29,2 (CH2βTrp), 32,7 (CH2-CH2-fenyl), 45,3 (CH2-p-metoksybenzyl), 45,7 (CH αTrp), 55,5 (OCH3), 56,8 (Cq Aib), 109,9 (C3Trp), 111,8 (C7Trp), 114,6 (C3og C5p- metoksybenzyl), 118,3 (C4Trp), 118,7 (C5Trp), 121,3 (C6Trp), 124,8 (C2Trp), 126,5 (C4fenyl), 127,3 (C9Trp og C1p-metoksybenzyl), 127,9 (C2og C6p-metoksybenzyl), 128,7 (C2, C3, C5og C6pmetoksybenzyl), 136,5 (C8Trp), 140,9 (C1fenyl), 154,4 (Cq triazol), 154,7 (Cq triazol), 159,2 (C4p-metoksybenzyl), 171,9 (CO amid).
(R)-N-(1-(4-(4-metoksyfenetyl)-5-fenetyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid (forbindelse 130):
<1>H NMR (300 MHz, DMSO-d<6>, 300°K):
δ (ppm) 1,30 (3H, s, CH3Aib), 1,35 (3H, s, CH3Aib), 2,55 (4H, m, CH2-CH2-fenyl og CH2-CH2-p-metoksybenzyl), 2,83 (2H, t, J = 8 Hz, CH2-CH2-fenyl), 3,37 (2H, m, CH2-CH2-p-metoksybenzyl), 3,65 (3H, s, OCH3), 3,77 (1H, m, CH2βTrp), 3,89 (1H, m, CH2βTrp), 5,20 (1H, m, CH αTrp), 6,72 (4H, s, CHar p-metoksybenzyl), 6,94 (1H, t, Jo= 7 Hz, H5Trp), 7,02 (1H, t, Jo= 8 Hz, H6Trp), 7,05 (1H, d, J = 2 Hz, H2Trp), 7,11 (2H, d, Jo= 7 Hz, H2og H6fenyl), 7,16 (1H, d, Jo= 7 Hz, H4Trp), 7,25 (3H m, H3, H4, H5fenyl), 7,50 (1H, d, Jo= 8 Hz, H7Trp), 8,05 (3H, brs, NH2Aib), 9,02 (1H, d, J = 8 Hz, NH amid), 10,83 (1H, d, J = 2 Hz, NH indol Trp).
<13>C NMR (75 MHz, DMSO-d<6>, 300°K):
δ (ppm) 23,5 (CH3Aib), 23,8 (CH3Aib), 26,0 (CH2-CH2-fenyl), 29,5 (CH2βTrp), 32,5 (CH2-CH2-fenyl), 35,0 (CH2-CH2-p-metoksybenzyl), 44,4 (CH2-CH2-p-metoksybenzyl), 45,8 (CH αTrp), 55,4 (OCH3), 56,8 (Cq Aib), 109,9 (C3Trp), 111,9 (C7Trp), 114,2 (C3og C5p-metoksybenzyl), 118,4 (C4Trp), 118,9 (C5Trp), 121,4 (C6Trp), 124,7 (C2Trp), 126,5 (C4fenyl), 127,4 (C9Trp), 128,7 (C2, C3, C5og C6fenyl), 129,4 (C1pmetoksybenzyl), 130,3 (C2og C6p-metoksybenzyl), 136,5 (C8Trp), 141,0 (C1fenyl), 154,0 (Cq triazol), 154,5 (Cq triazol), 158,6 (C4p-metoksybenzyl), 171,8 (CO amid).
(R)-N-(2-(1H-indol-3-yl)-1-(5-fenetyl-4-(pyridin-2-ylmetyl)-4H-1,2,4-triazol-3-yl)etyl)-2-amino-2-metylpropanamid (forbindelse 132):
<1>H NMR (300 MHz, DMSO-d<6>, 300°K):
δ (ppm) 1,26 (3H, s, CH3Aib), 1,29 (3H, s, CH3Aib), 2,95 (4H, m, CH2-CH2-fenyl), 3,40 (2H, m, CH2βTrp), 5,26 (1H, m, CH αTrp), 5,37 (2H, s, CH2-o-pyridyl), 6,83 (1H, t, Jo= 7 Hz, H5Trp), 6,98 (1H, t, Jo= 8 Hz, H6Trp), 7,11-7,30 (10H, m, H2, H4og H7Trp, CHar fenyl, H3og H5o-pyridyl), 7,71 (1H, t, Jo= 7 Hz, H4o-pyridyl), 8,22 (3H, brs, NH2Aib), 8,42 (1H, d, J α β = 4 Hz, HB o-pyridyl), 9,05 (1H, d, J = 8 Hz, NH amid), 10,87 (1H, s, NH indol Trp).
<13>C NMR (75 MHz, DMSO-d<6>, 300°K):
δ (ppm) 23,4 (CH3Aib), 23,7 (CH3Aib), 26,4 (CH2-CH2-fenyl), 28,6 (CH2βTrp), 32,5 (CH2-CH2-fenyl), 45,7 (CH αTrp), 47,6 (CH2o-pyridyl), 56,8 (Cq Aib), 109,8 (C3Trp), 111,8 (C7Trp), 118,3 (C4Trp), 118,6 (C5Trp), 121,2 (C6Trp), 122,0 (C3o-pyridyl), 123,6 (C5o-pyridyl), 126,3 (C2Trp), 126,6 (C4fenyl), 127,3 (C9Trp), 128,7 (C2, C3, C5og C6fenyl), 136,4 (C8trypofan), 137,7 (C4o-pyridyl), 140,7 (C1fenyl), 150,1 (C6opyridyl), 154,9 (Cq triazol), 155,2 (Cq triazol), 158,7 (C2o-pyridyl), 172,0 (CO amid).
N-((R)-1-(4-(2,4-dimetoksybenzyl)-5-fenetyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid (forbindelse 179):
<1>H NMR (300 MHz, DMSO d<6>, 300°K):
δ (ppm) 1,26 (s, 3H, CH3Aib), 1,30 (s, 3H, CH3Aib), 2,82 (m, 4H, CH2-CH2-fenyl), 3,29 (t, 2H, J = 8 Hz, CH2βTrp), 3,61 (s, 3H, OCH3), 3,68 (s, 3H, OCH3), 4,85 (d, 1H, J = 17 Hz, CH2-o,p-dimetoksybenzyl), 5,02 (d, 1H, J = 17 Hz, CH2-o,p-dimetoksybenzyl), 5,18 (m, 1H, CH αTrp), 6,29 (dd, 1H, Jo= 8 Hz og Jm= 2 Hz, H5o,pdimetoksybenzyl), 6,40 (d, 1H, Jo= 8 Hz, H6o,p-dimetoksybenzyl), 6,55 (d, 1H, Jm= 2 Hz, H3o,p-dimetoksybenzyl), 6,82 (t, 1H, Jo= 8 Hz, H5Trp), 6,99 (t, 1H, Jo= 8 Hz, H6Trp), 7,05 (s, 1H, H2Trp), 7,09-7,24 (m, 6H, H4Trp og CHar fenyl), 7,27 (d, 1H, Jo= 8 Hz, H7Trp), 7,99 (s, 3H, large, NH2Aib TFA-salt), 8,89 (d, 1H, J = 8 Hz, NH amid), 10,77 (s, 1H, NH indol Trp).
<13>C NMR (75 MHz, DMSO d<6>, 300°K):
δ (ppm) 23,6 (CH3Aib), 23,7 (CH3Aib), 26,5 (CH2-CH2-fenyl), 29,2 (CH2βTrp), 32,7 (CH2-CH2-fenyl), 41,6 (CH2-o,p-dimetoksybenzyl), 45,7 (CH αTrp), 55,7 (OCH3), 55,9 (OCH3), 56,7 (Cq Aib), 99,1 (C3o,p-dimetoksybenzyl), 105,2 (C5o,p-dimetoksybenzyl), 110,0 (C3Trp), 111,8 (C7Trp), 115,7 (C1o,p-dimetoksybenzyl), 118,3 (C4Trp), 118,7 (C5Trp), 121,3 (C6Trp), 126,5 (C2Trp og C6o,p-dimetoksybenzyl), 127,3 (C9Trp), 128,1 (C4fenyl), 128,7 (C2, C3, C5og C6fenyl), 136,4 (C8Trp), 140,9 (C1fenyl), 154,5 (Cq triazol), 155,0 (Cq triazol), 157,8 (C2o,p-dimetoksybenzyl), 160,9 (C4o,p-dimetoksybenzyl), 171,7 (CO amid).
N-((R)-1-(4-(4-metoksybenzyl)-5-fenetyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)-etyl)-tetrahydro-2H-pyran-4-karboksamid (forbindelse 184):
<1>H NMR (300 MHz, DMSO d<6>, 300°K):
δ (ppm) 1,20 (m, 1H, H5tetrahydropyran), 1,30 (m, 3H, H3og H5tetrahydropyran), 2,17 (m, 1H, H4tetrahydropyran), 2,82 (m, 4H, CH2-CH2-fenyl), 3,16 (m, 2H, H2og H6tetrahydropyran), 3,31 (dd, 1H, J = 14 Hz og 8 Hz, CH2βTrp), 3,35 (dd, 1H, J = 14 Hz og 7 Hz, CH2βTrp), 3,66 (s, 3H, OCH3), 3,72 (m, 2H, H2og H6tetrahydropyran), 5,08 (m, 2H, CH2-p-metoksybenzyl), 5,26 (m, 1H, CH αTrp), 6,73 (s, 4H, CHar p-metoksybenzyl), 6,87 (t, 1H, Jo= 8 Hz, H5Trp), 7,02 (m, 2H, H2og H6Trp), 7,07 (d, 2H, Jo= 7 Hz, H2og H6fenyl), 7,18 (m, 3H, H3, H4og H5fenyl), 7,30 (m, 2H, H4og H7Trp), 8,52 (d, 1H, J = 8 Hz, NH amid), 10,77 (s, 1H, NH indol Trp).
<13>C NMR (75 MHz, DMSO d<6>, 300°K):
δ (ppm) 26,3 (CH2-CH2-fenyl), 28,8 (C3og C5tetrahydropyran), 29,2 (CH2βTrp), 32,2 (CH2-CH2-fenyl), 40,7 (C4tetrahydropyran), 44,8 (CH αTrp), 45,9 (CH2-p-metoksybenzyl), 55,5 (OCH3), 66,6 (C2og C6tetrahydropyran), 109,8 (C3Trp), 111,7 (C7Trp), 114,5 (C3og C5p-metoksybenzyl), 118,4 (C4Trp), 118,7 (C5Trp), 121,3 (C6Trp), 124,5 (C2Trp), 126,7 (C4fenyl), 127,2 (C9Trp), 127,5 (C1p-metoksybenzyl), 128,8 (C2og C6fenyl), 128,7 (C3og C5fenyl), 127,9 (C2og C6p-metoksybenzyl), 136,4 (C8Trp), 140,4 (C1fenyl), 154,7 (Cq triazol), 155,7 (Cq triazol), 159,2 (C4p-metoksybenzyl), 174,2 (CO amid).
N-((R)-1-(5-((1H-indol-3-yl)metyl)-4-(3-metoksybenzyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid (forbindelse 185):
<1>H NMR (300 MHz, DMSO d<6>, 300°K):
δ (ppm) 1,19 (s, 3H, CH3Aib), 1,23 (s, 3H, CH3Aib), 3,14 (dd, 1H, J = 14 Hz og 5 Hz, CH2βTrp), 3,34 (dd, 1H, J = 14 Hz og 9 Hz, CH2βTrp), 3,46 (s, 3H, OCH3), 3,72 (m, 2H, CH2-indol), 5,06 (m, 1H, CH αTrp), 5,14 (m, 2H, CH2-m-metoksybenzyl), 6,31 (s, 1H, H2m-metoksybenzyl), 6,32 (d, 1H, Jo= 7 Hz, H6m-metoksybenzyl), 6,77 (m, 3H, H5indol, H5Trp og H4m-metoksybenzyl), 6,92 (m, 2H, H6indol og H6Trp), 7,02 (m, 2H, H2indol og H2Trp), 7,26-7,30 (m, 3H, H5m-metoksybenzyl, H4og H7indol, H4Trp), 7,41 (d, 1H, Jo= 8 Hz, H7Trp), 7,94 (brs, 3H, NH2Aib TFA-salt), 8,87 (d, 1H, J = 8 Hz, NH amid), 10,73 (d, 1H, J = 2 Hz, NH indol), 10,85 (s, 1H, NH indol Trp).
<13>C NMR (75 MHz, DMSO d<6>, 300°K):
δ (ppm) 21,7 (CH2-indol), 23,5 (CH3Aib), 23,7 (CH3Aib), 28,9 (CH2βTrp), 45,5 (CH αTrp), 46,2 (CH2-m-metoksybenzyl), 55,2 (OCH3), 56,7 (Cq Aib), 108,2 (C3indol), 109,8 (C3Trp), 111,7 (C7Trp), 111,9 (C7indol og C2m-metoksybenzyl), 113,7 (C4mmetoksybenzyl), 118,2 (C6m-metoksybenzyl), 118,4 (C4Trp), 118,6 (C4indol), 118,9 (C5indol og C5Trp), 121,2 (C6indol), 121,6 (C6Trp), 127,1 (C9indol), 127,2 (C9Trp), 136,4 (C8Trp), 136,7 (C8indol), 137,5 (C1m-metoksybenzyl), 154,2 (Cq triazol), 155,3 (Cq triazol), 160,0 (C3m-metoksybenzyl), 171,8 (CO amid).
Tabell 1
Ytterligere eksempler på utførelsesformer med syntesesekvens og MS-data (forbindelse nr. 2, 3, 14, 16, 17, 19-22, 24, 26-35, 36-122, 124-126, 128-150, 152-190):
II) GHS-R 1a-reseptorligandbindingsundersøkelse (membranfremstillinger fra transfekterte LLC PK-1-celler)
GHS-R 1a-reseptorbindings/affinitetsstudier ble utført i henhold til Guerlavais et al. (J. Med. Chem. 2003, 46:1191-1203).
Isolerte plasmamembraner fra LLC PK-1-celler, en renal epitelcellelinje opprinnelig utledet fra grisenyrer (ECACC nr.86121112) (10 µg protein), som ble forbigående transfektert med human GHS-R 1a cDNA (Guerlavais et al., J. Med. Chem.2003, 46: 1191-1203), ble inkubert i homogeniseringsbuffer HB [50 mM Tris (pH 7,3), 5 mM MgCl2, 2,5 mM EDTA og 30 µg/ml bacitracin (Sigma)] i 60 min ved 25 ºC (stabile forhold) med 60 pM<125>I-His<9>-ghrelin (Amersham) i nærvær av eller fravær av konkurrerende forbindelser (forbindelser ifølge oppfinnelsen).
Bindingsaffiniteten til hver forbindelse som ble testet for human GHS-R 1a, ble målt ved erstatning av det radiomerkede ghrelin med økende konsentrasjoner av testforbindelsen (10<-11>M til 10<-2>M) (hvert eksperiment utført i triplikater).
Ikke-spesifikk binding ble definert ved anvendelse av et overskudd (10<-5>M) ghrelin. Bindingsreaksjonen ble stoppet ved tilsetting av 4 ml iskald HB, fulgt av rask filtrering over Whatman GP/C-filtere på forhånd gjennombløtt med 5 % polyetylenimin for å hindre overdreven binding av radioligand med filtrene. Filtre ble skylt tre ganger med 3 ml iskald vaskebuffer [50 mM Tris (pH 7,3), 10 mM MgCl2, 2,5 mM EDTA og 0,015 % (vekt/volum) X-100 Triton] og den radioaktive binding til membraner ble målt i en gammateller (Kontron Analytical Gamma Matic, Automatic gamma counting system).
Konsentrasjonen til testforbindelsene krevde å inhibere radiomerket ghrelinbinding med 50 % (IC50) bestemt ved å tilpasse konkurrerende bindingskurver ved anvendelse av ikke-lineær regresjon (PRISM 3.0, Graph Pad San Diego, USA).
I den følgende tabell 2 ble resultater erholdt for utvalgte forbindelser ifølge oppfinnelsen, presentert til sammenligning med et eksempel av kjent teknikk. De IC50-verdier som er vist, er gjennomsnittet av minst to uavhengige eksperimenter utført i triplikater.
Figur 1-13 viser målte konkurranseplotter til GHS-R 1a reseptorligandbindingsanalyse med<125>I-His<9>-ghrelin og de valgte forbindelser 9, 31, 39, 45, 50, 62, 64, 71, 73, 74, 79, 81 og 90.
Tabell 2
GHS-R 1a reseptorligandbindingsanalysetestresultater (IC50-verdier for et antall utvalgte forbindelser som skal tjene som eksempler)
III) In vitro-intracellulær kalsiumfrigivelsesundersøkelse ved anvendelse av humane GHS-R 1a-transfekterte CHO-celler
Potensialet til forbindelsene ifølge oppfinnelsen til å modulere GHS-reseptoraktivitet ble målt med en in vitro-intracellulær kalsiumfrigivelsesundersøkelse ved anvendelse av CHO-celler som var transfektert med human GHS-R 1a.
Frigivelse av intracellulært kalsium eller inhibering derav ble målt ved anvendelse av fluorescenskalsiumindikatorundersøkelsen (FLIPR) og Fluo-4 AM.
CHO-celler (CHO-KI kinesisk hamstereggstokkcellelinje, ATCC nr. CCL-61) ble forbigående transfektert med human GHS-R 1a cDNA ved elektroporasjon og tilsatt til 96-brønns svartbunnede plater (Corning 3603) (80000 celler/brønn). Forbigående transfeksjoner ble utført ved anvendelse av Easyject Optima Electroporator (Equibio) i henhold til produsentens instruksjoner.
Transfekterte celler ble dyrket i Dulbeccos modifiserte Eagles medium uten fenolrød, supplementert med 10 % (volum/volum) ikke-essensielle aminosyrer, 2 nM glutamin og streptomycin-penicillin (250 µg/ml-250 u/ml) (alle levert fra Cambrex) ved 37 °C, 5 % CO2i en fuktighetsinnstilt atmosfære i 24 timer.
Etter inkubering ble transfekterte celler vasket med 150 µl Buffer A [Hanks balanserte saltløsning (Sigma H-6648), 0,5 % (volum/volum) BSA (Sigma A-7906), 20 mM CaCl2, 2,5 mM probenecid (pH 7,4, løst i 1 M NaOH) (Sigma P-8761)] og ble deretter tilsatt med fluorescenskalsiumindikator Fluo-4 AM (10<-6>M) (Interchim UP72972) fremstilt i buffer A som i tillegg inneholder 0,06 % pluronsyre (Molecular probes P-6867) (en mild, ionisk detergent som letter Fluo-4AM-estertilsetting). (Tilsetting:
100 µl per brønn av buffer A som inneholder 120 µl/ml pluronsyre og 1 µM Fluo-4AM ble tilsatt til cellene).
Etter tilsetting med Fluo-4 AM ble transfekterte celler inkubert i 1 time i mørket ved 37 ºC.
Forbindelser som skal testes, ble løst i buffer A i triplikater ved en konsentrasjon på 10<-6>M og fordelt i en annen 96-brønns plate (Fisher Labosi A1210500).
Etterfølgende inkubering ble overskudd Fluo-4AM fjernet, 100 µl buffer A ble tilsatt til hver brønn ved romtemperatur og umiddelbart fjernet ved utlufting. Dette ble deretter gjentatt, før tilsetting av 50 µl buffer A til hver brønn.
Transfekterte celler ble ytterligere inkubert ved romtemperatur i 30 min for å muliggjøre fullstendig deforestring av intracellulære Fluo-4AM-estere.
Deretter ble begge platene, den svartbunnede platen som inneholder transfekterte celler og mikrotiterplaten som inneholder forbindelsene som skal testes, plassert i en temperaturregulert (25 ºC) FlexStation maskin (benchtop skanningfluorometer Flex Station II, Molecular Devices, Sunnyvale, California, USA) for fluorescensutbyttemålinger.
Siden Fluo-4AM fremviser en stor fluorescensintensitetsøkning etter binding av kalsium, kan fluorescensutbyttet anvendes direkte som et proporsjonalt mål på intracellulær kalsiumfrigivelse.
Basal fluorescensutbytte fra de transfekterte cellene ble målt i 15 sekunder og deretter ble 15 µl av forbindelsene som skal testes, automatisk fordelt i brønnene som inneholder de transfekterte cellene. Fluorescensutbyttet ble deretter avlest i ytterligere 45 sekunder.
Eksitasjon og emisjonsbølgelengder var 485 nm og 525 nm, respektivt. Basal fluorescensintensitet til Fluo-4AM-tilsatte, transfekterte celler uten forbindelser som skulle testes, varierte mellom 800-1200 arbitrære enheter, mens det maksimale fluorescensutbyttet til de fargestofftilsatte, transfekterte cellene etter inkubering med forbindelsene som skulle testes, varierte fra 5000 til 7000 arbitrære enheter og var ekvivalent med det som ble oppnådd ved stimulering av de fargestofftilsatte, transfekterte cellene med 10<-6>M ghrelin.
For hver forbindelse som skulle testes ble forandring i fluorescensutbyttet etter tilsetting av den respektive forbindelsen sammenlignet med det basale fluorescensutbyttet målt med en negativ kontroll, det vil si tilsetting av 50 µl buffer A til de transfekterte cellene alene.
Evnen og omfanget når det gjelder forårsaking av kalsiumfrigivelse for hver testede forbindelse ble bestemt relativt til basalnivået (0 %) og maksimalnivået (100 %) oppnådd med 1 µM ghrelin.
For forbindelsene som skulle testes som ble identifisert som GHS-reseptoragonister, ble EC50- og Ki-verdier bestemt ved anvendelse av en doseresponskurve.
Som for forbindelsene som skulle testes som ble identifisert som GHS-reseptorantagonister, ble IC50og Kb(antagonistdissosiasjonskonstant)-verdier bestemt ved anvendelse av antagonistinhiberingskurver under nærvær av 10<-7>M ghrelin (undermaksimal konsentrasjon). IC50-verdiene ble beregnet som den molare konsentrasjonen av GHS-reseptorantagonist som reduserer den maksimale responsen av ghrelin med 50 %. Kb-verdier ble estimert ved anvendelse av Cheng-Prusoff-ligningen (Lazareno S og BirdsalI NJ, Trends Pharmacol Sci.1993, 14(6):237-239).
Figurer 14-40 viser de beregnede dose-responsverdiene for den in vitro-intracellulære kalsiumfrigivelsesundersøkelsen med human GHS-R 1a-transfekterte CHO-celler til valgte forbindelser 1, 9, 12, 20, 22, 31, 39, 41, 42, 45, 46, 47, 48, 49, 50, 51, 55, 62, 64, 67, 71, 73, 74, 79, 81, 90 og ghrelin, så vel som individuelle EC50- og KI-verdier for agonistforbindelser og IC50- og Kb-verdier for antagonistiske forbindelser.
IV) Undersøkelsen av in vivo-GH-konsentrasjon i plasma til hannkjønnsrottevalper
GH-plasma konsentrasjoner til hannkjønnsrottevalper ble undersøkt for å karakterisere moduleringseffekten (antagonistisk eller agonistisk) til forbindelsene ifølge oppfinnelsen værende GHS-reseptoranalogligander.
I prinsippet ble undersøkelse av in vivo-GH-konsentrasjon i rotteplasma utført i henhold til Torsello et al. (Eur. J. Pharmacol.1998, 360: 123-129).
Hannkjønns Sprague-Dawley-rottevalper (Charles River, Calco, Italia) ble separert sju dager etter fødsel av deres mødre og randomisert redistribuert til mødrene, slik at hver oppfostret ti til tolv valper. Ti dager etter fødselen ble valpene igjen separert fra deres mødre.
Forbindelsene som skulle testes ble løst i løsemiddel [DMSO (0,4 % av totalvolum), destillert vann (4 % av totalvolum) brakt til sluttvolumet med fysiologisk saltvann].
Én time etter separasjon fra deres mødre ble valpene gitt isovolumetriske mengder av forbindelsene som skulle testes (160 µg/kg kroppsvekt s.c.) på tid -10 min og deretter administrert med hexarelin (80 µg/kg kroppsvekt s.c.) eller løsemiddel på tid 0 min før avliving 15 min senere ved dekapitasjon. Hovedåreblod ble samlet opp, umiddelbart sentrifugert og plasmaprøver ble lagret ved -20 °C til undersøkelse for å bestemmelse av GH-konsentrasjoner.
Plasma GH-konsentrasjoner ble målt ved anvendelse av rotteveksthormonenzymimmunoundersøkelseskitt (SPIbio, Frankrike, katalog nr.589601) i henhold til produsentens instruksjoner. Verdier ble uttrykt som NIDDK rotte-GH-RP2-standard (potens 2 IU/mg) som ng/ml plasma.
Deteksjonsgrensen beregnet som konsentrasjon som gir 15 % erstatning av initielt tracer, var 0,5 ng/ml; intraundersøkelsen og interundersøkelsesvariasjonskoeffisient var 4 % (n = 24) og 14 % (n = 9).
I følgende tabell 3 er resultater oppnådd for utvalgte forbindelser ifølge oppfinnelsen presentert.
Tabell 3
Relativ GH-konsentrasjon i rotteplasma etter behandling med valgte forbindelser ifølge oppfinnelsen (160 µg/kg kroppsvekt s.c.) og/eller hexarelin (80 µg/kg kroppsvekt s.c.) og/eller løsemiddel
V) Undersøkelse av fôringsoppførsel (matinntak) for unge-voksne hannkjønnsrotter
Virkningen av forbindelsene ifølge oppfinnelsen værende GHS-reseptoranalogligander på fôringsoppførselen, det vil si matinntak, til unge-voksne hannkjønnsrotter ble undersøkt.
I prinsippet ble undersøkelsen av fôringsoppførselen (matinntak) til unge-voksne hannkjønnsrotter utført i henhold til Torsello et al. (Eur. J. Pharmacol. 1998, 360: 123-129).
For undersøkelsen ble unge-voksne hannkjønns Sprague-Dawley-rotter (Charles River, Calco, Italia) som veide 200-250 g, anvendt.
Rotter hadde 1 uke med akklimatisering i individuelle hjembur og dyrerombetingelser (22 ± 2 ºC, 65 % fuktighet, kunstig lys fra 08:00 til 20:00 timer). Etterfølgende uke ble de daglig trent for å etterligne eksperimentprosedyren. Rottene opprettholdt fri adgang til tørrpellets og springvann i løpet av hele eksperimentperioden. Ved slutten av treningen ble rottene administrert (rundt 10:00-11:00) subkutant med forbindelsene som skulle testes (160 µg/kg kroppsvekt) og/eller hexarelin (80 µg/kg kroppsvekt) og/eller løsemiddel [DMSO (0,4 % av totalvolum), destillert vann (4 % av totalvolum), brakt til sluttvolumet med fysiologisk saltvann].
Hexarelin ble anvendt for å studere effektene av forbindelsene som skulle testes på stimulert fôringsoppførsel. Umiddelbart etter injeksjonene returnerte dyrene til deres hjembur, som inneholdt en kjent mengde standard rottemat og ad libitum vann. Hver time i de etterfølgende 6 timene ble gjenværende mat nøye samlet opp og veid til nærmeste 0,1 g. Vanninntak ble normalisert for kroppsvekten til dyrene og uttrykt som gram mat spist per 100 g kroppsvekt rotte.
I følgende tabell 4 er resultater, oppnådd for utvalgte forbindelser ifølge oppfinnelsen, presentert.
Tabell 4
Kumulativt matinntak (g mat/100 g kroppsvekt) for unge-voksne rotter etter 2 timer og 6 timer og etter behandling med valgte forbindelser ifølge oppfinnelsen (160 µg/kg kroppsvekt s.c.) og/eller hexarelin (80 µg/kg kroppsvekt s.c.) og/eller løsemiddel
VI) Motilin reseptorligandbindingsundersøkelse (ved anvendelse av humane rekombinante HEK-293-celler)
Motilin reseptorbindings/affinitetsstudier ble utført slik det er beskrevet av Feighner SD et al. (Science 1999, 284: 2184-2188). Undersøkelsene ble gjort under følgende betingelser:
Kilde: Humane, rekombinante HEK-293-celler [Motilin-reseptor 1a (MTL-R1a)]
Ligand: 0,1 nM [<125>I] Motilin (human, porcin)
Vehikkel: 1 % DMSO
Inkuberingstid/temperatur: 2,5 timer ved 25 ºC
Inkuberingsbuffer: 50 mM Tris, pH 7,4, 10 mM MgCl2, 0,5 % BSA
Ikke-spesifikk ligand: 1 µM Motilin (human, porcin)
Forbindelser ifølge oppfinnelsen ble testet i konsentrasjoner som innbefatter 0,01 µM, 0,1 µM, 1 µM og 10 µM.
IC50-verdier ble bestemt ved en ikke-lineær, minste kvadrat regresjonsanalyse ved anvendelse av Data Analysis Toolbox (MDL Information Systems, USA).
I følgende tabell 5 er resultater, oppnådd for utvalgte forbindelser ifølge oppfinnelsen, presentert.
Tabell 5
Motilin reseptorligandbindingsundersøkelsestestresultater (IC50-verdier for et antall utvalgte eksempelforbindelser)
VII) Studie av antikakeksieffekter i et adjuvansindusert artrittmodellsystem Effektiviteten til forbindelsene ifølge oppfinnelsen for behandling av kakeksi ble undersøkt i henhold til Ibanez de Caceres I et al. (J Endocrinol.2000, 165(3): 537-544) ved anvendelse av et kakeksimodellsystem (Roubenoff R et al., Arthritis Rheum. 1997, 40(3): 534-539).
Tabell 6 viser antikakeksieffekten til forbindelse 44 (0,1 µg/kg/dag s.c. injeksjon) hos artrittrotter sammenlignet med adjuvansindusert artritt uten medisinsk behandling.
Tabell 6
Kroppsvektforandring i gram (middelverdi av 6 dyr per gruppe)
VIII) Studie av antiinhiberingseffekter av isoproterolindusert lipolyse i adipocyttmodeller
Effektiviteten til forbindelser ifølge oppfinnelsen når det gjelder inhibering av ikkeacetylert ghrelinindusert inhibering av isoproteolindusert lipolyse ble undersøkt ved anvendelse av adipocyttmodeller.
Isolering av primære museadipocytter
Mus ble fôret med høyvektdiett som induserer fedme (60 % lipider) som starter ved 4 ukers alder i 12 og 18 uker.
Hvitt adiposevev fra epididymal fett ble oppmalt og digestert i KrebsRinger-Bikarbonat-Hepes(KRBH)-buffer (20 mM Hepes pH 7,4, 120 mM NaCl, 4,7 mM KCl, 1,2 mM K2HPO4, 2,5 mM CaCl2, 1,2 mM MgSO4, 24 mM NaHCO3) mettet med CO2-inneholdende glukose (1 µg/ml), 1 % BSA og kollagenase (2 µg/g vev). Digesjonen ble gjort under konstant risting (250 rpm) ved 37 °C i 45 min.
Cellesuspensjonen ble filtrert gjennom en nylonmesh for å separere adipocytter fra vevsfragmenter og vasket tre ganger i 3 ml varm KRBH 1 % BSA.
Cellene ble resuspendert i KRBH 1 % BSA og inkubert i rister (75 rpm) ved 37 ºC i 30 min.
Lipolyseundersøkelse
Lipolyse i primære adipocyttceller ble indusert med 30 nM isoproterenol i KRBH 4 % BSA i 90 min med konstant (125 rpm) risting ved 37 ºC.
Lipolyse i differensierte celler ble indusert med 30 nM isoproterenol i DMEM FBS fri i 90 min ved 37 ºC med risting hvert 15. minutt.
Inhiberingseffekten av ikke-acetylert ghrelin (UAG) på isoproterenolindusert lipolyse ble dokumentert med økende konsentrasjon av UAG fra 10<-11>M til 10<-6>M under nærvær eller fravær av valgte forbindelser ifølge oppfinnelsen ved 10<-7>M.
Lipolyseindeksen ble bestemt ved å måle glyserolfrigivelse etterfølgende triglyseridhydrolyse.
Den antagonistiske effekten ble bestemt som følger:
med
Figurene 41-46 viser effektene av valgte forbindelser 9, 38, 50, 64, 74, 81 på isoprorerenolindusert lipolyseinhiberingskurven til ikke-acetylert ghrelin (UAG) i primære adipocytter fra mus under diettindusert fedme.
Claims (13)
1.
Anvendelse av en forbindelse valgt fra gruppen som består av:
forbindelse 1 (R)-N-(1-(5-(2-(1H-indol-3-yl)etyl)-4-(2,4-dimetoksybenzyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid,
forbindelse 2 (R)-N-(1-(5-(2-(1H-indol-3-yl)etyl)-4-fenetyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid,
forbindelse 3 (R)-N-(1-(5-(3-(1H-indol-3-yl)propyl)-4-fenetyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid,
forbindelse 4 (R)-N-(1-(5-benzyl-4-(naftalen-1-ylmetyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid,
forbindelse 5 (R)-N-(1-(5-(2-(1H-indol-3-yl)etyl)-4(naftalen-1-ylmetyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid,
forbindelse 6 (R)-N-(1-(5-(2-(1H-indol-3-yl)etyl)-4-(3-metoksybenzyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid,
forbindelse 7 (R)-N-(1-(4-(3-metoksybenzyl)-5-benzyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid,
forbindelse 8 (R)-N-(1-(5-(2-(1H-indol-3-yl)etyl)-4-benzyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid,
forbindelse 9 (R)-N-(1-(5-(3-(1H-indol-3-yl)propyl)-4-benzyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid, forbindelse 10 (R)-N-(1-(5-(3-(1H-indol-3-yl)propyl}-4-(3-metoksybenzyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid,
forbindelse 11 (R)-N-(1-(5-(3-(1H-indol-3-yl)propyl)-4-(naftalen-1-ylmetyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid,
forbindelse 12 (R)-N-(1-(5-(2-(1H-indol-3-yl)etyl)-4-(4-metoksybenzyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid,
forbindelse 13 (R)-N-(1-(4-(4-metoksybenzyl)-5-benzyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid,
forbindelse 14 (R)-N-(1-(5-(3-(1H-indol-3-yl)propyl)-4-(4-brombenzyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid,
forbindelse 15 (R)-N-(1-(5-(2-(1H-indol-3-yl)etyl)-4-heksyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid,
forbindelse 16 (R)-N-(1-(5-(3-(1H-indol-3-yl)propyl)-4-heksyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid,
forbindelse 17 (R)-N-(1-(4,5-bis-(2-(1H-indol-3-yl)etyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid,
forbindelse 18 (S)-N-(1-(5-(2-(1H-indol-3-yl)etyl)-4-(2,4-dimetoksybenzyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid,
forbindelse 19 (R)-N-(1-(4-(3-metoksybenzyl)-5-fenetyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid, forbindelse 20 (R)-N-(1-(4-(4-metoksybenzyl)-5-fenetyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid,
forbindelse 21 (R)-N-(1-(5-(2-(1H-indol-3-yl)etyl)-4-(3,5-dimetoksybenzyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid,
forbindelse 22 (R)-N-(1-(4-(4-metoksybenzyl)-5-(3-fenylpropyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid,
forbindelse 23 (R)-N-(1-(5-(3-(1H-indol-3-yl)propyl)-4-(4-metoksybenzyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid,
forbindelse 24 (R)-N-(1-(4-(2-(1H-indol-3-yl)etyl)-5-(3-(1H-indol-3-yl)propyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid,
forbindelse 25 (R)-N-(1-(5-(2-(1H-indol-3-yl)etyl)-4-(2-metoksy)benzyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid,
forbindelse 26 (R)-N-(1-(4-(2-metoksybenzyl)-5-fenetyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid,
forbindelse 27 (R)-N-(2-(1H-indol-3-yl)-1-(4-(naftalen-1-ylmetyl)-5-fenetyl-4H-1,2,4-triazol-3-yl)etyl)-2-amino-2-metylpropanamid,
forbindelse 28 (R)-N-(1-(5-(2-(1H-indol-3-yl)etyl)-4-(3,4-diklorbenzyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid,
forbindelse 29 (R)-N-(1-(5-(2-(1H-indol-3-yl)etyl)-4-(4-fluorbenzyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid, forbindelse 30 (R)-N-(1-(4-(4-fluorbenzyl)-5-benzyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid,
forbindelse 31 (R)-N-(1-(5-(2-(1H-indol-3-yl)etyl)-4-(2,4-dimetoksybenzyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)piperidin-4-karboksamid,
forbindelse 32 (R)-N-(1-(5-(2-(1H-indol-3-yl)etyl)-4-(2,4-dimetoksybenzyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)piperidin-3-karboksamid,
forbindelse 33 (R)-N-(1-(4-(4-metylbenzyl)-5-(3-fenylpropyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid,
forbindelse 34 (R)-N-(1-(5-(2-(1H-indol-3-yl)etyl)-4-(4-metylbenzyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid,
forbindelse 36 (R)-N-(1-(5-(2-(1H-indol-3-yl)etyl)-4-(2,4-dimetoksybenzyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)piperidin-2-karboksamid,
forbindelse 37 (R)-N-(1-(4-(4-metylbenzyl)-5-fenetyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid,
forbindelse 38 (R)-N-(1-(5-(2-(1H-indol-3-yl)etyl)-4-(2,4-dimetoksybenzyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-aminobenzamid,
forbindelse 39 (R)-N-(1-(5-benzyl-4-(pyndin-2-ylmetyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid,
forbindelse 40 (2S,4R)-N((R)-1-(4-(4-metoksybenzyl)-5-fenetyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-4-hydroksypyrrolidin-2-karboksamid,
forbindelse 41 (S)-N-((R)-1-(4-(4-metoksybenzyl)-5-fenyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)piperidin-3-karboksamid,
forbindelse 42 (R)-N-((R)-1-(4-(4-metoksybenzyl)-5-fenetyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)piperidin-3-karboksamid,
forbindelse 43 (R)-N-(1-(4-(4-etylbenzyl)-5-fenetyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid,
forbindelse 44 (R)-N-(1-(4-(4-metoksybenzyl)-5-fenetyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)piperidin-4-karboksamid,
forbindelse 45 (R)-N-(1-(5-(2-(1H-indol-3-yl)etyl)-4-(4-metoksybenzyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)piperidin-4-karboksamid,
forbindelse 46 (S)-N-((R)-1-(4-(4-metoksybenzyl)-5-fenetyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)pyrrolidin-2-karboksamid,
forbindelse 47 (R)-N-((R)-1-(4-(4-metoksybenzyl)-5-fenetyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)pyrrolidin-2-karboksamid,
forbindelse 48 (S)-N-((R)-1-(4-(4-metoksybenzyl)-5-fenetyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)piperidin-2-karboksamid,
forbindelse 49 (R)-N-((R)-1-(4-(4-metoksybenzyl)-5-fenetyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)piperidin-2-karboksamid,
forbindelse 50 (R)-N-(1-(4-(4-metoksybenzyl)-5-fenetyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-aminoacetamid,
forbindelse 51 (R)-N-(1-(4-(4-metoksybenzyl)-5-fenetyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-(pyridin-2-yl)acetamid, forbindelse 52 (R)-N-(1-(4-(4-metoksybenzyl)-5-fenetyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-(pyridin-4-yl)acetamid,
forbindelse 53 (R)-N-(1-(4-(4-metoksybenzyl)-5-fenetyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)sykloheksankarboksamid,
forbindelse 54 (R)-N-(1-(5-(2-(1H-indol-3-yl)etyl)-4-benzyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)piperidin-4-karboksamid,
forbindelse 55 (R)-N-(1-(5-(2-(1H-indol-3-yl)etyl)-4-benzyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)piperidin-3-karboksamid,
forbindelse 56 (R)-N-(1-(4-(4-metoksybenzyl-5-fenetyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-3-aminopropanamid,
forbindelse 57 (S)-N-((R)-1-(4-(4-metoksybenzyl)-5-fenetyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-aminopropanamid,
forbindelse 58 (R)-N-(1-(4-(4-metoksybenzyl)-5-fenetyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-(pyridin-3-yl)acetamid,
forbindelse 59 (R)-N-(1-(4-(4-metoksybenzyl)-5-fenetyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-3-(pyridin-3-yl)propanamid,
forbindelse 60 (R)-N-(1-(5-(2-(1H-indol-3-yl)etyl)-4-benzyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-(pyridin-2-yl)acetamid,
forbindelse 61 (R)-N-(1-(5-(2-(1H-indol-3-yl)etyl)-4-(2,4-dimetoksybenzyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-(pyridin-2-yl)acetamid,
forbindelse 62 (R)-N-(1-(4-(2,4-dimetoksybenzyl)-5-fenetyl-4H-1,2,4-triazol-3-yl-2-(1H-indol-3-yl)etyl)piperidin-4-karboksamid, forbindelse 63 (R)-N-((R)-1-(4-(2,4-dimetoksybenzyl)-5-fenetyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)piperidin-2-karboksamid,
forbindelse 64 (R)-N-(1-(4-(2,4-dimetoksybenzyl)-5-fenetyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)pikolinamid,
forbindelse 65 (R)-N-(1-(4-(2,4-dimetoksybenzyl)-5-fenetyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)isonikotinamid,
forbindelse 66 (R)-N-(1-(4-(2,4-dimetoksybenzyl)-5-fenetyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)pyrazin-2-karboksamid,
forbindelse 67 (R)-N-1-(4-(2,4-dimetoksybenzyl)-5-fenetyl-4H-1,2,4-triazol-3-yl)-1H-indol-3-yl)etyl)piperazin-2-karboksamid,
forbindelse 68 (S)-N-((R)-1-(4-(2,4-dimetoksybenzyl)-5-fenyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)pyrrolidin-2-karboksamid,
forbindelse 69 (R)-N-(1-(5-(2-(1H-indol-3-yl)etyl)-4-(2,4-dimetoksybenzyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-aminoacetamid,
forbindelse 70 (S)-N-((R)-1-(5-(2-(1H-indol-3-yl)etyl)-4-(2,4-dimetoksybenzyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)pyrrolidin-2-karboksamid,
forbindelse 71 (R)-N-(1-(5-(2-(1H-indol-3-yl)etyl)-4-(2,4-dimetoksybenzyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)pyrazin-2-karboksamid,
forbindelse 72 (R)-N-1-(5-(2-(1H-indol-3-yl)etyl)-4-(2,4-dimetoksybenzyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)piperazin-2-karboksamid,
forbindelse 73 (R)-N-(1-(5-(2-(1H-indol-3-yl)etyl)-4-(2,4-dimetoksybenzyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)pikolinamid, forbindelse 74 (R)-1-(5-(2-(1H-indol-3-yl)etyl)-4-(2,4-dimetoksybenzyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etanamin,
forbindelse 75 (R)-N-(1-(4-(2,4-dimetoksybenzyl)-5-fenetyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-aminoacetamid,
forbindelse 76 (R)-N-(1-(4-(4-metoksybenzyl)-5-fenetyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)pyrazin-2-karboksamid,
forbindelse 77 (R)-N-(1-(4-(4-metoksybenzyl)-5-fenetyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)isonikotinamid,
forbindelse 78 (R)-N-1-(4-(4-metoksybenzyl)-5-fenetyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)piperazin-2-karboksamid,
forbindelse 79 (R)-N-1-(4-(4-metoksybenzyl)-5-fenetyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)pikolinamid,
forbindelse 80 (R)-N-(1-(5-(2-(1H-indol-3-yl)etyl)-4-(4-metoksybenzyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)pikolinamid,
forbindelse 81 (R)-N-1-(5-(2-(1H-indol-3-yl)etyl)-4-(4-metoksybenzyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)piperazin-2-karboksamid,
forbindelse 82 (R)-N-1-(4-(4-etylbenzyl)-5-fenetyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-(pyridin-2-yl)acetamid,
forbindelse 83 (R)-N-(1-(4-(4-etylbenzyl)-5-fenetyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)piperidin-4-karboksamid,
forbindelse 84 (R)-N-1-(4-(4-etylbenzyl)-5-fenetyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)piperazin-2-karboksamid,
forbindelse 85 (R)-N-(1-(4-(4-etylbenzyl)-5-fenetyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)pyrazin-2-karboksamid,
forbindelse 86 (R)-N-(1-(5-(2-(1H-indol-3-yl)etyl)-4-(2,4-dimetoksybenzyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-cis-aminosykloheksankarboksamid,
forbindelse 87 (S)-N-((R)-1-(5-(2-(1H-indol-3-yl)etyl)-4-(4-metoksybenzyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)piperidin-3-karboksamid,
forbindelse 88 (R)-N-((R)-1-(5-(2-(1H-indol-3-yl)etyl)-4-(4-metoksybenzyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)piperidin-2-karboksamid,
forbindelse 89 (S)-N-((R)-1-(5-(2-(1H-indol-3-yl)etyl)-4-(4-metoksybenzyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)pyrrolidin-2-karboksamid,
forbindelse 90 (R)-N-((R)-1-(5-(2-(1H-indol-3-yl)etyl)-4-(4-metoksybenzyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)pyrrolidin-2-karboksamid,
forbindelse 91 (R)-N-(1-(5-(2-(1H-indol-3-yl)etyl)-4-(4-metoksybenzyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-(pyridin-2-yl)-acetamid,
forbindelse 92 (R)-N-(1-(5-(2-(1H-indol-3-yl)etyl)-4-(4-brombenzyl}-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid,
forbindelse 93 (R)-N-(1-(5-(2-(1H-indol-3-yl)etyl)-4-(4-metoksybenzyl)-4H-1,2,4-triazol-3-yl)-2-fenyletyl)-2-amino-2-metylpropanamid,
forbindelse 94 (R)-N-(2-(1H-indol-3-yl)-1-(5-fenetyl-4-(tiofen-2-ylmetyl)-4H-1,2,4-triazol-3-yl)etyl)piperidin-4-karboksamid,
forbindelse 95 (R)-N-(1-(4-(2-(1H-indol-3-yl)etyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid,
forbindelse 96 (R)-N-(1-(5-((1H-indol-3-yl)metyl)-4-metyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid,
forbindelse 97 (R)-N-(1-(5-(2-(1H-indol-3-yl)etyl)-4-metyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid,
forbindelse 98 (R)-N-(1-(5-((1H-indol-3-yl)metyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid,
forbindelse 99 (R)-N-(1-(5-((1H-indol-3-yl)metyl)-4-(2,4-dimetoksybenzyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid,
forbindelse 100 (R)-N-(1-(4-(2,4-dimetoksybenzyl)-5-metyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid,
forbindelse 101 (R)-N-(1-(5-((1H-indol-3-yl)metyl)-4(4-metoksybenzyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid,
forbindelse 102 (R)-N-(1-(4-(2,4-dimetoksybenzyl)-5-benzyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid,
forbindelse 103 (R)-N-(1-(5-(3-(1H-indol-3-yl)propyl)-4-(2,4-dimetoksybenzyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid,
forbindelse 104 (R)-N-(1-(5-((1H-indol-3-yl)metyl)-4-fenetyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid,
forbindelse 105 (R)-N-(1-(5-benzyl-4-fenetyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid,
forbindelse 106 (R)-N-(1-(5-benzyl-4-(2,2-difenyletyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid,
forbindelse 107 (R)-N-(1-(5-(2-(1H-indol-3-yl)etyl)-4-(2,2-difenyletyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid,
forbindelse 108 (R)-N-(1-(4-(3,5-dimetoksybenzyl)-5-benzyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid,
forbindelse 109 (R)-N-(1-(4,5-dibenzyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid,
forbindelse 110 (R)-N-(1-(5-benzyl-4-heksyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid,
forbindelse 111 (R)-N-(1-(4-(2-(1H-indol-3-yl)etyl)-5-benzyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid,
forbindelse 112 (S)-N-(1-(4-(2,4-dimetoksybenzyl)-5-benzyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid,
forbindelse 113 (R)-N-(1-(4-(3,5-dimetoksybenzyl)-5-fenetyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid,
forbindelse 114 (R)-N-(1-(4-(4-brombenzyl)-5-benzyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid,
forbindelse 115 (R)-N-1-(4-(2-metoksybenzyl)-5-benzyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid,
forbindelse 116 (S)-N-(1-(4-(2,4-dimetoksybenzyl)-5-fenetyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid,
forbindelse 117 (R)-N-(1-(4,5-difentyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid,
forbindelse 118 (R)-N-(1-(4-(3,4-diklorbenzyl)-5-benzyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid,
forbindelse 119 (R)-1-(5-(2-(1H-indol-3-yl)etyl)-4-(2,4-dimetoksybenzyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etanamin,
forbindelse 120 (R)-N-(1-(4-(4-metoksybenzyl)-5-benzyl-4H-1,2,4-triazol-3-yl)-2-fenyletyl)-2-amino-2-metylpropanamid,
forbindelse 121 (R)-N-(1-(4-(4-fluorbenzyl)-5-fenetyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid,
forbindelse 122 (R)-N-(1-(4-(3,4-diklorbenzyl)-5-fenetyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid,
forbindelse 124 (R)-N-(1-(4-(4-metylbenzyl)-5-benzyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid,
forbindelse 125 (S)-N-(1-(4-(4-metoksybenzyl)-5-(3-fenylpropyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid,
forbindelse 126 (S)-N-(1-(4-(4-metoksybenzyl)-5-benzyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid,
forbindelse 128 N-((R)-1-(4-(4-nitrobenzyl)-5-fenetyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid,
forbindelse 129 (S)-N-(1-(4-(4-metoksybenzyl)-5-fenetyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid,
forbindelse 130 (R)-N-(1-(4-(4-metoksyfenetyl)-5-fenetyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid,
forbindelse 131 (R)-N-(2-(1H-indol-3-yl)-1-(5-fenetyl-4-(tiofen-2-ylmetyl)-4H-1,2,4-triazol-3-yl)etyl)-2-amino-2-metylpropanamid, forbindelse 132 (R)-N-(2-(1H-indol-3-yl)-1-(5-fenetyl-4-(pyridin-2-ylmetyl)-4H-1,2,4-triazol-3-yl)etyl)-2-amino-2-metylpropanamid,
forbindelse 133 (R)-N-(2-(1H-indol-3-yl)-1-(5-fenetyl-4-(pyridin-2-ylmetyl)-4H-1,2,4-triazol-3-yl)etyl)piperidin-3-karboksamid,
forbindelse 134 (S)-N-((R)-1-(4-(4-etylbenzyl)-5-fenetyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)pyrrolidin-2-karboksamid,
forbindelse 135 N-((R)-1-(4-(4-etylbenzyl)-5-fenetyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-aminoacetamid,
forbindelse 136 N-((R)-1-(5-(2-(1H-indol-3-yl)etyl)-4-(4-metoksybenzyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-(pyridin-4-yl)-acetamid,
forbindelse 137 (2R)-N-((R)-1-(4-(4-etylbenzyl)-5-fenetyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)piperidin-2-karboksamid,
forbindelse 138 N-((R)-1-(4-(4-etylbenzyl)-5-fenetyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)pikolinamid,
forbindelse 139 N-((R)-1-(4-(4-etylbenzyl)-5-fenetyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-aminopyridin-3-karboksamid,
forbindelse 140 (2S)-N-((R)-1-(4-(4-etylbenzyl)-5-fenetyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-aminopropanamid,
forbindelse 141 N-((R)-1-(4-(4-etylbenzyl)-5-fenetyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)isonikotinamid,
forbindelse 142 N-((R)-2-(1H-indol-3-yl)-1-(5-fenetyl-4-fenyl-4H-1,2,4-triazol-3-yl)etyl)piperidin-4-karboksamid,
forbindelse 143 (2S)-N-((R)-2-(1H-indol-3-yl)-1-(5-fenetyl-4-fenyl-4H-1,2,4-triazol-3-yl)etyl)pyrrolidin-2-karboksamid,
forbindelse 144 N-((R)-2-(1H-indol-3-yl)-1-(5-fenetyl-4-fenyl-4H-1,2,4-triazol-3-yl)etyl)-2-aminoacetamid,
forbindelse 145 N-((R)-2-(1H-indol-3-yl)-1-(5-fenetyl-4-fenyl-4H-1,2,4-triazol-3-yl)etyl)-2-(pyridin-2-yl)acetamid,
forbindelse 146 N-((R)-2-(1H-indol-3-yl)-1-(5-fenetyl-4-fenyl-4H-1,2,4-triazol-3-yl)etyl)pikolinamid,
forbindelse 147 N-((R)-1-(5-(2-(1H-indol-3-yl)etyl)-4-(4-etylfenyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)pikolinamid,
forbindelse 148 N-((R)-1-(5-(2-(1H-indol-3-yl)etyl)-4-(4-etylfenyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-(pyridin-2-yl)acetamid,
forbindelse 149 N-((R)-1-(5-(2-(1H-indol-3-yl)etyl)-4-(4-etylfenyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-aminoacetamid,
forbindelse 150 (2S)-N-((R)-1-(5-(2-(1H-indol-3-yl)etyl)-4-(4-etylfenyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)pyrrolidin-2-karboksamid,
forbindelse 152 N-((R)-1-(5-(2-(1H-indol-3-yl)etyl)-4-(4-metoksybenzyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-aminoacetamid,
forbindelse 153 N-((R)-1-(4-(4-metoksybenzyl)-5-fenetyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-trans-aminosykloheksankarboksamid,
forbindelse 154 N-((R)-1-(4-(4-etylbenzyl)-5-fenetyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-(pyridin-3-yl)acetamid,
forbindelse 155 (3S)-N-((R)-1-(4-(4-etylbenzyl)-5-fenetyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)piperidin-3-karboksamid,
forbindelse 156 N-((R)-1-(4-(4-etylbenzyl)-5-fenetyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-aminobenzamid,
forbindelse 157 N-((R)-1-(5-(2-(1H-indol-3-yl)etyl)-4-fenyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)pikolinamid,
forbindelse 158 N-((R)-1-(5-(2-(1H-indol-3-yl)etyl)-4-fenyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)piperidin-4-karboksamid,
forbindelse 159 N-((R)-2-(1H-indol-3-yl)-1-(4-(2,4-dimetoksyfenyl)-5-fenetyl-4H-1,2,4-triazol-3-yl)etyl)pikolinamid,
forbindelse 160 N-((R)-2-(1H-indol-3-yl)-1-(4-(2,4-dimetoksyfenyl)-5-fenetyl-4H-1,2,4-triazol-3-yl)etyl)-2-(pyridin-2-yl)acetamid,
forbindelse 161 N-((R)-2-(1H-indol-3-yl)-1-(4-(2,4-dimetoksyfenyl)-5-fenetyl-4H-1,2,4-triazol-3-yl)etyl)pyrazin-2-karboksamid,
forbindelse 162 N-((R)-2-(1H-indol-3-yl)-1-(4-(2,4-dimetoksyfenyl)-5-fenetyl-4H-1,2,4-triazol-3-yl)etyl)-2-aminoacetamid,
forbindelse 163 N-((R)-2-(1H-indol-3-yl)-1-(4-(2,4-dimetoksyfenyl)-5-fenetyl-4H-1,2,4-triazol-3-yl)etyl)piperidin-4-karboksamid,
forbindelse 164 N-((R)-1-(5-benzyl-4-((pyridin-2-yl)metyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)pikolinamid,
forbindelse 165 N-((R)-1-(5-benzyl-4-((pyridin-2-yl)metyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-aminoacetamid,
forbindelse 166 N-((R)-1-(5-benzyl-4-((pyridin-2-yl)metyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)piperidin-4-karboksamid, forbindelse 167 N-((R)-1-(5-benzyl-4-((pyridin-4-yl)metyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid,
forbindelse 168 N-((R)-1-(5-(4-metoksybenzyl)-4-fenetyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid,
forbindelse 169 N-((R)-1-(5-benzyl-4-((pyridin-4-yl)metyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)pikolinamid,
forbindelse 170 N-((R)-1-(5-benzyl-4-((pyridin-4-yl)metyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-acetamid,
forbindelse 171 (R)-benzyl-3-(2-aminoisobutyramido)-3-(5-(2-(1H-indol-3-yl)etyl)-4-(4-metoksybenzyl)-4H-1,2,4-triazol-3-yl)-propanoat,
forbindelse 172 N-((R)-1-(5-benzyl-4-((pyridin-3-yl)metyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid,
forbindelse 173 N-((R)-1-(4-benzyl-5-fenetyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid,
forbindelse 174 N-((R)-2-(1H-indol-3-yl)-1-(4-metyl-5-fenetyl-4H-1,2,4-triazol-3-yl)etyl)pikolinamid,
forbindelse 175 N-((R)-1-(5-(2-(1H-indol-3-yl)etyl)-4-fenyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid,
forbindelse 176 N-((R)-1-(4-(4-metoksybenzyl)-5-fenetyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)benzamid,
forbindelse 177 (R)-1-(4-(2,4-dimetoksybenzyl)-5-fenetyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)-N-fenylmetansulfonylamin,
forbindelse 178 (R)-1-(4-(2,4-dimetoksybenzyl)-5-fenetyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)-N-tosyletanamin,
forbindelse 179 N-((R)-1-(4-(2,4-dimetoksybenzyl)-5-fenetyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid,
forbindelse 180 N-1-((R)-1-(4-(2,4-dimetoksybenzyl)-5-fenetyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)etan-1,2-diamin,
forbindelse 181 N-((R)-1-(4-((furan-2-yl)metyl)-5-fenetyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid,
forbindelse 182 N-((R)-1-(4-((furan-2-yl)metyl)-5-fenetyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)pikolinamid,
forbindelse 183 N-((R)-1-(4-((furan-2-yl)metyl)-5-fenetyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)piperidin-4-karboksamid,
forbindelse 184 N-((R)-1-(4-(4-metoksybenzyl)-5-fenetyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-tetrahydro-2H-pyran-4-karboksamid,
forbindelse 185 N-((R)-1-(5-((1H-indol-3-yl)metyl)-4-(3-metoksybenzyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid,
forbindelse 186 (2S)-N-((R)-1-(4-(4-metoksybenzyl)-5-fenetyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-3-penylpropanamid,
forbindelse 187 (R)-1-(5-(2-(1H-indol-3-yl)etyl)-4-(2,4-dimetoksybenzyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)-N-tosyletanamin,
forbindelse 188 N-((R)-1-(4-(2,4-dimetoksybenzyl)-5-fenetyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-4-azidobenzamid,
forbindelse 189 N-benzyl-(R)-1-(4-(2,4-dimetoksybenzyl)-5-fenetyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etanamin,
forbindelse 190 (2S)-N-((R)-1-(5-(2-(1H-indol-3-yl)etyl)-4-(4-metoksybenzyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2,5-dihydro-1H-pyrrol-2-karboksamid,
for fremstilling av et medikament for behandling eller profylakse av fysiologiske og/eller patofysiologiske tilstander valgt fra gruppen som består av
c)”kort-, middels- og/eller langtidsregulering av energibalanse, kort-, middelsog/eller langtidsregulering (stimulering og/eller inhibering) av matinntak, behandling av adipogenese, adipositet, kroppsvektøkning og/eller reduksjon” hos pattedyr som medieres av GHS-reseptorer, hvor behandlingen oppnås ved modulering av GHS-reseptorer og hvor forbindelsen er en GHS reseptor antagonist; eller
d) ”vekstretardasjon, kakeksi, inflammasjon, inflammatoriske effekter, gastrisk postoperativ ileus, postoperativ ileus og/eller gastrektomi (ghrelinerstatningsbehandling)” hos pattedyr som medieres av GHS-reseptorer, hvor behandlingen oppnås ved en GHS-reseptorer agonist.
2.
Anvendelse ifølge krav 1, hvor GHS-reseptorantagonisten er valgt fra gruppen som består av: forbindelse 1, 3, 12, 13, 14, 18, 20, 22, 23, 33, 36, 37, 38, 41, 46, 47, 48, 49, 50, 51, 52, 53, 57, 58, 59, 60, 61, 63, 64, 65, 66, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 79, 80, 82, 85, 86, 87, 88, 89, 90, 91, 93, 101, 102, 109, 114, 116, 119, 134, 135, 136, 137, 138, 139, 140, 145, 146, 147, 148, 150, 152, 153, 154, 156, 157, 159, 160, 161, 164, 171, 174, 176, 178, 179, 182, 184, 186, 188 og/eller forbindelse 190.
3.
Anvendelse ifølge krav 1, hvor GHS-reseptorantagonisten er valgt fra gruppen som består av: forbindelse 2, 4, 5, 6, 7, 8, 9, 10, 11, 15, 16, 17, 19, 21, 24, 25, 26, 27, 28, 29, 30, 31, 32, 34, 39, 40, 42, 43, 44, 45, 54, 55, 56, 62, 67, 78, 81, 83, 84, 87, 92, 94, 99, 103, 104, 105, 106, 107, 108, 110, 111, 115, 117, 118, 121, 122, 124, 130, 131, 142, 155, 158, 163, 173, 175, 180, 181, 183, 185 og/eller forbindelse 187.
4.
Anvendelse ifølge et hvilket som helst av kravene 1 til 3, hvor et slikt medikament omfatter minst en ytterligere farmakologisk substans.
5.
Anvendelse ifølge krav 4, hvor slikt medikament innbefatter en GHS-reseptorantagonist og en endokannabinoidreseptorantagonist, rimonabant[1H-pyrazol-3-karboksamid, 5-(4-klorfenyl)-1-(2,4-diklorfenyl)-4-metyl-N-1-piperidinyl-, monohydroklorid], som ytterligere farmakologisk aktiv substans.
6.
Anvendelse ifølge et hvilket som helst av kravene 1 til 5, hvor medikamentet påføres før og/eller i løpet av og/eller etter behandling med minst en ytterligere farmakologisk aktiv substans.
7.
Anvendelse ifølge krav 6, hvor medikamentet innbefatter en GHS-reseptorantagonist og den ytterligere farmakologisk aktive substansen er en endokannabinoid reseptorantagonist, rimonabant[1H-pyrazol-3-karboksamid, 5-(4-klorfenyl)-1-(2,4-diklorfenyl)-4-metyl-N-1-piperidinyl-, monohydroklorid].
8.
Triazolforbindelse, k a r a k t e r i s e r t v e d at den er valgt fra gruppen som består av:
forbindelse 1 (R)-N-(1-(5-(2-(1H-indol-3-yl)etyl)-4-(2,4-dimetoksybenzyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid,
forbindelse 2 (R)-N-(1-(5-(2-(1H-indol-3-yl)etyl)-4-fenetyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid,
forbindelse 3 (R)-N-(1-(5-(3-(1H-indol-3-yl)propyl)-4-fenetyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid,
forbindelse 4 (R)-N-(1-(5-benzyl-4-(naftalen-1-ylmetyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid, forbindelse 5 (R)-N-(1-(5-(2-(1H-indol-3-yl)etyl)-4(naftalen-1-ylmetyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid,
forbindelse 6 (R)-N-(1-(5-(2-(1H-indol-3-yl)etyl)-4-(3-metoksybenzyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid,
forbindelse 7 (R)-N-(1-(4-(3-metoksybenzyl)-5-benzyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid,
forbindelse 8 (R)-N-(1-(5-(2-(1H-indol-3-yl)etyl)-4-benzyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid,
forbindelse 9 (R)-N-(1-(5-(3-(1H-indol-3-yl)propyl)-4-benzyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid,
forbindelse 10 (R)-N-(1-(5-(3-(1H-indol-3-yl)propyl}-4-(3-metoksybenzyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid,
forbindelse 11 (R)-N-(1-(5-(3-(1H-indol-3-yl)propyl)-4-(naftalen-1-ylmetyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid,
forbindelse 12 (R)-N-(1-(5-(2-(1H-indol-3-yl)etyl)-4-(4-metoksybenzyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid,
forbindelse 13 (R)-N-(1-(4-(4-metoksybenzyl)-5-benzyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid, forbindelse 14 (R)-N-(1-(5-(3-(1H-indol-3-yl)propyl)-4-(4-brombenzyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid,
forbindelse 15 (R)-N-(1-(5-(2-(1H-indol-3-yl)etyl)-4-heksyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid,
forbindelse 16 (R)-N-(1-(5-(3-(1H-indol-3-yl)propyl)-4-heksyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid,
forbindelse 17 (R)-N-(1-(4,5-bis-(2-(1H-indol-3-yl)etyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid,
forbindelse 18 (S)-N-(1-(5-(2-(1H-indol-3-yl)etyl)-4-(2,4-dimetoksybenzyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid,
forbindelse 19 (R)-N-(1-(4-(3-metoksybenzyl)-5-fenetyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid,
forbindelse 20 (R)-N-(1-(4-(4-metoksybenzyl)-5-fenetyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid,
forbindelse 21 (R)-N-(1-(5-(2-(1H-indol-3-yl)etyl)-4-(3,5-dimetoksybenzyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid,
forbindelse 22 (R)-N-(1-(4-(4-metoksybenzyl)-5-(3-fenylpropyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid,
forbindelse 23 (R)-N-(1-(5-(3-(1H-indol-3-yl)propyl)-4-(4-metoksybenzyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid,
forbindelse 24 (R)-N-(1-(4-(2-(1H-indol-3-yl)etyl)-5-(3-(1H-indol-3-yl)propyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid,
forbindelse 25 (R)-N-(1-(5-(2-(1H-indol-3-yl)etyl)-4-(2-metoksy)benzyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid,
forbindelse 26 (R)-N-(1-(4-(2-metoksybenzyl)-5-fenetyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid,
forbindelse 27 (R)-N-(2-(1H-indol-3-yl)-1-(4-(naftalen-1-ylmetyl)-5-fenetyl-4H-1,2,4-triazol-3-yl)etyl)-2-amino-2-metylpropanamid,
forbindelse 28 (R)-N-(1-(5-(2-(1H-indol-3-yl)etyl)-4-(3,4-diklorbenzyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid,
forbindelse 29 (R)-N-(1-(5-(2-(1H-indol-3-yl)etyl)-4-(4-fluorbenzyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid,
forbindelse 30 (R)-N-(1-(4-(4-fluorbenzyl)-5-benzyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid,
forbindelse 31 (R)-N-(1-(5-(2-(1H-indol-3-yl)etyl)-4-(2,4-dimetoksybenzyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)piperidin-4-karboksamid,
forbindelse 32 (R)-N-(1-(5-(2-(1H-indol-3-yl)etyl)-4-(2,4-dimetoksybenzyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)piperidin-3-karboksamid,
forbindelse 33 (R)-N-(1-(4-(4-metylbenzyl)-5-(3-fenylpropyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid, forbindelse 34 (R)-N-(1-(5-(2-(1H-indol-3-yl)etyl)-4-(4-metylbenzyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid,
forbindelse 36 (R)-N-(1-(5-(2-(1H-indol-3-yl)etyl)-4-(2,4-dimetoksybenzyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)piperidin-2-karboksamid,
forbindelse 37 (R)-N-(1-(4-(4-metylbenzyl)-5-fenetyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid,
forbindelse 38 (R)-N-(1-(5-(2-(1H-indol-3-yl)etyl)-4-(2,4-dimetoksybenzyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-aminobenzamid,
forbindelse 39 (R)-N-(1-(5-benzyl-4-(pyndin-2-ylmetyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid,
forbindelse 40 (2S,4R)-N((R)-1-(4-(4-metoksybenzyl)-5-fenetyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-4-hydroksypyrrolidin-2-karboksamid,
forbindelse 41 (S)-N-((R)-1-(4-(4-metoksybenzyl)-5-fenyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)piperidin-3-karboksamid,
forbindelse 42 (R)-N-((R)-1-(4-(4-metoksybenzyl)-5-fenetyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)piperidin-3-karboksamid,
forbindelse 43 (R)-N-(1-(4-(4-etylbenzyl)-5-fenetyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid,
forbindelse 44 (R)-N-(1-(4-(4-metoksybenzyl)-5-fenetyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)piperidin-4-karboksamid,
forbindelse 45 (R)-N-(1-(5-(2-(1H-indol-3-yl)etyl)-4-(4-metoksybenzyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)piperidin-4-karboksamid,
forbindelse 46 (S)-N-((R)-1-(4-(4-metoksybenzyl)-5-fenetyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)pyrrolidin-2-karboksamid,
forbindelse 47 (R)-N-((R)-1-(4-(4-metoksybenzyl)-5-fenetyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)pyrrolidin-2-karboksamid,
forbindelse 48 (S)-N-((R)-1-(4-(4-metoksybenzyl)-5-fenetyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)piperidin-2-karboksamid,
forbindelse 49 (R)-N-((R)-1-(4-(4-metoksybenzyl)-5-fenetyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)piperidin-2-karboksamid,
forbindelse 50 (R)-N-(1-(4-(4-metoksybenzyl)-5-fenetyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-aminoacetamid,
forbindelse 51 (R)-N-(1-(4-(4-metoksybenzyl)-5-fenetyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-(pyridin-2-yl)acetamid,
forbindelse 52 (R)-N-(1-(4-(4-metoksybenzyl)-5-fenetyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-(pyridin-4-yl)acetamid,
forbindelse 53 (R)-N-(1-(4-(4-metoksybenzyl)-5-fenetyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)sykloheksankarboksamid,
forbindelse 54 (R)-N-(1-(5-(2-(1H-indol-3-yl)etyl)-4-benzyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)piperidin-4-karboksamid,
forbindelse 55 (R)-N-(1-(5-(2-(1H-indol-3-yl)etyl)-4-benzyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)piperidin-3-karboksamid,
forbindelse 56 (R)-N-(1-(4-(4-metoksybenzyl-5-fenetyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-3-aminopropanamid,
forbindelse 57 (S)-N-((R)-1-(4-(4-metoksybenzyl)-5-fenetyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-aminopropanamid,
forbindelse 58 (R)-N-(1-(4-(4-metoksybenzyl)-5-fenetyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-(pyridin-3-yl)acetamid,
forbindelse 59 (R)-N-(1-(4-(4-metoksybenzyl)-5-fenetyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-3-(pyridin-3-yl)propanamid,
forbindelse 60 (R)-N-(1-(5-(2-(1H-indol-3-yl)etyl)-4-benzyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-(pyridin-2-yl)acetamid,
forbindelse 61 (R)-N-(1-(5-(2-(1H-indol-3-yl)etyl)-4-(2,4-dimetoksybenzyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-(pyridin-2-yl)acetamid,
forbindelse 62 (R)-N-(1-(4-(2,4-dimetoksybenzyl)-5-fenetyl-4H-1,2,4-triazol-3-yl-2-(1H-indol-3-yl)etyl)piperidin-4-karboksamid,
forbindelse 63 (R)-N-((R)-1-(4-(2,4-dimetoksybenzyl)-5-fenetyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)piperidin-2-karboksamid,
forbindelse 64 (R)-N-(1-(4-(2,4-dimetoksybenzyl)-5-fenetyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)pikolinamid,
forbindelse 65 (R)-N-(1-(4-(2,4-dimetoksybenzyl)-5-fenetyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)isonikotinamid,
forbindelse 66 (R)-N-(1-(4-(2,4-dimetoksybenzyl)-5-fenetyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)pyrazin-2-karboksamid,
forbindelse 67 (R)-N-1-(4-(2,4-dimetoksybenzyl)-5-fenetyl-4H-1,2,4-triazol-3-yl)-1H-indol-3-yl)etyl)piperazin-2-karboksamid,
forbindelse 68 (S)-N-((R)-1-(4-(2,4-dimetoksybenzyl)-5-fenyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)pyrrolidin-2-karboksamid, forbindelse 69 (R)-N-(1-(5-(2-(1H-indol-3-yl)etyl)-4-(2,4-dimetoksybenzyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-aminoacetamid,
forbindelse 70 (S)-N-((R)-1-(5-(2-(1H-indol-3-yl)etyl)-4-(2,4-dimetoksybenzyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)pyrrolidin-2-karboksamid,
forbindelse 71 (R)-N-(1-(5-(2-(1H-indol-3-yl)etyl)-4-(2,4-dimetoksybenzyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)pyrazin-2-karboksamid,
forbindelse 72 (R)-N-1-(5-(2-(1H-indol-3-yl)etyl)-4-(2,4-dimetoksybenzyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)piperazin-2-karboksamid,
forbindelse 73 (R)-N-(1-(5-(2-(1H-indol-3-yl)etyl)-4-(2,4-dimetoksybenzyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)pikolinamid,
forbindelse 74 (R)-1-(5-(2-(1H-indol-3-yl)etyl)-4-(2,4-dimetoksybenzyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etanamin,
forbindelse 75 (R)-N-(1-(4-(2,4-dimetoksybenzyl)-5-fenetyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-aminoacetamid,
forbindelse 76 (R)-N-(1-(4-(4-metoksybenzyl)-5-fenetyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)pyrazin-2-karboksamid,
forbindelse 77 (R)-N-(1-(4-(4-metoksybenzyl)-5-fenetyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)isonikotinamid,
forbindelse 78 (R)-N-1-(4-(4-metoksybenzyl)-5-fenetyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)piperazin-2-karboksamid,
forbindelse 79 (R)-N-1-(4-(4-metoksybenzyl)-5-fenetyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)pikolinamid,
forbindelse 80 (R)-N-(1-(5-(2-(1H-indol-3-yl)etyl)-4-(4-metoksybenzyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)pikolinamid,
forbindelse 81 (R)-N-1-(5-(2-(1H-indol-3-yl)etyl)-4-(4-metoksybenzyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)piperazin-2-karboksamid,
forbindelse 82 (R)-N-1-(4-(4-etylbenzyl)-5-fenetyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-(pyridin-2-yl)acetamid,
forbindelse 83 (R)-N-(1-(4-(4-etylbenzyl)-5-fenetyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)piperidin-4-karboksamid,
forbindelse 84 (R)-N-1-(4-(4-etylbenzyl)-5-fenetyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)piperazin-2-karboksamid,
forbindelse 85 (R)-N-(1-(4-(4-etylbenzyl)-5-fenetyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)pyrazin-2-karboksamid,
forbindelse 86 (R)-N-(1-(5-(2-(1H-indol-3-yl)etyl)-4-(2,4-dimetoksybenzyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-cisaminosykloheksankarboksamid,
forbindelse 87 (S)-N-((R)-1-(5-(2-(1H-indol-3-yl)etyl)-4-(4-metoksybenzyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)piperidin-3-karboksamid,
forbindelse 88 (R)-N-((R)-1-(5-(2-(1H-indol-3-yl)etyl)-4-(4-metoksybenzyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)piperidin-2-karboksamid,
forbindelse 89 (S)-N-((R)-1-(5-(2-(1H-indol-3-yl)etyl)-4-(4-metoksybenzyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)pyrrolidin-2-karboksamid,
forbindelse 90 (R)-N-((R)-1-(5-(2-(1H-indol-3-yl)etyl)-4-(4-metoksybenzyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)pyrrolidin-2-karboksamid,
forbindelse 91 (R)-N-(1-(5-(2-(1H-indol-3-yl)etyl)-4-(4-metoksybenzyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-(pyridin-2-yl)-acetamid,
forbindelse 92 (R)-N-(1-(5-(2-(1H-indol-3-yl)etyl)-4-(4-brombenzyl}-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid,
forbindelse 93 (R)-N-(1-(5-(2-(1H-indol-3-yl)etyl)-4-(4-metoksybenzyl)-4H-1,2,4-triazol-3-yl)-2-fenyletyl)-2-amino-2-metylpropanamid,
forbindelse 94 (R)-N-(2-(1H-indol-3-yl)-1-(5-fenetyl-4-(tiofen-2-ylmetyl)-4H-1,2,4-triazol-3-yl)etyl)piperidin-4-karboksamid,
forbindelse 95 (R)-N-(1-(4-(2-(1H-indol-3-yl)etyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid,
forbindelse 96 (R)-N-(1-(5-((1H-indol-3-yl)metyl)-4-metyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid,
forbindelse 97 (R)-N-(1-(5-(2-(1H-indol-3-yl)etyl)-4-metyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid,
forbindelse 98 (R)-N-(1-(5-((1H-indol-3-yl)metyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid,
forbindelse 99 (R)-N-(1-(5-((1H-indol-3-yl)metyl)-4-(2,4-dimetoksybenzyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid,
forbindelse 100 (R)-N-(1-(4-(2,4-dimetoksybenzyl)-5-metyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid, forbindelse 101 (R)-N-(1-(5-((1H-indol-3-yl)metyl)-4(4-metoksybenzyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid,
forbindelse 102 (R)-N-(1-(4-(2,4-dimetoksybenzyl)-5-benzyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid,
forbindelse 103 (R)-N-(1-(5-(3-(1H-indol-3-yl)propyl)-4-(2,4-dimetoksybenzyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid,
forbindelse 104 (R)-N-(1-(5-((1H-indol-3-yl)metyl)-4-fenetyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid,
forbindelse 105 (R)-N-(1-(5-benzyl-4-fenetyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid,
forbindelse 106 (R)-N-(1-(5-benzyl-4-(2,2-difenyletyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid,
forbindelse 107 (R)-N-(1-(5-(2-(1H-indol-3-yl)etyl)-4-(2,2-difenyletyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid,
forbindelse 108 (R)-N-(1-(4-(3,5-dimetoksybenzyl)-5-benzyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid,
forbindelse 109 (R)-N-(1-(4,5-dibenzyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid,
forbindelse 110 (R)-N-(1-(5-benzyl-4-heksyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid,
forbindelse 111 (R)-N-(1-(4-(2-(1H-indol-3-yl)etyl)-5-benzyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid, forbindelse 112 (S)-N-(1-(4-(2,4-dimetoksybenzyl)-5-benzyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid,
forbindelse 113 (R)-N-(1-(4-(3,5-dimetoksybenzyl)-5-fenetyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid,
forbindelse 114 (R)-N-(1-(4-(4-brombenzyl)-5-benzyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid,
forbindelse 115 (R)-N-1-(4-(2-metoksybenzyl)-5-benzyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid,
forbindelse 116 (S)-N-(1-(4-(2,4-dimetoksybenzyl)-5-fenetyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid,
forbindelse 117 (R)-N-(1-(4,5-difentyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid,
forbindelse 118 (R)-N-(1-(4-(3,4-diklorbenzyl)-5-benzyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid,
forbindelse 119 (R)-1-(5-(2-(1H-indol-3-yl)etyl)-4-(2,4-dimetoksybenzyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etanamin,
forbindelse 120 (R)-N-(1-(4-(4-metoksybenzyl)-5-benzyl-4H-1,2,4-triazol-3-yl)-2-fenyletyl)-2-amino-2-metylpropanamid,
forbindelse 121 (R)-N-(1-(4-(4-fluorbenzyl)-5-fenetyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid,
forbindelse 122 (R)-N-(1-(4-(3,4-diklorbenzyl)-5-fenetyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid,
forbindelse 124 (R)-N-(1-(4-(4-metylbenzyl)-5-benzyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid, forbindelse 125 (S)-N-(1-(4-(4-metoksybenzyl)-5-(3-fenylpropyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid,
forbindelse 126 (S)-N-(1-(4-(4-metoksybenzyl)-5-benzyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid,
forbindelse 128 N-((R)-1-(4-(4-nitrobenzyl)-5-fenetyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid,
forbindelse 129 (S)-N-(1-(4-(4-metoksybenzyl)-5-fenetyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid,
forbindelse 130 (R)-N-(1-(4-(4-metoksyfenetyl)-5-fenetyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid,
forbindelse 131 (R)-N-(2-(1H-indol-3-yl)-1-(5-fenetyl-4-(tiofen-2-ylmetyl)-4H-1,2,4-triazol-3-yl)etyl)-2-amino-2-metylpropanamid,
forbindelse 132 (R)-N-(2-(1H-indol-3-yl)-1-(5-fenetyl-4-(pyridin-2-ylmetyl)-4H-1,2,4-triazol-3-yl)etyl)-2-amino-2-metylpropanamid,
forbindelse 133 (R)-N-(2-(1H-indol-3-yl)-1-(5-fenetyl-4-(pyridin-2-ylmetyl)-4H-1,2,4-triazol-3-yl)etyl)piperidin-3-karboksamid,
forbindelse 134 (S)-N-((R)-1-(4-(4-etylbenzyl)-5-fenetyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)pyrrolidin-2-karboksamid,
forbindelse 135 N-((R)-1-(4-(4-etylbenzyl)-5-fenetyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-aminoacetamid,
forbindelse 136 N-((R)-1-(5-(2-(1H-indol-3-yl)etyl)-4-(4-metoksybenzyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-(pyridin-4-yl)-acetamid,
forbindelse 137 (2R)-N-((R)-1-(4-(4-etylbenzyl)-5-fenetyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)piperidin-2-karboksamid,
forbindelse 138 N-((R)-1-(4-(4-etylbenzyl)-5-fenetyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)pikolinamid,
forbindelse 139 N-((R)-1-(4-(4-etylbenzyl)-5-fenetyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-aminopyridin-3-karboksamid,
forbindelse 140 (2S)-N-((R)-1-(4-(4-etylbenzyl)-5-fenetyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-aminopropanamid,
forbindelse 141 N-((R)-1-(4-(4-etylbenzyl)-5-fenetyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)isonikotinamid,
forbindelse 142 N-((R)-2-(1H-indol-3-yl)-1-(5-fenetyl-4-fenyl-4H-1,2,4-triazol-3-yl)etyl)piperidin-4-karboksamid,
forbindelse 143 (2S)-N-((R)-2-(1H-indol-3-yl)-1-(5-fenetyl-4-fenyl-4H-1,2,4-triazol-3-yl)etyl)pyrrolidin-2-karboksamid,
forbindelse 144 N-((R)-2-(1H-indol-3-yl)-1-(5-fenetyl-4-fenyl-4H-1,2,4-triazol-3-yl)etyl)-2-aminoacetamid,
forbindelse 145 N-((R)-2-(1H-indol-3-yl)-1-(5-fenetyl-4-fenyl-4H-1,2,4-triazol-3-yl)etyl)-2-(pyridin-2-yl)acetamid,
forbindelse 146 N-((R)-2-(1H-indol-3-yl)-1-(5-fenetyl-4-fenyl-4H-1,2,4-triazol-3-yl)etyl)pikolinamid,
forbindelse 147 N-((R)-1-(5-(2-(1H-indol-3-yl)etyl)-4-(4-etylfenyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)pikolinamid,
forbindelse 148 N-((R)-1-(5-(2-(1H-indol-3-yl)etyl)-4-(4-etylfenyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-(pyridin-2-yl)acetamid, forbindelse 149 N-((R)-1-(5-(2-(1H-indol-3-yl)etyl)-4-(4-etylfenyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-aminoacetamid,
forbindelse 150 (2S)-N-((R)-1-(5-(2-(1H-indol-3-yl)etyl)-4-(4-etylfenyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)pyrrolidin-2-karboksamid,
forbindelse 152 N-((R)-1-(5-(2-(1H-indol-3-yl)etyl)-4-(4-metoksybenzyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-aminoacetamid,
forbindelse 153 N-((R)-1-(4-(4-metoksybenzyl)-5-fenetyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-trans-aminosykloheksankarboksamid,
forbindelse 154 N-((R)-1-(4-(4-etylbenzyl)-5-fenetyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-(pyridin-3-yl)acetamid,
forbindelse 155 (3S)-N-((R)-1-(4-(4-etylbenzyl)-5-fenetyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)piperidin-3-karboksamid,
forbindelse 156 N-((R)-1-(4-(4-etylbenzyl)-5-fenetyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-aminobenzamid,
forbindelse 157 N-((R)-1-(5-(2-(1H-indol-3-yl)etyl)-4-fenyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)pikolinamid,
forbindelse 158 N-((R)-1-(5-(2-(1H-indol-3-yl)etyl)-4-fenyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)piperidin-4-karboksamid,
forbindelse 159 N-((R)-2-(1H-indol-3-yl)-1-(4-(2,4-dimetoksyfenyl)-5-fenetyl-4H-1,2,4-triazol-3-yl)etyl)pikolinamid,
forbindelse 160 N-((R)-2-(1H-indol-3-yl)-1-(4-(2,4-dimetoksyfenyl)-5-fenetyl-4H-1,2,4-triazol-3-yl)etyl)-2-(pyridin-2-yl)acetamid, forbindelse 161 N-((R)-2-(1H-indol-3-yl)-1-(4-(2,4-dimetoksyfenyl)-5-fenetyl-4H-1,2,4-triazol-3-yl)etyl)pyrazin-2-karboksamid,
forbindelse 162 N-((R)-2-(1H-indol-3-yl)-1-(4-(2,4-dimetoksyfenyl)-5-fenetyl-4H-1,2,4-triazol-3-yl)etyl)-2-aminoacetamid,
forbindelse 163 N-((R)-2-(1H-indol-3-yl)-1-(4-(2,4-dimetoksyfenyl)-5-fenetyl-4H-1,2,4-triazol-3-yl)etyl)piperidin-4-karboksamid,
forbindelse 164 N-((R)-1-(5-benzyl-4-((pyridin-2-yl)metyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)pikolinamid,
forbindelse 165 N-((R)-1-(5-benzyl-4-((pyridin-2-yl)metyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-aminoacetamid,
forbindelse 166 N-((R)-1-(5-benzyl-4-((pyridin-2-yl)metyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)piperidin-4-karboksamid,
forbindelse 167 N-((R)-1-(5-benzyl-4-((pyridin-4-yl)metyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid,
forbindelse 168 N-((R)-1-(5-(4-metoksybenzyl)-4-fenetyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid,
forbindelse 169 N-((R)-1-(5-benzyl-4-((pyridin-4-yl)metyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)pikolinamid,
forbindelse 170 N-((R)-1-(5-benzyl-4-((pyridin-4-yl)metyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-acetamid,
forbindelse 171 (R)-benzyl-3-(2-aminoisobutyramido)-3-(5-(2-(1H-indol-3-yl)etyl)-4-(4-metoksybenzyl)-4H-1,2,4-triazol-3-yl)-propanoat,
forbindelse 172 N-((R)-1-(5-benzyl-4-((pyridin-3-yl)metyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid, forbindelse 173 N-((R)-1-(4-benzyl-5-fenetyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid,
forbindelse 174 N-((R)-2-(1H-indol-3-yl)-1-(4-metyl-5-fenetyl-4H-1,2,4-triazol-3-yl)etyl)pikolinamid,
forbindelse 175 N-((R)-1-(5-(2-(1H-indol-3-yl)etyl)-4-fenyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid,
forbindelse 176 N-((R)-1-(4-(4-metoksybenzyl)-5-fenetyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)benzamid,
forbindelse 177 (R)-1-(4-(2,4-dimetoksybenzyl)-5-fenetyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)-N-fenylmetansulfonylamin,
forbindelse 178 (R)-1-(4-(2,4-dimetoksybenzyl)-5-fenetyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)-N-tosyletanamin,
forbindelse 179 N-((R)-1-(4-(2,4-dimetoksybenzyl)-5-fenetyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid,
forbindelse 180 N-1-((R)-1-(4-(2,4-dimetoksybenzyl)-5-fenetyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)etan-1,2-diamin,
forbindelse 181 N-((R)-1-(4-((furan-2-yl)metyl)-5-fenetyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid,
forbindelse 182 N-((R)-1-(4-((furan-2-yl)metyl)-5-fenetyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)pikolinamid,
forbindelse 183 N-((R)-1-(4-((furan-2-yl)metyl)-5-fenetyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)piperidin-4-karboksamid,
forbindelse 184 N-((R)-1-(4-(4-metoksybenzyl)-5-fenetyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-tetrahydro-2H-pyran-4-karboksamid, forbindelse 185 N-((R)-1-(5-((1H-indol-3-yl)metyl)-4-(3-metoksybenzyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-2-metylpropanamid,
forbindelse 186 (2S)-N-((R)-1-(4-(4-metoksybenzyl)-5-fenetyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2-amino-3-penylpropanamid,
forbindelse 187 (R)-1-(5-(2-(1H-indol-3-yl)etyl)-4-(2,4-dimetoksybenzyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)-N-tosyletanamin,
forbindelse 188 N-((R)-1-(4-(2,4-dimetoksybenzyl)-5-fenetyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-4-azidobenzamid,
forbindelse 189 N-benzyl-(R)-1-(4-(2,4-dimetoksybenzyl)-5-fenetyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etanamin,
forbindelse 190 (2S)-N-((R)-1-(5-(2-(1H-indol-3-yl)etyl)-4-(4-metoksybenzyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)etyl)-2,5-dihydro-1H-pyrrol-2-karboksamid.
9.
Farmasøytisk sammensetning, k a r a k t e r i s e r t v e d at den innbefatter en farmakologisk aktiv mengde av minst en forbindelse ifølge krav 8.
10.
Farmasøytisk sammensetning ifølge krav 9, k a r a k t e r i s e r t v e d at den aktive ingrediensen er til stede i en enhetsdose på fra 0,001 mg til 100 mg per kg av pasientens kroppsvekt.
11.
Farmasøytisk sammensetning ifølge et hvilket som helst av kravene 9 til 10,
k a r a k t e r i s e r t v e d at sammensetningen i tillegg innbefatter minst en farmasøytisk akseptabel bærer og/eller eksipient.
12.
Farmasøytisk sammensetning ifølge et hvilket som helst av kravene 9 til 11, k a r a k t e r i s e r t v e d at sammensetningen innbefatter minst en ytterligere farmakologisk aktiv substans.
13.
Farmasøytisk sammensetning ifølge krav 12, k a r a k t e r i s e r t v e d at den ytterligere farmakologisk aktive substansen er en endokannabinoidreseptorantagonist, rimonabant [1H-pyrazol-3-karboksamid, 5-(4-klorfenyl)-1-(2,4-diklorfenyl)-4-metyl-N-1-piperidinyl-, monohydroklorid].
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EP05017732A EP1757290A1 (en) | 2005-08-16 | 2005-08-16 | Novel triazole derivatives as ghrelin analogue ligands of growth hormone secretagogue receptors |
US78754306P | 2006-03-31 | 2006-03-31 | |
PCT/EP2006/007945 WO2007020013A2 (en) | 2005-08-15 | 2006-08-11 | Novel triazole derivatives as ghrelin analogue ligands of growth hormone secretagogue receptors |
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WO2000054729A2 (en) * | 1999-03-12 | 2000-09-21 | Bristol-Myers Squibb Company | Heterocyclic aromatic compounds useful as growth hormone secretagogues |
WO2001036395A1 (en) * | 1999-11-15 | 2001-05-25 | Janssen Pharmaceutica N.V. | Triazoles as farnesyl transferase inhibitors |
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WO2000054729A2 (en) * | 1999-03-12 | 2000-09-21 | Bristol-Myers Squibb Company | Heterocyclic aromatic compounds useful as growth hormone secretagogues |
WO2001036395A1 (en) * | 1999-11-15 | 2001-05-25 | Janssen Pharmaceutica N.V. | Triazoles as farnesyl transferase inhibitors |
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