ITFI980186A1 - MONOCYCLIC COMPOUNDS WITH NK-2 ANTAGONIST ACTION AND FORMULATIONS THAT CONTAIN THEM - Google Patents
MONOCYCLIC COMPOUNDS WITH NK-2 ANTAGONIST ACTION AND FORMULATIONS THAT CONTAIN THEM Download PDFInfo
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- ITFI980186A1 ITFI980186A1 IT98FI000186A ITFI980186A ITFI980186A1 IT FI980186 A1 ITFI980186 A1 IT FI980186A1 IT 98FI000186 A IT98FI000186 A IT 98FI000186A IT FI980186 A ITFI980186 A IT FI980186A IT FI980186 A1 ITFI980186 A1 IT FI980186A1
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- 150000001875 compounds Chemical class 0.000 title claims description 89
- 239000000203 mixture Substances 0.000 title claims description 25
- 239000002746 neurokinin 2 receptor antagonist Substances 0.000 title claims description 3
- 230000009471 action Effects 0.000 title description 3
- -1 pyrrolidyl Chemical group 0.000 claims description 60
- 125000001424 substituent group Chemical group 0.000 claims description 43
- 229910052739 hydrogen Inorganic materials 0.000 claims description 35
- 125000000217 alkyl group Chemical group 0.000 claims description 31
- 239000001257 hydrogen Substances 0.000 claims description 27
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 21
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 19
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 18
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 17
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 16
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 claims description 16
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 claims description 16
- 238000000034 method Methods 0.000 claims description 16
- 125000002252 acyl group Chemical group 0.000 claims description 14
- 235000001014 amino acid Nutrition 0.000 claims description 14
- 229910052757 nitrogen Inorganic materials 0.000 claims description 14
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 14
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 13
- 150000001413 amino acids Chemical class 0.000 claims description 13
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 13
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 12
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims description 12
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 12
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 12
- 229910052731 fluorine Inorganic materials 0.000 claims description 12
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 12
- 229910052801 chlorine Inorganic materials 0.000 claims description 11
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 10
- 239000005557 antagonist Substances 0.000 claims description 9
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 9
- FCEHBMOGCRZNNI-UHFFFAOYSA-N 1-benzothiophene Chemical compound C1=CC=C2SC=CC2=C1 FCEHBMOGCRZNNI-UHFFFAOYSA-N 0.000 claims description 8
- ZRALSGWEFCBTJO-UHFFFAOYSA-N Guanidine Chemical compound NC(N)=N ZRALSGWEFCBTJO-UHFFFAOYSA-N 0.000 claims description 8
- 229910003204 NH2 Inorganic materials 0.000 claims description 8
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 claims description 8
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 claims description 8
- 102000003141 Tachykinin Human genes 0.000 claims description 8
- IOJUPLGTWVMSFF-UHFFFAOYSA-N benzothiazole Chemical compound C1=CC=C2SC=NC2=C1 IOJUPLGTWVMSFF-UHFFFAOYSA-N 0.000 claims description 8
- 125000002795 guanidino group Chemical group C(N)(=N)N* 0.000 claims description 8
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 claims description 8
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 claims description 8
- 108060008037 tachykinin Proteins 0.000 claims description 8
- 229930192474 thiophene Natural products 0.000 claims description 8
- 125000003545 alkoxy group Chemical group 0.000 claims description 7
- 125000001188 haloalkyl group Chemical group 0.000 claims description 7
- 229910052736 halogen Inorganic materials 0.000 claims description 7
- 150000002367 halogens Chemical class 0.000 claims description 7
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 claims description 7
- QIVBCDIJIAJPQS-VIFPVBQESA-N L-tryptophane Chemical compound C1=CC=C2C(C[C@H](N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-VIFPVBQESA-N 0.000 claims description 6
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 claims description 6
- KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Chemical compound C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 claims description 6
- QIVBCDIJIAJPQS-UHFFFAOYSA-N Tryptophan Natural products C1=CC=C2C(CC(N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-UHFFFAOYSA-N 0.000 claims description 6
- 125000003118 aryl group Chemical group 0.000 claims description 6
- 229910052794 bromium Inorganic materials 0.000 claims description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 6
- 239000008194 pharmaceutical composition Substances 0.000 claims description 6
- ZFXYFBGIUFBOJW-UHFFFAOYSA-N theophylline Chemical compound O=C1N(C)C(=O)N(C)C2=C1NC=N2 ZFXYFBGIUFBOJW-UHFFFAOYSA-N 0.000 claims description 6
- 125000002088 tosyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])S(*)(=O)=O 0.000 claims description 6
- 206010011224 Cough Diseases 0.000 claims description 5
- 206010017999 Gastrointestinal pain Diseases 0.000 claims description 5
- 208000007101 Muscle Cramp Diseases 0.000 claims description 5
- 206010038419 Renal colic Diseases 0.000 claims description 5
- 206010038731 Respiratory tract irritation Diseases 0.000 claims description 5
- 208000005392 Spasm Diseases 0.000 claims description 5
- 125000002431 aminoalkoxy group Chemical group 0.000 claims description 5
- 208000006673 asthma Diseases 0.000 claims description 5
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 5
- 239000004044 bronchoconstricting agent Substances 0.000 claims description 5
- 230000002741 bronchospastic effect Effects 0.000 claims description 5
- 201000003146 cystitis Diseases 0.000 claims description 5
- 208000015181 infectious disease Diseases 0.000 claims description 5
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 5
- 235000008729 phenylalanine Nutrition 0.000 claims description 5
- 238000002360 preparation method Methods 0.000 claims description 5
- JAAIPIWKKXCNOC-UHFFFAOYSA-N 1h-tetrazol-1-ium-5-thiolate Chemical compound SC1=NN=NN1 JAAIPIWKKXCNOC-UHFFFAOYSA-N 0.000 claims description 4
- CHJJGSNFBQVOTG-UHFFFAOYSA-N N-methyl-guanidine Natural products CNC(N)=N CHJJGSNFBQVOTG-UHFFFAOYSA-N 0.000 claims description 4
- PCNDJXKNXGMECE-UHFFFAOYSA-N Phenazine Natural products C1=CC=CC2=NC3=CC=CC=C3N=C21 PCNDJXKNXGMECE-UHFFFAOYSA-N 0.000 claims description 4
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 claims description 4
- 239000002253 acid Substances 0.000 claims description 4
- RFRXIWQYSOIBDI-UHFFFAOYSA-N benzarone Chemical compound CCC=1OC2=CC=CC=C2C=1C(=O)C1=CC=C(O)C=C1 RFRXIWQYSOIBDI-UHFFFAOYSA-N 0.000 claims description 4
- 125000004122 cyclic group Chemical group 0.000 claims description 4
- SWSQBOPZIKWTGO-UHFFFAOYSA-N dimethylaminoamidine Natural products CN(C)C(N)=N SWSQBOPZIKWTGO-UHFFFAOYSA-N 0.000 claims description 4
- 125000004193 piperazinyl group Chemical group 0.000 claims description 4
- 125000005936 piperidyl group Chemical group 0.000 claims description 4
- PBMFSQRYOILNGV-UHFFFAOYSA-N pyridazine Chemical compound C1=CC=NN=C1 PBMFSQRYOILNGV-UHFFFAOYSA-N 0.000 claims description 4
- 150000003839 salts Chemical class 0.000 claims description 4
- 150000003536 tetrazoles Chemical class 0.000 claims description 4
- 210000000626 ureter Anatomy 0.000 claims description 4
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 claims description 3
- 101000600912 Homo sapiens Substance-K receptor Proteins 0.000 claims description 3
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 claims description 3
- 229930182830 galactose Natural products 0.000 claims description 3
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 3
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 claims description 3
- 229960000278 theophylline Drugs 0.000 claims description 3
- 125000000008 (C1-C10) alkyl group Chemical group 0.000 claims description 2
- VSIXIFOXMNNBAM-UHFFFAOYSA-N 4-pyrrolidin-1-ylmorpholine Chemical compound C1CCCN1N1CCOCC1 VSIXIFOXMNNBAM-UHFFFAOYSA-N 0.000 claims description 2
- HMFHBZSHGGEWLO-SOOFDHNKSA-N D-ribofuranose Chemical compound OC[C@H]1OC(O)[C@H](O)[C@@H]1O HMFHBZSHGGEWLO-SOOFDHNKSA-N 0.000 claims description 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 claims description 2
- PYMYPHUHKUWMLA-LMVFSUKVSA-N Ribose Natural products OC[C@@H](O)[C@@H](O)[C@@H](O)C=O PYMYPHUHKUWMLA-LMVFSUKVSA-N 0.000 claims description 2
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 2
- 125000005119 alkyl cycloalkyl group Chemical group 0.000 claims description 2
- HMFHBZSHGGEWLO-UHFFFAOYSA-N alpha-D-Furanose-Ribose Natural products OCC1OC(O)C(O)C1O HMFHBZSHGGEWLO-UHFFFAOYSA-N 0.000 claims description 2
- WQZGKKKJIJFFOK-PHYPRBDBSA-N alpha-D-galactose Chemical compound OC[C@H]1O[C@H](O)[C@H](O)[C@@H](O)[C@H]1O WQZGKKKJIJFFOK-PHYPRBDBSA-N 0.000 claims description 2
- PYMYPHUHKUWMLA-WDCZJNDASA-N arabinose Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)C=O PYMYPHUHKUWMLA-WDCZJNDASA-N 0.000 claims description 2
- PYMYPHUHKUWMLA-UHFFFAOYSA-N arabinose Natural products OCC(O)C(O)C(O)C=O PYMYPHUHKUWMLA-UHFFFAOYSA-N 0.000 claims description 2
- SRBFZHDQGSBBOR-UHFFFAOYSA-N beta-D-Pyranose-Lyxose Natural products OC1COC(O)C(O)C1O SRBFZHDQGSBBOR-UHFFFAOYSA-N 0.000 claims description 2
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 claims description 2
- 230000037396 body weight Effects 0.000 claims description 2
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 2
- 239000008103 glucose Substances 0.000 claims description 2
- 150000002402 hexoses Chemical class 0.000 claims description 2
- 150000007522 mineralic acids Chemical class 0.000 claims description 2
- BKIMMITUMNQMOS-UHFFFAOYSA-N nonane Chemical group CCCCCCCCC BKIMMITUMNQMOS-UHFFFAOYSA-N 0.000 claims description 2
- 150000002972 pentoses Chemical class 0.000 claims description 2
- 150000002994 phenylalanines Chemical class 0.000 claims description 2
- 125000004482 piperidin-4-yl group Chemical group N1CCC(CC1)* 0.000 claims description 2
- 125000003373 pyrazinyl group Chemical group 0.000 claims description 2
- 229910052717 sulfur Inorganic materials 0.000 claims description 2
- 125000004434 sulfur atom Chemical group 0.000 claims description 2
- HYZJCKYKOHLVJF-UHFFFAOYSA-N 1H-benzimidazole Chemical compound C1=CC=C2NC=NC2=C1 HYZJCKYKOHLVJF-UHFFFAOYSA-N 0.000 claims 2
- BKQQPCDQZZTLSE-UHFFFAOYSA-N 2-amino-3-naphthalen-1-ylpropanoic acid;hydrochloride Chemical compound Cl.C1=CC=C2C(CC(N)C(O)=O)=CC=CC2=C1 BKQQPCDQZZTLSE-UHFFFAOYSA-N 0.000 claims 1
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 claims 1
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 claims 1
- 235000004279 alanine Nutrition 0.000 claims 1
- 150000007524 organic acids Chemical class 0.000 claims 1
- 235000005985 organic acids Nutrition 0.000 claims 1
- 239000000546 pharmaceutical excipient Substances 0.000 claims 1
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 claims 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 71
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 65
- 229910001868 water Inorganic materials 0.000 description 47
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 46
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 46
- 229940126062 Compound A Drugs 0.000 description 42
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 description 42
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 41
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 34
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 29
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 29
- 238000005160 1H NMR spectroscopy Methods 0.000 description 28
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 27
- 239000002904 solvent Substances 0.000 description 27
- 239000000047 product Substances 0.000 description 25
- 239000000243 solution Substances 0.000 description 25
- 238000003756 stirring Methods 0.000 description 25
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 18
- 239000007787 solid Substances 0.000 description 18
- 150000002500 ions Chemical class 0.000 description 16
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 16
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 16
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 15
- 230000015572 biosynthetic process Effects 0.000 description 15
- 229910052938 sodium sulfate Inorganic materials 0.000 description 15
- 235000011152 sodium sulphate Nutrition 0.000 description 15
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 14
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 14
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 14
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 14
- 239000012074 organic phase Substances 0.000 description 14
- 238000002953 preparative HPLC Methods 0.000 description 14
- 239000012265 solid product Substances 0.000 description 14
- 238000003786 synthesis reaction Methods 0.000 description 14
- 239000012267 brine Substances 0.000 description 13
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 13
- 239000012071 phase Substances 0.000 description 12
- 229940024606 amino acid Drugs 0.000 description 11
- 238000004128 high performance liquid chromatography Methods 0.000 description 11
- 238000005303 weighing Methods 0.000 description 10
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 238000001704 evaporation Methods 0.000 description 9
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- 108010040722 Neurokinin-2 Receptors Proteins 0.000 description 8
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- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 7
- 230000008020 evaporation Effects 0.000 description 7
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- 125000004055 thiomethyl group Chemical group [H]SC([H])([H])* 0.000 description 7
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- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- 238000001035 drying Methods 0.000 description 6
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 5
- 229960000583 acetic acid Drugs 0.000 description 5
- 238000006243 chemical reaction Methods 0.000 description 5
- 239000011734 sodium Substances 0.000 description 5
- 229910052708 sodium Inorganic materials 0.000 description 5
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 4
- XXROGKLTLUQVRX-UHFFFAOYSA-N allyl alcohol Chemical compound OCC=C XXROGKLTLUQVRX-UHFFFAOYSA-N 0.000 description 4
- 239000012043 crude product Substances 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- 229910000343 potassium bisulfate Inorganic materials 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Substances C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 101000610640 Homo sapiens U4/U6 small nuclear ribonucleoprotein Prp3 Proteins 0.000 description 3
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 3
- 102400000097 Neurokinin A Human genes 0.000 description 3
- 101800000399 Neurokinin A Proteins 0.000 description 3
- 101001110823 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) 60S ribosomal protein L6-A Proteins 0.000 description 3
- 101000712176 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) 60S ribosomal protein L6-B Proteins 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 102100040374 U4/U6 small nuclear ribonucleoprotein Prp3 Human genes 0.000 description 3
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 3
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
- C07K7/04—Linear peptides containing only normal peptide links
- C07K7/22—Tachykinins, e.g. Eledoisins, Substance P; Related peptides
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- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
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- A61P1/06—Anti-spasmodics, e.g. drugs for colics, esophagic dyskinesia
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61P11/06—Antiasthmatics
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A—HUMAN NECESSITIES
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- A61P13/00—Drugs for disorders of the urinary system
- A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
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- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/02—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link
- C07K5/0202—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing the structure -NH-X-X-C(=0)-, X being an optionally substituted carbon atom or a heteroatom, e.g. beta-amino acids
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Animal Behavior & Ethology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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Description
Domanda di Brevetto per invenzione Industriale da! titolo: Patent Application for Industrial Invention from! title:
Composti monociclici ad azione NK-2 antagonista e formulazioni che li contengono. Monocyclic compounds with NK-2 antagonist action and formulations containing them.
Campo dell’ invenzione Field of invention
La presente invenzione si riferisce a nuovi composti aventi formula generale (I) The present invention refers to new compounds having general formula (I)
in cui in which
X1, X2, X3, X4 possono essere uguali o diversi tra loro e rappresentano un gruppo scelto tra -CONR-, -NRCO-, -CH2-NR-, -NR-CH2- ove R è H o un C1 -3 alchile o benzile; X1, X2, X3, X4 can be the same or different from each other and represent a group chosen from among -CONR-, -NRCO-, -CH2-NR-, -NR-CH2- where R is H or a C1 -3 alkyl or benzyl;
f, m, uguali o diversi tra loro, rappresentano un numero scelto tra 0, 1 o 2; f, m, the same or different from each other, represent a number chosen from 0, 1 or 2;
R1 ed R2, uguali o diversi tra loro, rappresentano un gruppo -(CH2)r -Ar dove r = 0, 1, 2 e dove Ar è un gruppo aromatico scelto tra benzene, naftalene, tiofene, benzotiofene, piridina, chinolina, indolo, furano, benzofurano, tiazolo, benzotiazolo, imidazolo, benzoimidazoio, eventualmente sostituito fino a 2 residui scelti tra. Ci-3 alchilici . o alogenoalchilici, C1-3 alcossilici, C2-4 ammino alcossilici, alogeni, OH, NH2, NR6R7, dove R6 ed R7 possono essere uguali o diversi e rappresentano un gruppo idrogeno o C1 -3 alchilico; R1 and R2, the same or different from each other, represent a group - (CH2) r -Ar where r = 0, 1, 2 and where Ar is an aromatic group chosen from benzene, naphthalene, thiophene, benzothiophene, pyridine, quinoline, indole , furan, benzofuran, thiazole, benzothiazole, imidazole, benzoimidazoium, possibly substituted up to 2 residues selected from among. C1-3 alkyls. or halogenalkyls, C1-3 alkoxyls, C2-4 amino alkoxyls, halogens, OH, NH2, NR6R7, where R6 and R7 can be the same or different and represent a hydrogen or C1 -3 alkyl group;
R3 rappresenta un gruppo scelto tra: R3 represents a group chosen from:
- idrogeno, - hydrogen,
- gruppi alchilici lineari o ramificati di formula CnH2n+1 con n = 1-5 , . gruppi cicloalchilici o alchilcicloalchilici di. formula CnH2n-1 con n = 5-9, - linear or branched alkyl groups of formula CnH2n + 1 with n = 1-5,. cycloalkyl or alkylcycloalkyl groups of. formula CnH2n-1 with n = 5-9,
- gruppi (CH2)r-Ari dove r = 0, 1, 2 e dove Ar1 è un gruppo aromatico scelto tra benzene, nafialene, tiofene, benzotiofene,· piridina, chinolina, indolo, furano, benzofurano, tiazolo, benzotiazolo, imidazolo, benzoimidazoio, eventualmente sostituito fino a 2 residui scelti tra C1 -3 alchilici o alogenoalchilici, C1-3 alcossilici o ammino alcossilici, alogeni, OH, NH2, NR6R7, dove R6 ed R7 possono essere uguali o diversi e rappresentano un gruppo idrogeno o C1 -3 alchilico; - r-Ari (CH2) groups where r = 0, 1, 2 and where Ar1 is an aromatic group chosen from benzene, naphialene, thiophene, benzothiophene, pyridine, quinoline, indole, furan, benzofuran, thiazole, benzothiazole, imidazole, benzoimidazoium, possibly substituted up to 2 residues selected from C1 -3 alkyl or halogenalkyl, C1-3 alkoxy or amino alkoxy, halogen, OH, NH2, NR6R7, where R6 and R7 can be the same or different and represent a hydrogen or C1 group - 3 alkyl;
uno dei gruppi R4 ed R5 è idrogeno mentre l'altro è scelto nel gruppo costituito da: one of the groups R4 and R5 is hydrogen while the other is chosen from the group consisting of:
- NR18SO2R8, dove R18 è un gruppo H oppure. un gruppo C1 -3 alchile ed Re rappresenta un gruppo C1 -3 alchile, fenile, fenile sostituito con un gruppo C1 -3 alchile, - NR18SO2R8, where R18 is an H group or. a C1 -3 alkyl group and Re represents a C1 -3 alkyl, phenyl, phenyl group substituted with a C1 -3 alkyl group,
- NR9R10, dove R9 ed R10, uguali 0 diversi<1 >tra loro, rappresentano un gruppo: idrogeno, tetraidropiranil, tetraidrotiopiranil eventualmente mono- o di-ossigenato sull'atomo di zolfo, pirrolidii, piperidil, pirrolidil eventualmente N-sostituito con un gruppo C1 -3 alchìle o C1 -3 acile, piperidil eventualmente N-sostituito con un gruppo C1 -3 alchìle o C1 -3 acile, (CH2)g-R11 in cui g può essere 1,2,3 ed R11 rappresenta un gruppo scelto fra CN, morfolina, pirrolidina, piperidina, piperazina, piperidine N-sostituite con C1 -3 alchili, piperazine N-sostituite con un gruppo C1 -3 alchile o C1 -3 acile o metansolfonile o tosile, o un eterociclo aromatico ;seelto fra furano, tiofene, piridina, pirrolo, indolo, tiazolo, oppure, R9 e R10 . uniti tra loro, formano, con l’atomo di azoto cui sono, legati, un anello piperazinico eventualmente sostituito sull'azoto in 4 con. un gruppo C1 -3 acile , metansolfonile o tosile, considerando che R9 ed R10 non possono essere contemporaneamente idrogeno, - NR9R10, where R9 and R10, equal or different <1> from each other, represent a group: hydrogen, tetrahydropyranil, tetrahydrothiopyranil possibly mono- or di-oxygenated on the sulfur atom, pyrrolidii, piperidyl, pyrrolidyl possibly N-substituted with a C1 -3 alkyl or C1 -3 acyl group, piperidyl possibly N-substituted with a C1 -3 alkyl or C1 -3 acyl group, (CH2) g-R11 in which g can be 1,2,3 and R11 represents a group selected from CN, morpholine, pyrrolidine, piperidine, piperazine, N-substituted piperidines with C1 -3 alkyls, N-substituted piperazines with a C1 -3 alkyl or C1 -3 acyl or methanesulfonyl or tosyl group, or an aromatic heterocycle; furan, thiophene, pyridine, pyrrole, indole, thiazole, or, R9 and R10. joined together, they form, with the nitrogen atom to which they are bonded, a piperazine ring possibly substituted on the nitrogen in 4 with. a C1 -3 acyl, methanesulfonyl or tosyl group, whereas R9 and R10 cannot be hydrogen simultaneously,
- N(R12)COR13 in cui R12 è idrogeno oppure un gruppo C1 -3 alchìle, ed R13 è scelto nel gruppo C1 -10 alchìle; fenile eventualmente sostituito fino a 3 gruppi uguali 0 diversi fra loro scelti fra OH, guanidino, CI, F, Br, NH2, OCH3; piridina eventualmente sostituita fino a 2 gruppi uguali o diversi fra loro scelti fra OH, guanidino,. CI, F, Br, NH2, OCH3; piridazina o pirazina eventualmente sostituite fino a 2 gruppi uguali o diversi fra loro scelti fra OH, guanidino, CI, F, Br, NH2, OCH3, o (CH2)h-R14 in cui h può essere 1,2,3 e R14 rappresenta un gruppo scelto . fra guanidina, morfolina, pirrolidina, piperidina, piperazina, piperazina N-sostituita con C1 -3 alchìle, teofillina, tetrazolo, 5-mercapto-tetrazolo, carbossimetilossi, - N (R12) COR13 wherein R12 is hydrogen or a C1 -3 alkyl group, and R13 is selected from the C1 -10 alkyl group; phenyl optionally substituted up to 3 equal O groups different from each other selected from OH, guanidino, Cl, F, Br, NH2, OCH3; pyridine optionally substituted up to 2 equal or different groups selected from among OH, guanidino ,. Cl, F, Br, NH2, OCH3; pyridazine or pyrazine optionally substituted up to 2 equal or different groups selected from among OH, guanidino, CI, F, Br, NH2, OCH3, or (CH2) h-R14 in which h can be 1,2,3 and R14 represents a chosen group. between guanidine, morpholine, pyrrolidine, piperidine, piperazine, N-substituted piperazine with C1 -3 alkyl, theophylline, tetrazole, 5-mercapto-tetrazole, carboxymethyloxy,
- CON(R15)2 in cui R15 rappresenta una catena alchilica C1 -6, lineare o ciclica, contenente uno o più gruppi polari scelti nel gruppo OH, NH2 - (CH2)q-S-R16 in cui q può essere 0,1,2 ed R16 rappresenta un gruppo mono o di-glicosidico eventualmente protetto con uno o più gruppi C1 -3 acilici o sostituito con gruppi amminici o C1 -3 acilamminici, oppure - CON (R15) 2 in which R15 represents a C1 -6 alkyl chain, linear or cyclic, containing one or more polar groups selected in the OH group, NH2 - (CH2) q-S-R16 in which q can be 0,1,2 and R16 represents a mono or di-glycosidic group optionally protected with one or more C1 -3 acyl groups or substituted with amino or C1 -3 acylamine groups, or
R4 ed R<5>, uguali ò diversi tra loro, rappresentano un gruppo OR17 in cui R17 è scelto fra H o un gruppo C2-3 acile. R4 and R <5>, equal or different from each other, represent an OR17 group in which R17 is selected from H or a C2-3 acyl group.
Considerata la presenza di centri chirali nei composti di formula (I), fanno parte della presente invenzione anche i singoli enantiomeri e le miscele di loro diasteroisomeri. Considering the presence of chiral centers in the compounds of formula (I), the single enantiomers and the mixtures of their diasteroisomers also form part of the present invention.
Stato dell'arte State of the art
Il recettore NK2 delle tachichinine è, largamente espresso nel sistema nervoso periferico dei mammiferi. Uno dei vari effetti prodotti dalia stimolazione selettiva del recettore NK2 è la contrazione delia muscolatura liscia. Quindi antagonisti del recettore NK2 possono essere considerati agenti capaci di controllare l eccessiva contrazione della muscolatura liscia in qualsiasi condizione patologica in cui il rilascio di tachichinine concorre alla genesi del corrispondente disturbo.. The NK2 receptor of tachykinins is widely expressed in the peripheral nervous system of mammals. One of the various effects produced by selective stimulation of the NK2 receptor is the contraction of smooth muscle. Therefore, NK2 receptor antagonists can be considered agents capable of controlling the excessive contraction of smooth muscle in any pathological condition in which the release of tachykinins contributes to the genesis of the corresponding disorder.
In particolare, la componente broncospastica dell' asma, della tosse, delle irritazioni polmonari, gli spasmi intestinali o gli spasmi locali della vescica e dell'uretere durante cistiti, infezioni e coliche renali possono essere considerate condizioni in cui la somministrazione di antagonisti NK2 può essere efficace (E. M. Kudlacz et al. Eur. j. Pharmacol., 1993 36, 17-25)· In particular, the bronchospastic component of asthma, cough, lung irritation, intestinal spasms or local spasms of the bladder and ureter during cystitis, infections and renal colic can be considered conditions in which the administration of NK2 antagonists can be effective (E. M. Kudlacz et al. Eur. j. Pharmacol., 1993 36, 17-25) ·
Composti ciclici, in particolare esapeptidi ciclici (A.T. McKriight et al. Br. J. Pharmacol. 1991., 104, 355) e biciclici (V. Pavone et al. WO 93/212227) o pseudopeptidi ciclici (L. Quartara et al. J. Med. Chem., 1994, 37, 3630; S. L. Harbeson et al. Peptides, Chemistry and Biology, Prpceedings of Twelth American Peptidè Symposium, 1992, 124) sono noti in letteratura per una elevata attività antagonista al recettore NK-2 delle. tachichinine. Cyclic compounds, in particular cyclic hexapeptides (A.T. McKriight et al. Br. J. Pharmacol. 1991., 104, 355) and bicyclic (V. Pavone et al. WO 93/212227) or cyclic pseudopeptides (L. Quartara et al. J. Med. Chem., 1994, 37, 3630; S. L. Harbeson et al. Peptides, Chemistry and Biology, Prpceedings of Twelth American Peptidè Symposium, 1992, 124) are known in the literature for a high antagonist activity to the NK-2 receptor of . tachykinins.
Sorprendentemente è stato ora trovato che prodotti a più . basso peso molecolare, monociclici, contenenti solamente quattro residui bifunzioriali legati tra loro con legame peptidico o pseudopeptidico, presentano attività farmacologica uguale o superiore a quella dei composti noti e soprattutto mostrano una notevole selettività per. il recettore NK-2 umano, per cui sono proposti-come valide alternative: Descrizione dettagliata dell' invenzióne . Surprisingly it has now been found that multiple products. low molecular weight, monocyclic, containing only four bifunctional residues linked together with peptide or pseudopeptide bond, have pharmacological activity equal to or greater than that of known compounds and above all show a remarkable selectivity for. the human NK-2 receptor, for which valid alternatives are proposed: Detailed description of the invention.
La presente invenzione si propone quindi di rendere disponibili nuovi composti monociclici, contenenti quattro residui legati fra loro con legame peptidico o pseudopeptidico, ad azione antagonista sul recettore NK2, di formula generale (I) come precedentemente definiti . Fanno parte della presente invenzione anche i sali farmaceuticamente accettabili, i processi per la loro preparazione e le composizioni farmaceutiche che li contengono. The present invention therefore proposes to make available new monocyclic compounds, containing four residues linked together with peptide or pseudopeptide bond, with antagonist action on the NK2 receptor, of general formula (I) as previously defined. The pharmaceutically acceptable salts, the processes for their preparation and the pharmaceutical compositions containing them also form part of the present invention.
Vista la presenza di centri chirali nei composti di formula (I), fanno parte della presente invenzione anche i singoli enantiomeri e le miscele di loro diasteroisomeri. Given the presence of chiral centers in the compounds of formula (I), the single enantiomers and the mixtures of their diasteroisomers also form part of the present invention.
Costituiscono composti preferiti dell' invenzione i compósti di formula generale (I) in cui: Preferred compounds of the invention are the compounds of general formula (I) in which:
f ed m, uguali o diversi tra loro, sono 0 od.1; . f and m, the same or different from each other, are 0 od.1; .
R è H o metile; R is H or methyl;
R1 ed R2, uguali o diversi tra loro, rappresentano: R1 and R2, the same or different from each other, represent:
- la catena laterale di un amminoacido naturale scelto fra triptofano; fenil alanina, tirosiria, . - the side chain of a natural amino acid selected from tryptophan; phenyl alanine, tyrosyria,.
-o la catena laterale di un ammino acido non naturale scelto nel gruppo: -or the side chain of a non-natural amino acid selected from the group:
triptofano e fenil alanine mono o disostituiti con residui scelti tra C1 -3 alchilici o aiogenoalchilicr. C1 -3 alcossilici o ammino alcossilici, alogeni, OH, NH2, NR6R7, dove R6 ed R7. possono essere uguali o diversTi e rappresentano un gruppo idrogeno o C1 -3 alchilico; alfanaftilalanina; beta-naftilafanina; tryptophan and mono or disubstituted phenyl alanines with residues selected from C1 -3 alkyl or aiogenic alkyl. C1 -3 alkoxy or amino alkoxy, halogen, OH, NH2, NR6R7, where R6 and R7. they can be the same or different and represent a hydrogen or C1 -3 alkyl group; alpha-naphtylalanine; beta-naphthylafanine;
R3 rappresenta un gruppo scelto tra: R3 represents a group chosen from:
- idrogeno - hydrogen
- gruppi alchilici lineari o ramificati di formula CnH2n+1 con n = 1-5, - gruppi CH2-Ar1 dove Ar1 è un gruppo aromatico scelto tra : alfa naftiie, beta naftile, fenile, fenile sostituiti fino a 2 residui scelti tra C1 -3 alchilici o alogenoalchilici, C1 -3 alcossilici, alogeni, OH, NH2, uno dei gruppi R4 ed R5 è idrogeno mentre l’altro e scelto nel gruppo costituito da: - linear or branched alkyl groups of formula CnH2n + 1 with n = 1-5, - CH2-Ar1 groups where Ar1 is an aromatic group chosen from: alpha naphthyia, beta naphthyl, phenyl, phenyl substituted up to 2 residues selected from C1 - 3 alkyl or halogen alkyl, C1 -3 alkoxy, halogen, OH, NH2, one of the R4 and R5 groups is hydrogen while the other is selected from the group consisting of:
- NR18SO2R8, dove R18 è scelto fra H o metile ed R8 rappresenta un gruppo metile, fenile, tolile - NR18SO2R8, where R18 is selected from H or methyl and R8 represents a methyl, phenyl, tolyl group
- NR9R10, dove R9 ed R10 possono essere uguali o diversi e rappresentano un gruppo idrogeno, tetraidropiran-4-il , tetraidrotiopiran-4-il, 1-oGsido-tetraidrotiopiran-4-il, 1 , 1 -diossidotetraidrotiopiran-4-il, piperidin-4-il, N-metil-piperidin-4-il, (CH2)g-Rl 1 in cui g può essere 1 o 2 e R-] 1 rappresenta un gruppo scelto fra CN, morfolino, pirrolidina, piperidina, piperazina, piperidine N-sostituite con , C1 -3 alchili, piperazine N-sostituite con un gruppo C1 -3 alchile o C1 -3 acile o metansolfonile o tosile, o un eteróciclo aromatico scelto fra furano, tiofene, pirrolo; indolo; oppure R9 e R10 uniti fra loro, formano, con l’atomo di azoto cui sono legati, un anello piperazinico eventualmente sostituito sull' azoto in 4 con un gruppo metansòlfonilè, considerando che R9 ed R10 non possono essere contemporaneamente idrogeno; - NR9R10, where R9 and R10 can be the same or different and represent a hydrogen group, tetrahydropyran-4-yl, tetrahydrothiopyran-4-yl, 1-oGsido-tetrahydrothiopyran-4-yl, 1, 1-dioxydotetrahydrothiopyran-4-yl, piperidin-4-yl, N-methyl-piperidin-4-yl, (CH2) g-Rl 1 in which g can be 1 or 2 and R-] 1 represents a group selected from CN, morpholino, pyrrolidine, piperidine, piperazine , N-substituted piperidines with, C1 -3 alkyls, N-substituted piperazines with a C1 -3 alkyl or C1 -3 acyl or methanesulfonyl or tosyl group, or an aromatic heterocycle selected from furan, thiophene, pyrrole; indole; or R9 and R10 joined together, form, with the nitrogen atom to which they are linked, a piperazine ring possibly substituted on the nitrogen in 4 with a methanesolphonilè group, considering that R9 and R10 cannot be hydrogen at the same time;
- N(R12)COR13 in cui R12 è idrogeno oppure un gruppo C1 -3 alchile, ed Ri 3 è scelto nel gruppo nonano; fenile;eventùalmente sostituito fino a 3 gruppi uguali o diversi fra loro scelti fra OH, guanidino, CI, F; piridina eventualmente sostituita fino a 2 gruppi uguali o diversi fra loro scelti fra OH, CI, F; piridazina o pirazina eventualmente sostituite con un gruppo scelio fra OH, CI, F, NH2; o (CH2)-R14 in cui R14 rappresenta un gruppo scelto fra guanidina, morfoiina, teofillina, tetrazolo, 5-mercapto-tetrazolo, carbossimetilossi; - N (R12) COR13 wherein R12 is hydrogen or a C1 -3 alkyl group, and Ri 3 is selected from the nonane group; phenyl; optionally substituted up to 3 equal or different groups selected from among OH, guanidino, Cl, F; pyridine optionally substituted up to 2 equal or different groups selected from among OH, Cl, F; pyridazine or pyrazine optionally substituted with a group chosen from OH, Cl, F, NH2; or (CH2) -R14 wherein R14 represents a group selected from guanidine, morphoin, theophylline, tetrazole, 5-mercapto-tetrazole, carboxymethyloxy;
- CON( R15)2 in cui R15 rappresenta un gruppo idrossietile - CON (R15) 2 wherein R15 represents a hydroxyethyl group
- (CH2)-S- R16 in cui R16 rappresenta un gruppo mono glicosidico scelto nella serie dei D o L pentosi o esosi quali ribosio, arabinosio, glucosio, galattosio; - (CH2) -S-R16 in which R16 represents a mono glycosidic group selected from the D or L series of pentoses or hexoses such as ribose, arabinose, glucose, galactose;
oppure: or:
R4 ed R5, uguali o diversi fra loro, rappresentano un gruppo OR17 in cui R17 rappresenta H o un gruppo acetile. R4 and R5, the same or different from each other, represent an OR17 group in which R17 represents H or an acetyl group.
Costituiscono una ulteriore selezione preferita della presente invenzione i composti di formula generale (I) in cui: A further preferred selection of the present invention constitutes the compounds of general formula (I) in which:
- R1 è la catena laterale dell’ amminoacido naturale triptofano , - R1 is the side chain of the natural amino acid tryptophan,
- R2 è la catena laterale dell' amminoacido naturale fenilalanina ed - R3 è scelto fra idrogeno o benzile. - R2 is the side chain of the natural amino acid phenylalanine and - R3 is chosen from hydrogen or benzyl.
e gli altri sostituenti sono come qui sopra definiti. and the other substituents are as defined above.
Sono inoltre da considerare particolarmente preferiti i composti di formula generale (ì) di seguito elencati: The compounds of general formula (ì) listed below are also to be considered particularly preferred:
Sali farmaceuticamente accettabili di composti di formula (I) includono i sali con acidi inorganici (come cloridrico, bromidrico, iodidrico, solforico, nìtrico, fosforico) che organici (quali , acetico, propionico, succinico, maionico, citrico, tartarico, metansolfonico, ptoluensolfonico). Pharmaceutically acceptable salts of compounds of formula (I) include salts with inorganic acids (such as hydrochloric, hydrobromic, hydrogen iodide, sulfuric, nitric, phosphoric) and organic (such as, acetic, propionic, succinic, mayionic, citric, tartaric, methanesulfonic, ptoluenesulfonic ).
Secondo l'invenzione i composti di formula (I) contenenti legami peptidici o pseudopeptidici possono essere ottenuti mediante classiche condensazioni con tecniche note in letteratura. Il metodo generale da noi prescelto per la preparazione dei composti peptidici (X1-X4 = C0NR-, -NRCO-) prevede la sintesi in soluzione della catena peptidica lineare utilizzando amminoacidi, derivati dicarbossilici o diamminici opportunamente protetti e, dopo deprotezione selettiva delie catene C-ed N- terminali, la ciclizzazione in solventi organici polari in soluzione diluita. Come metodi di attivazione dei gruppi carbossilici sono stati preferiti generalmente quello con EDCI.HCI e HOBt oppure PyBOP e DIEA in DMF. According to the invention, the compounds of formula (I) containing peptide or pseudopeptide bonds can be obtained by classical condensations with techniques known in the literature. The general method we have chosen for the preparation of peptide compounds (X1-X4 = C0NR-, -NRCO-) involves the synthesis in solution of the linear peptide chain using amino acids, dicarboxylic or diamine derivatives suitably protected and, after selective deprotection of the C chains -and N-terminus, cyclization in polar organic solvents in dilute solution. As methods of activation of the carboxy groups, the one with EDCI.HCI and HOBt or PyBOP and DIEA in DMF was generally preferred.
I precursori dicarbossilici contenenti il gruppo R4 e quelli diamminici contenenti i gruppi R3 sono stati preparati con metodi riportati in letteratura. The dicarboxylic precursors containing the R4 group and the diamine precursors containing the R3 groups were prepared with methods reported in the literature.
Ih particolare la sintesi dei derivati succinici con R4 = alchile o (CH2)rr Ar è descritta da R. Conrow et al. J. Org. Chem. 1986, 51, 938 e da S.G. Cohen et al. J. Am. Chem. Soc. 1968, 90, 3495, mentre nel caso di R4 = H, gruppo amminico, ossidrilico o carbossilico sono stati usati rispettivamente anidride succinica, acido aspartico, acido malico o carbossisuccinico opportunamente protetti. In particular, the synthesis of succinic derivatives with R4 = alkyl or (CH2) rr Ar is described by R. Conrow et al. J. Org. Chem. 1986, 51, 938 and by S.G. Cohen et al. J. Am. Chem. Soc. 1968, 90, 3495, while in the case of R4 = H, amino, hydroxy or carboxylic group, suitably protected succinic anhydride, aspartic acid, malic acid or carboxy-succinic acid were used respectively.
La sintesi dei derivati etilendiamminici contenenti i gruppi R3 è stata effettuata a partire dai corrispondenti -amminoacidi N-protetti, per riduzione del carbossile ad alcool con BH3.THF (CiF. Stanfield et al· J. Org. Chem. 1981, 46, 4797, 4799; I.R. Oilmann et al. Bioorg. Med. Chem. 1995, 3, 969), conversione ad azide via mesilato e successiva riduzione ad ammino gruppo (P.G. Mattingly, Synthesis, 1990, 366; P.M. O'Brien et al. J. Med. Chem. 1994, 37, 1810) The synthesis of the ethylenediamine derivatives containing the R3 groups was carried out starting from the corresponding N-protected amino acids, by reducing the carboxyl to alcohol with BH3.THF (CiF. Stanfield et al. J. Org. Chem. 1981, 46, 4797 , 4799; I.R. Oilmann et al. Bioorg. Med. Chem. 1995, 3, 969), conversion to azide via mesylate and subsequent reduction to amino group (P.G. Mattingly, Synthesis, 1990, 366; P.M. O'Brien et al. J . Med. Chem. 1994, 37, 1810)
I composti contenenti legami peptidici ridotti (X1 - X4 = -CH2-NR-, -NR-CH2-), sono sintetizzati in soluzione impiegando metodi noti, corsie per esempio l'amminazione riduttiva dell'aldeide di un amminoacido con la funzióne amminica di un amminoacido o peptide protetto, in presenza di NaCNBH4 come riducente. in CH3OH/ACOH (K. A. Jacobson et al. J. Med. Chem. 1983, 26, 492; R. F. Borch et ai. J. Am. Chem. Soc. 1971, 93, 2897; J. P. Salvi et al. Tetr. Lett. 1994, 35, 1181). Le aldeidi sono state ottenute per riduzione con UAIH4 dei corrispondenti amminoacidi protetti,. Ν,Ο-dimetilidrossamrnati secondo il metodo di J. A. Feherentz et al. Synthesis, 1983, 676 e Int. J. Peptide Protein Res. 1985, 26, 236. Compounds containing reduced peptide bonds (X1 - X4 = -CH2-NR-, -NR-CH2-), are synthesized in solution using known methods, for example the reductive amination of the aldehyde of an amino acid with the amino function of a protected amino acid or peptide, in the presence of NaCNBH4 as a reducing agent. in CH3OH / ACOH (K. A. Jacobson et al. J. Med. Chem. 1983, 26, 492; R. F. Borch et al. J. Am. Chem. Soc. 1971, 93, 2897; J. P. Salvi et al. Tetr. Lett. 1994, 35, 1181). The aldehydes were obtained by reduction of the corresponding protected amino acids with UAIH4. Ν, Ο-dimethylhydroxamate according to the method of J. A. Feherentz et al. Synthesis, 1983, 676 and Int. J. Peptide Protein Res. 1985, 26, 236.
I composti di formula (I) come sopra indicati si sono-rivelati potenti antagonisti del recettore NK-2 delle tachichinine e pertanto possono essere somministrati come agenti capaci di controllare l eccessiva contrazione della muscolatura liscia in qualsiasi condizione patologica in cui il rilascio di tachichinine concorre alla genesi del corrispondente disturbo. The compounds of formula (I) as indicated above have proved to be powerful antagonists of the NK-2 receptor of tachykinins and therefore can be administered as agents capable of controlling the excessive contraction of smooth muscle in any pathological condition in which the release of tachykinins contributes. to the genesis of the corresponding disorder.
In particolare, la componente broncospastica, dell' asma, della tosse, delle irritazioni polmonari, gli spasmi intéstinali o gli spasmi locali della vescica e dell'uretere durante cistiti, infezioni e coliche renali possono essere considerate condizioni in cui la somministrazione dei composti di formula (l), quali antagonisti NK-2, può essere efficace. In particular, the bronchospastic component, asthma, cough, pulmonary irritation, intestinal spasms or local spasms of the bladder and ureter during cystitis, infections and renal colic can be considered conditions in which the administration of the compounds of formula (l), such as NK-2 antagonists, may be effective.
I composti di formula (I) oggetto della presente invenzione sono adatti per la. somministrazione a fini terapeutici agli animali superiori ed all' uomo attraverso la via parenterale, orale, inalatoria e sublinguale raggiungendo effetti farmacologici in accordo con le proprietà sopra descritte. Per le vie parenterali (endovenosa; intramuscolare e intradermale) si impiegano soluzioni sterili o preparati liofilizzati. Per le vie di instillazione nasale, inalatoria e sublinguale si usano, a seconda del caso, soluzioni acquose, preparati aereosolici, polveri o capsule. Le dosi di principio attivo nelle composizioni suddette possono essere comprese fra 0,1 e 10 mg/kg di peso corporeo. The compounds of formula (I) object of the present invention are suitable for the. administration for therapeutic purposes to higher animals and to man through the parenteral, oral, inhalation and sublingual routes, achieving pharmacological effects in accordance with the properties described above. For the parenteral routes (intravenous; intramuscular and intradermal) sterile solutions or lyophilized preparations are used. For the nasal, inhalation and sublingual instillation routes, aqueous solutions, aerosol preparations, powders or capsules are used, depending on the case. The doses of active principle in the above compositions can be comprised between 0.1 and 10 mg / kg of body weight.
Qui di seguito sono riportati alcuni esempi non limitativi della presente invenzione: Some non-limiting examples of the present invention are reported below:
ESEMPIO 1 EXAMPLE 1
viene utilizzato come prodotto di partenza il composto ciclo{-Suc[1-(S)- detto Composto A the compound cycle {-Suc [1- (S) - called Compound A is used as the starting product
(composto di formula (I) in cui: X1 = X2 = X3 = X4 = -CO-NH-; R1 = -CH2-(indol-3-ìl); R2 = R3 = -CH2-C6H5; R4 = -NH2; R5 = H; m = 0, f -1; gli atomi di carbonio C-R1 e C- R2 hanno configurazione S, mentre il C-R3 ha configurazione R e C-R4 ha configurazione S) preparato come segue. (composed of formula (I) where: X1 = X2 = X3 = X4 = -CO-NH-; R1 = -CH2- (indole-3-ìl); R2 = R3 = -CH2-C6H5; R4 = -NH2 ; R5 = H; m = 0, f -1; the carbon atoms C-R1 and C-R2 have configuration S, while C-R3 has configuration R and C-R4 has configuration S) prepared as follows.
a) Sintesi del. dipeptide BOC-Trp-Phe-OH a) Summary of. dipeptide BOC-Trp-Phe-OH
Ad una soluzione di H-Trp-Phe-OH (5 g,) in diossano (30 mi), H2O (15 mi) e NaOH 1M (15.6 mi), raffreddata a 0-5°C, sotto agitazione, fu aggiunto, di-tert-butiidicarbonato (3.4 g). La miscela di reazione fu lasciata in agitazione per 2 ore, concentrata ed estratta con pentano (2 x 20 mi). La fase acquosa fu raffreddata con ghiaccio, addizionata con AcOEt (50 mi), acidificata con KHSO4 fino a pH .2-3, separata ed estratta con AcOEt (2 x 50 mi). Le fasi organiche riunite furono lavate con. salamoia (50 ml), seccate ed evaporate sotto vuoto a 30°C, ottenendo 6 g del composto desiderato come residuo semisolido bianco. To a solution of H-Trp-Phe-OH (5 g) in dioxane (30 ml), H2O (15 ml) and 1M NaOH (15.6 ml), cooled to 0-5 ° C, under stirring, was added, di-tert-butiidicarbonate (3.4 g). The reaction mixture was left under stirring for 2 hours, concentrated and extracted with pentane (2 x 20 ml). The aqueous phase was cooled with ice, added with AcOEt (50 ml), acidified with KHSO4 to pH .2-3, separated and extracted with AcOEt (2 x 50 ml). The combined organic phases were washed with. brine (50 ml), dried and evaporated under vacuum at 30 ° C, obtaining 6 g of the desired compound as a white semisolid residue.
TLC: r.f. 0.55 (cloroformio/ cicloesano/AcOH /H2O = 45/4515 15), 0.52 (CHCl3/ MeOH = 9/1) TLC: r.f. 0.55 (chloroform / cyclohexane / AcOH / H2O = 45/4515 15), 0.52 (CHCl3 / MeOH = 9/1)
b) Sintesi di (R)-1-benzii-2-benzilossicarbonilammino-etilammina b) Synthesis of (R) -1-benzii-2-benzyloxycarbonylamino-ethylamine
La sintesi è. stata effettuata secondo .il metodo di P.G. Mattingly, Synthesis, 1990, 366, a partire da BOC-D-fenilalaninolo. The summary is. was carried out according to the method of P.G. Mattingly, Synthesis, 1990, 366, from BOC-D-phenylalaninol.
c) Sintesi di BOC-Trp-Phe-[(R)-NH-CH(CH2-C6H5)-CH2-NH-Z] c) Synthesis of BOC-Trp-Phe - [(R) -NH-CH (CH2-C6H5) -CH2-NH-Z]
Ad una soluzione di BOC-Trp-Phe-OH (1.19 g, 2.63 mmoli) in DMF anidra (10 ml) furono aggiunti sotto azoto (R)-1-benzil-2-benzilgssicarbpnilammino-etilammina (750 mg,), PyBOP (1.37 g) e DIEA (0.9 mi). To a solution of BOC-Trp-Phe-OH (1.19 g, 2.63 mmoles) in anhydrous DMF (10 ml), PyBOP ( 1.37 g) and DIEA (0.9 ml).
La miscela di reazione fu lasciata in agitazione per una notte a temperatura ambiente, addizionata con AcOEt (80 ml), lavata con HCI 1N (3 x 30 mi), Na2CO3 5% (3 x 30 mi) e H2O (30 mi). La fase organica fu evaporata sotto vuoto a 30°C, Ottenendo 1.8 g di residuo solido avorio. The reaction mixture was left under stirring overnight at room temperature, added with AcOEt (80 ml), washed with 1N HCl (3 x 30 ml), 5% Na2CO3 (3 x 30 ml) and H2O (30 ml). The organic phase was evaporated under vacuum at 30 ° C, obtaining 1.8 g of ivory solid residue.
Il composto grezzo fu purificato mediante un lavaggio in sospensione, con AcOEt a caldo e con MeOH a temperatura ambiente, ottenendo 1.15 g del prodotto desiderato 5 come solido bianco MS (TS) : [MH<+>] = 718 The crude compound was purified by washing in suspension, with hot AcOEt and with MeOH at room temperature, obtaining 1.15 g of the desired product 5 as a white solid MS (TS): [MH <+>] = 718
d) Sintesi di H-Trp-Phe-[(R)-NH-CH(CH2-C6H5)-CH2-NH-Z] d) Synthesis of H-Trp-Phe - [(R) -NH-CH (CH2-C6H5) -CH2-NH-Z]
Ad una sospensione del composto precedente (1.1 g) in CHCI3 (30 ml) fu addizionato, sotto; agitazione, a temperatura ambiente, TFA (6 mi), osservando immediata formazione di uria soluzione limpida. La miscela di reazione fu lasciata in agitazione per 1.5 ore, controllando mediante analisi HPLC la scomparsa del precursore. Dopo evaporazione del solvente, il residuo fu ripreso con AcOEt (100. mi), lavato con NaHC03 5% (2 x 30 ml)e salamoia (30 ml). To a suspension of the previous compound (1.1 g) in CHCl3 (30 ml) was added, below; agitation, at room temperature, TFA (6 ml), observing the immediate formation of a clear solution. The reaction mixture was left under stirring for 1.5 hours, checking the disappearance of the precursor by HPLC analysis. After evaporation of the solvent, the residue was taken up with AcOEt (100. ml), washed with 5% NaHC03 (2 x 30 ml) and brine (30 ml).
La fase organica fu seccata con MgS04 ed evaporata sotto vuoto a 30°C. The organic phase was dried with MgSO 4 and evaporated under vacuum at 30 ° C.
Il residuo solido fu purificato per flash-chromatography (CHCI3/ MeOH = 95/ 5), ottenendo 821 mg del compósto desiderato come solido bianco. The solid residue was purified by flash chromatography (CHCI3 / MeOH = 95/5), obtaining 821 mg of the desired compound as a white solid.
TLC: r.f. 0.50 (CHCI3/ MeOH = 9/ 1 ) TLC: r.f. 0.50 (CHCI3 / MeOH = 9/1)
e) Sintesi di Boc-Asp{Trp-Phe-[(R)NH-CH(CH2-C6H5)-CH2-NH-Z}-OBzl e) Synthesis of Boc-Asp {Trp-Phe - [(R) NH-CH (CH2-C6H5) -CH2-NH-Z} -OBzl
Ad una soluzione del composto dellesempio 1d (650 mg) in DMF anidra (30 mi), sotto agitazione a temperatura ambiente e sotto azoto, furono aggiunti, Boc-Asp-OBzl (340 mg), PyBOP (656 mg) e Et3N (0.4 mi). La miscela di reazione fu lasciata in agitazione a temperatura ambiente per due ore. Dopo, evaporazione del solvente sotto vuoto- il residuo fu trattato con H2O ottenendo un solido che veniva filtrato, lavato con acqua e seccato. Fu cristallizzato da etanolo ottenendo 640 mg di composto desiderato come sòlido bianco. Boc-Asp-OBzl (340 mg), PyBOP (656 mg) and Et3N (0.4 me). The reaction mixture was left under stirring at room temperature for two hours. After, evaporation of the solvent under vacuum - the residue was treated with H2O obtaining a solid which was filtered, washed with water and dried. It was crystallized from ethanol to give 640 mg of the desired compound as a white solid.
MS (ES+): [MH+] = 923; HPLC nelle seguenti condizioni: colonna di silice C18 con grandezza delle particelle: 5mm e con pori di 100 A (dati analitici: 20% di carbonio e con C18 Surface Coverage 3.3 mmoles/m<2>), di lunghezza 3.9 x 150 mm; fase mobile con gradiente lineare di acetonitrile contenente lo 0.1% (v/v) di TFA (fase B) contro TFA acquoso 0.1% (v/v) (fase A), dal 20% al 80% in B in 20 minuti ad un flusso di 1 ml/min; cón rivelazione UV a 220 nrn Tempo di ritenzione(rt): rt=21.1 min. MS (ES +): [MH +] = 923; HPLC in the following conditions: C18 silica column with particle size: 5mm and with pores of 100 A (analytical data: 20% carbon and with C18 Surface Coverage 3.3 mmoles / m <2>), length 3.9 x 150 mm; mobile phase with linear gradient of acetonitrile containing 0.1% (v / v) of TFA (phase B) versus 0.1% (v / v) aqueous TFA (phase A), from 20% to 80% in B in 20 minutes at a flow of 1 ml / min; with UV detection at 220 nrn Retention time (rt): rt = 21.1 min.
f) Sìntesi di Boc-Asp{Trp-Phe-[(R)NH-CH(CH2-C6H5)-CH2-NH2]}-OH Il composto dell'esempio 1e (600 mg) fu solubilizzato in DMF (2ml) e diluito con MeOH (30 mi), quindi idrogenato in presenza di Pd/C 10% (100 mg) a pressione atmosferica e a temperatura ambiente per 5 ore. Il catalizzatore fu filtrato e lavato con MeOH. Dopo evaporazione del solvente furono ottenuti 420 mg del composto desiderato come solido bianco. f) Synthesis of Boc-Asp {Trp-Phe - [(R) NH-CH (CH2-C6H5) -CH2-NH2]} - OH The compound of Example 1e (600 mg) was solubilized in DMF (2ml) and diluted with MeOH (30 ml), then hydrogenated in the presence of 10% Pd / C (100 mg) at atmospheric pressure and at room temperature for 5 hours. The catalyst was filtered and washed with MeOH. After evaporation of the solvent, 420 mg of the desired compound were obtained as a white solid.
MS (ES+): [MH+] = 663; HPLC (eseguito nelle, condizioni sopra descritte): rt=11.07 MS (ES +): [MH +] = 663; HPLC (performed under the conditions described above): rt = 11.07
g) Sintesi di ciclo{-Suc[1(S)NHBoc]-Trp-Phe-[(R)NH-CH(CH2-C6H5)-CH2-NH]} g) Synthesis of cycle {-Suc [1 (S) NHBoc] -Trp-Phe - [(R) NH-CH (CH2-C6H5) -CH2-NH]}
Ad una soluzione del composto dell'esempio 1f (7.2 g) in DMF (900 mi) anidra, sotto agitazione e in atmosfera di azoto, furono aggiunti rispettivamente 4 g di HOBt, 2 g di EDCI.HCI, La miscela di reazione fu lasciata ih agitazione per 5 ore quindi, dopo evaporazione del solvente, il residuo fu trattato con una soluzione acquosa al 5% di KHSO4 ed estratto in etile acetato. To a solution of the compound of Example 1f (7.2 g) in anhydrous DMF (900 ml), under stirring and in a nitrogen atmosphere, 4 g of HOBt, 2 g of EDCI were added respectively. stirring for 5 hours then, after evaporation of the solvent, the residue was treated with a 5% aqueous solution of KHSO4 and extracted in ethyl acetate.
La fase organica fu lavata con salamoia, con NaHC03 al 5% ed ancora con salamoia, quindi fu seccata ed evaporata e il solido giallo ottenuto (5.2 g) fu cristallizzato da isopropanolo/acqua: 1/1 ottenendo 3.2 g di solido bianco. The organic phase was washed with brine, with 5% NaHC03 and again with brine, then it was dried and evaporated and the obtained yellow solid (5.2 g) was crystallized from isopropanol / water: 1/1 obtaining 3.2 g of white solid.
MS (ES+): [MH+] = 681; HPLC (eseguito nelle condizioni sopra descritte); rt=14.8 MS (ES +): [MH +] = 681; HPLC (performed under the conditions described above); rt = 14.8
h) Sintesi di ciclo{-Suci1(S)NH2]-Trp-Phe-[(R)NH-CH(CH2-C6H5)-CH2-NH]} Ad una sospensione del composto dell'esempio 1g (1 g) in CH2CI2 (20 mi), fu aggiunto sotto agitazione a 0 °C TFA (7 mi), ottenendo una soluzione limpida; dopo l'aggiunta si porta a temperatura ambiente. Dopo 90 minuti -a temperatura ambiente, il solvente fu evaporato, il residuo fu trattato con NaHC03 ed acqua ed estratto in etile acetato. La fase organica fu lavata con salamoia, seccata ed evaporata ottenendo un solido di 800 mg. h) Synthesis of cycle {-Suci1 (S) NH2] -Trp-Phe - [(R) NH-CH (CH2-C6H5) -CH2-NH]} To a suspension of the compound of example 1g (1 g) in CH 2 Cl 2 (20 ml), was added under stirring at 0 ° C TFA (7 ml), obtaining a clear solution; after the addition it is brought to room temperature. After 90 minutes at room temperature, the solvent was evaporated, the residue was treated with NaHC03 and water and extracted in ethyl acetate. The organic phase was washed with brine, dried and evaporated to obtain a solid of 800 mg.
MS (ES+): [MH+] = 581; HPLC (eseguito nelle condizioni sopra descritte); rt=9.4 MS (ES +): [MH +] = 581; HPLC (performed under the conditions described above); rt = 9.4
Un campione di 20 mg viene purificato -in HPLC preparativo ottenendo 15 mg di trifluoroacetato; ciclo{-Suc[1(S)NH2]-Trp-Phe-[(R)NH-CH(CH2-C6H5)-CH2-NH]-}.TFA A 20 mg sample is purified in preparative HPLC to obtain 15 mg of trifluoroacetate; cycle {-Suc [1 (S) NH2] -Trp-Phe - [(R) NH-CH (CH2-C6H5) -CH2-NH] -}. TFA
MS (ES+); [MH+] = 581; HPLC; rt=9.4 (eseguito nelle condizioni sopra descritte) ; 1H-NMR (DMSO): d 2.60-2.90 (m, 8H), 3.05-3.11 (m, 1H), 3.63-3.71 (m, 1H), 4..07-4.13 (m, 3H), 4.32-4.38 (m, 1H), 6.90-7.45 (m, 17H), 8.07 (bs, NH3<+>), 8.22-8.28 (m, 1H), 8.57 d;-1H), 10.82 (s, IH), k) Ad una soluzione di 60 mg di Composto A, preparato come descritto ai punti 1a-1h, in 1 mi di DMF, mantenuta a 0°C, si aggiungono 24 mi di N-metilmorfolina e 10. mi di metansolfonilcloruro; si lascia sotto agitazione per 2 ore e mezzo. La miscela di reazione viene concentrata sotto vuoto, diluita con etile- acetato e lavata in successione con soluzione acquosa di acido citrico (10%), acqua, soluzione satura di NaHC03 ed ancora con acqua. Dopo essiccamento su Na2SO4 ed evaporazione del solvente il prodotto viene isolato per HPLG preparativo. MS (ES +); [MH +] = 581; HPLC; rt = 9.4 (performed under the conditions described above); 1H-NMR (DMSO): d 2.60-2.90 (m, 8H), 3.05-3.11 (m, 1H), 3.63-3.71 (m, 1H), 4..07-4.13 (m, 3H), 4.32-4.38 (m, 1H), 6.90-7.45 (m, 17H), 8.07 (bs, NH3 <+>), 8.22-8.28 (m, 1H), 8.57 d; -1H), 10.82 (s, 1H), k) To a solution of 60 mg of Compound A, prepared as described in points 1a-1h, in 1 ml of DMF, kept at 0 ° C, 24 ml of N-methylmorpholine and 10 ml of methanesulfonyl chloride are added; it is left under stirring for 2 and a half hours. The reaction mixture is concentrated under vacuum, diluted with ethyl acetate and washed in succession with aqueous solution of citric acid (10%), water, saturated solution of NaHC03 and again with water. After drying on Na2SO4 and evaporation of the solvent, the product is isolated by preparative HPLG.
1H-NMR (DMSO-d6 500 MHz): d 10.80 (d, J = 1.6, 1H); 8.54 (s broad, 1H); 8.34 (dd,.J= 3.8, 8.6, 1H); 7.61. (d, J = 7.6, 1H); 6.90-7.40 (m, 16H); 6.64 (d, J = 9.5, IH) 4.30-4,38 (m, 1 H); 4.25-4.30 (m,1H); 4.00-4.10 (m, 2H); 3.65-3.77 (m, 1H); 3.30-3.35 (m, 1H); 2.97 (s, 3H); 2.58-2.95 (m, 8H). 1H-NMR (DMSO-d6 500 MHz): d 10.80 (d, J = 1.6, 1H); 8.54 (broad s, 1H); 8.34 (dd, .J = 3.8, 8.6, 1H); 7.61. (d, J = 7.6, 1H); 6.90-7.40 (m, 16H); 6.64 (d, J = 9.5, 1H) 4.30-4.38 (m, 1H); 4.25-4.30 (m, 1H); 4.00-4.10 (m, 2H); 3.65-3.77 (m, 1H); 3.30-3.35 (m, 1H); 2.97 (s, 3H); 2.58-2.95 (m, 8H).
MS: m/z = 659, MH<+>MS: m / z = 659, MH <+>
Con analoga· procedura sperimentale sono stati ottenuti i composti: ESEMPIO 2: ciclo{Suc[1-(R)-metansolfonilamino]-Trp-Phe-[(R)-NH-CH(CH2-C6H5)-CH2NH]} The following compounds were obtained with a similar experimental procedure: EXAMPLE 2: cycle {Suc [1- (R) -methanesulfonylamino] -Trp-Phe - [(R) -NH-CH (CH2-C6H5) -CH2NH]}
(composto di formula generale l in cui C-R4 ha configurazione R, R4 è metansolfonilammino e gli altri sostituenti sono còme descritto per il composto A) (compound of general formula l in which C-R4 has configuration R, R4 is methanesulfonylamino and the other substituents are as described for compound A)
1H-NMR (DMSO-d6, 500 MHz): d 10.83 (d, J = 1.6 1H); 8.82 (d, J= 4.7, 1H); 8.12 (s broad, 1H); 7.44 (d, J = 7.9, 1H); 6.92-7.42 (mi, 16H); 6.82 (d, J = 8.8, 1H) 4.11-4,23 (m, 3H); 4.02 (m, 1H); 3.35 (m, 2H); 2.95 (s, 3H); 270-2.95 (m; 6H); 2.34 (dd, J = 9.3, 13.5; 1 H). 1H-NMR (DMSO-d6, 500 MHz): d 10.83 (d, J = 1.6 1H); 8.82 (d, J = 4.7, 1H); 8.12 (broad s, 1H); 7.44 (d, J = 7.9, 1H); 6.92-7.42 (ml, 16H); 6.82 (d, J = 8.8, 1H) 4.11-4.23 (m, 3H); 4.02 (m, 1H); 3.35 (m, 2H); 2.95 (s, 3H); 270-2.95 (m; 6H); 2.34 (dd, J = 9.3, 13.5; 1H).
MS: m/z = 659, MH<+>. MS: m / z = 659, MH <+>.
ESEMPIO. 3: ciclo{Suc[1-(S)-(4-metilbenzen)solfonilamino]-Trp-Phe-[(R)-NH-CH(CH2-C6H5)-CH2NH]} EXAMPLE. 3: cycle {Suc [1- (S) - (4-methylbenzen) sulfonylamino] -Trp-Phe - [(R) -NH-CH (CH2-C6H5) -CH2NH]}
(composto di formula generale I in cui R4 è 4-metilbenzensolfonilamino e gli altri sostituenti sono come descritto per il composto MS: m/2 = 735, MH<+>(compound of general formula I in which R4 is 4-methylbenzenesulfonylamino and the other substituents are as described for the compound MS: m / 2 = 735, MH <+>
ESEMPIO 4: cicjo{Suc[1-(R)-(4-metilbenzen)solfonilamino]-Trp-Phe-[(R)-NH-CH(CH2-C6H5}-CH2NH]} EXAMPLE 4: cicjo {Suc [1- (R) - (4-methylbenzen) sulfonylamino] -Trp-Phe - [(R) -NH-CH (CH2-C6H5} -CH2NH]}
(composto di formula generale I in cui R4 è 4-metilbenzensolfonilamino, C-R4 ha configurazione R e gli altri sostituenti sono come descritto per il composto A) (compound of general formula I where R4 is 4-methylbenzenesulfonylamino, C-R4 has R configuration and the other substituents are as described for compound A)
1H-NMR (DMSO-d6, 500 MHz): d 10.81 (d, J = 1.5, 1H); 8.68 (d, J = 4.5, 1H); 7.95 (s broad, 1H); 7.90 (d, J = 8.8, 1H); 6.95-7.75 (m, 20H); 6.78 (d, J =,8.9, 1H) 4.17(m, 1 H); 4.10 (m,1 H); 4.05 (m, 1H); 3.94 (m, 1H); 3.17 (m, 1H); 2.97 (m, IH); 2.65-2.85 (m, 7H); 2.36 (s, 3H); 2.09 (dd, J = 9.1, 13.5, 1 H). 1H-NMR (DMSO-d6, 500 MHz): d 10.81 (d, J = 1.5, 1H); 8.68 (d, J = 4.5, 1H); 7.95 (broad s, 1H); 7.90 (d, J = 8.8, 1H); 6.95-7.75 (m, 20H); 6.78 (d, J =. 8.9, 1H) 4.17 (m, 1H); 4.10 (m, 1H); 4.05 (m, 1H); 3.94 (m, 1H); 3.17 (m, 1H); 2.97 (m, 1H); 2.65-2.85 (m, 7H); 2.36 (s, 3H); 2.09 (dd, J = 9.1, 13.5, 1H).
MS: m/z = 735, MH<+>. MS: m / z = 735, MH <+>.
ESEMPIO 5: ciclo{Suc[1-(S)-[bis(2-(4-morfolino)etil)-amino]-Trp-Phe-[(R)-NH-CH(CH2-C6H5)-CH2NH]} EXAMPLE 5: cycle {Suc [1- (S) - [bis (2- (4-morpholino) ethyl) -amino] -Trp-Phe - [(R) -NH-CH (CH2-C6H5) -CH2NH]}
(composto di formula generale I in cui R4 è bis(2-(4-morfolino)etil)-amino e gli altri sostituenti sono come descritto per il composto A) 50 mg di composto A vengono sciolti in 5 ml di metanolo. Si aggiungono in sequenza 20 mg di 2-(4-morfolino)acetaldeide, 150 mi di acido acetico glaciale e 90 mg di sodio cianoboroidruro. Si agita 2 ore a temperatura ambiente, si aggiunge 1 mi di acido citrico 10% aq, e si evapora la soluzione. Il residuo ottenuto viene ripreso con 25 mi di etile acetato; si . aggiungono acqua e sodio carbonato solido. La fase organica, separata, viene lavata con salamoia e essiccata su sodio solfato. Dopo evaporazione del solvente sotto vuoto si ottengono ca. (compound of general formula I wherein R4 is bis (2- (4-morpholino) ethyl) -amino and the other substituents are as described for compound A) 50 mg of compound A are dissolved in 5 ml of methanol. 20 mg of 2- (4-morpholino) acetaldehyde, 150 ml of glacial acetic acid and 90 mg of sodium cyanoborohydride are added in sequence. The mixture is stirred for 2 hours at room temperature, 1 ml of 10% aq citric acid is added, and the solution is evaporated. The residue obtained is taken up with 25 ml of ethyl acetate; yes . they add water and solid sodium carbonate. The separated organic phase is washed with brine and dried over sodium sulphate. After evaporation of the solvent under vacuum, approx.
100 mg di prodotto grezzo, che viene purificato per HPLC preparativo (colonna Delta Pak<TM >C18, 100A, 300x19 mm; flusso- = 1 Sml/min; I = 220, 270 nm; fase mobile: A= H2O . + 0.1% TFA, B = CH3CN 0.1% TFA, gradiente da A: B = 10:90 a A:B = 30:70 in 120 min) dando 39.2 mg di prodotto puro. 100 mg of crude product, which is purified by preparative HPLC (Delta Pak <TM> C18 column, 100A, 300x19 mm; flow- = 1 Sml / min; I = 220, 270 nm; mobile phase: A = H2O. + 0.1 % TFA, B = CH3CN 0.1% TFA, gradient from A: B = 10:90 to A: B = 30:70 in 120 min) giving 39.2 mg of pure product.
1H-NMR (DMSO-d6, 500 MHz): d 2.40-2.55 (m, sovrapposto al segnale del DMSO); 2E0-2.69 (1H, m); 2.78-2.90 (6H, m); 2.90-3.44 (m, sovrapposto al segnale dell'acqua); 3.65-3.93 (1ÒH, m); 4.08-4.16 (1H, m); 4.17-4:22 ( 1 H, m); 4.44 (1H, m); 6.67 (1H, d, J = 9.3 Hz); 6.96-7.02 (2H, m); 7.03 (1H, s); 7.09 (1H, m); 7.16:7.32 (10H, m); 7.36 (1H, d, J = 8.1 Hz); 7.45 (1H, d, J = 7.9 Hz); 8.17 (1H, bs); 8.32 (1H, d, J = 5.9 Hz); 10.72 (1H, d, J = 1.3 Hz). 1H-NMR (DMSO-d6, 500 MHz): d 2.40-2.55 (m, superimposed on the DMSO signal); 2E0-2.69 (1H, m); 2.78-2.90 (6H, m); 2.90-3.44 (m, superimposed on the water signal); 3.65-3.93 (1ÒH, m); 4.08-4.16 (1H, m); 4.17-4: 22 (1 H, m); 4.44 (1H, m); 6.67 (1H, d, J = 9.3 Hz); 6.96-7.02 (2H, m); 7.03 (1H, s); 7.09 (1H, m); 7.16: 7.32 (10H, m); 7.36 (1H, d, J = 8.1 Hz); 7.45 (1H, d, J = 7.9 Hz); 8.17 (1H, bs); 8.32 (1H, d, J = 5.9 Hz); 10.72 (1H, d, J = 1.3 Hz).
MS: m/z = 807, MH<+>. MS: m / z = 807, MH <+>.
Con la stessa procedura sperimentale, ma partendo da ciclo{Suc[1-(R)-amino]-Trp-Phe-[(R)-NH-CH(CH2-C6H5)-CH2NH]}, è stato ottenuto; ESEMPIO ; 6: ciclp{Suc[1-(R)-[bis(2-(4-morfolino)etil)-amino]-Trp-Phe-[(R)-NH-CH(CH2-C6H5)-CH2NH]} With the same experimental procedure, but starting from cycle {Suc [1- (R) -amino] -Trp-Phe - [(R) -NH-CH (CH2-C6H5) -CH2NH]}, was obtained; EXAMPLE ; 6: cyclp {Suc [1- (R) - [bis (2- (4-morpholino) ethyl) -amino] -Trp-Phe - [(R) -NH-CH (CH2-C6H5) -CH2NH]}
(composto di formula generale i in cui C-R4 ha configurazione R e gli altri sostituenti sono come descritto per il composto dell' Esempio 5) MS: m/z = 807, MH<+>. (compound of general formula i in which C-R4 has configuration R and the other substituents are as described for the compound of Example 5) MS: m / z = 807, MH <+>.
Con la procedura sperimentale descritta nell'Esempio 5, ma utilizzando 0.5 eq. di 2-(4-morfolino)acetaldeide, sono stati ottenuti i composti: ESEMPIO 7:. ciclo{Suc[1-(SH2-(4-morfolino)etilamino]-Trp-Phe-[(R)-NH-CH(CH2-C6H5)-CH2NH]} With the experimental procedure described in Example 5, but using 0.5 eq. of 2- (4-morpholino) acetaldehyde, the compounds were obtained: EXAMPLE 7 :. cycle {Suc [1- (SH2- (4-morpholino) ethylamino] -Trp-Phe - [(R) -NH-CH (CH2-C6H5) -CH2NH]}
(composto di formula generale I in cui - R4 è 2-(4-morfo!ino)etiiamino e gli altri sostituenti sono come descritto per il composto A) 1 H-NMR (DMSO-d6, 500 MHz): d 2.61-3:87 (15H, m); 3.14 (1H, dd, J = 4.6, 13.9 Hz); 3.19-3.90 (rn, sovrapposto al degnale dell'acqua); 3.98-4.06 (1 H, m); 4.08-4.16 (2 H, m); 4.30-4.37 (1H, m); 6.95 (1H, s);- 6.99 (1H, m); 7.03-7.10 (2H, m); 7.14-7.31 (11H, m); 7.33 (1H, d, J = 8.1. Hz); 7.37 (1H, d, J = 8.9 Hz); 7.42 (1H, d, J = 7.9 Hz); 3.25 (1H, d, J = 5.2 Hz); 8.52 (1H, d, J = 5.2 Hz); 10.83 (1H, d, J = 2.1 Hz). (compound of general formula I where - R4 is 2- (4-morpho! ino) ethyiamine and the other substituents are as described for compound A) 1 H-NMR (DMSO-d6, 500 MHz): d 2.61-3 : 87 (15H, m); 3.14 (1H, dd, J = 4.6, 13.9 Hz); 3.19-3.90 (rn, superimposed on the sign of water); 3.98-4.06 (1 H, m); 4.08-4.16 (2H, m); 4.30-4.37 (1H, m); 6.95 (1H, s); - 6.99 (1H, m); 7.03-7.10 (2H, m); 7.14-7.31 (11H, m); 7.33 (1H, d, J = 8.1. Hz); 7.37 (1H, d, J = 8.9 Hz); 7.42 (1H, d, J = 7.9 Hz); 3.25 (1H, d, J = 5.2 Hz); 8.52 (1H, d, J = 5.2 Hz); 10.83 (1H, d, J = 2.1 Hz).
MS: m/z = 694, MH<+>. MS: m / z = 694, MH <+>.
ESEMPIO 8: ciclo{Suc[1-(R)-(2-(4-morfolino)etilamino]-Trp-Phe-[(R)-NH-CH(CH2-G6H5)-CH2NH]}. EXAMPLE 8: {Suc [1- (R) - (2- (4-morpholino) ethylamino] -Trp-Phe - [(R) -NH-CH (CH2-G6H5) -CH2NH]} cycle.
(composto di formula generale I in cui R4 è 2-(4-morfolino)etilamino, C-R4 ha configurazione R e gli altri sostituenti sono come descritto per il composto A) (compound of general formula I where R4 is 2- (4-morpholino) ethylamino, C-R4 has R configuration and the other substituents are as described for compound A)
MS: m/z = 694, MH<+>. MS: m / z = 694, MH <+>.
ESEMPIO 9: cicio{Suc[1 -(R)-(piperazin-l -il)]-Trp-Phe-[(R)-NH-CH(CH2-C6H5)-CH2NH]} EXAMPLE 9: cycle {Suc [1 - (R) - (piperazin-1 -yl)] - Trp-Phe - [(R) -NH-CH (CH2-C6H5) -CH2NH]}
(composto di formula generale I in cui R4 è piperazin-1-il, C-R4 ha configurazione R è gli altri sostituenti sono come descritto per il composto A) (compound of general formula I where R4 is piperazin-1-yl, C-R4 has R configuration and the other substituents are as described for compound A)
Il composto è stato preparato utilizzando, una procedura analoga a quella descritta nell’Esempio 5 utilizzando come reagente N-Boc iminodiacetaldeide, lasciando reagire per 16 ore e rimuovendo il gruppo protettivo N-Boc con acido trifluoroacetico in metilene cloruro. Il prodotto così ottenuto è stato purificato per HPLC preparativo (colonna: Symrhetry RP 18, 7 μ,100 A, 300 x 19 mm; flusso 15 ml/min; I = 220, 270 nm; fase mobile: A- H2O 0.1% TFA, B = CH3CN 0.1% TFA, gradiente da A:B = .25:75 a A:B = 15:85 in 120 min). The compound was prepared using a procedure similar to that described in Example 5 using N-Boc iminodiacetaldehyde as reagent, letting it react for 16 hours and removing the N-Boc protective group with trifluoroacetic acid in methylene chloride. The product thus obtained was purified by preparative HPLC (column: Symrhetry RP 18, 7 μ, 100 A, 300 x 19 mm; flow 15 ml / min; I = 220, 270 nm; mobile phase: A- H2O 0.1% TFA , B = CH3CN 0.1% TFA, gradient from A: B = .25: 75 to A: B = 15:85 in 120 min).
1H-NMR (DMSO-d6, 500 MHz): d 2.39 (1H, .dd, J = 10.2, 12.4 Hz); 2.65-2.79 (5H, m); 2.79-2.91 (3H, m); 2.99-3.15 (6H, m); 3.22-3.48 (m, sovrappósto al segnale dell'acqua); 3.51 (1 H, dd,. J = 4.4, 10.1 Hz); 3.95-4.04 (1 H, m); 4.08-4.18 (2H,- m); 6.92;<’ >(IH, d, J = 8.7 Hz); 6.98 (1H, m); 7.04-7.11 {2H, rn); 7.11-7.28 (Ì0H, m); 7.33 (1Ή, d, J = 8.1 Hz); 7.32-7.37 (IH, m); 7.44 (1H, d, J = 7.9 Hz); 8.32 (1H, d, J = 7:4 Hz); 8.40 (1H, bs); 8.71 (1H, d, J = 5.0 Hz); 10.82 (1H, d, J = 2.1 Hz). MS: m/z = 650, MH<+>. 1H-NMR (DMSO-d6, 500 MHz): d 2.39 (1H, .dd, J = 10.2, 12.4 Hz); 2.65-2.79 (5H, m); 2.79-2.91 (3H, m); 2.99-3.15 (6H, m); 3.22-3.48 (m, superimposed on the water mark); 3.51 (1H, dd ,. J = 4.4, 10.1 Hz); 3.95-4.04 (1H, m); 4.08-4.18 (2H, - m); 6.92; <’> (1H, d, J = 8.7 Hz); 6.98 (1H, m); 7.04-7.11 {2H, rn); 7.11-7.28 (10H, m); 7.33 (1Ή, d, J = 8.1 Hz); 7.32-7.37 (1H, m); 7.44 (1H, d, J = 7.9 Hz); 8.32 (1H, d, J = 7: 4 Hz); 8.40 (1H, bs); 8.71 (1H, d, J = 5.0 Hz); 10.82 (1H, d, J = 2.1 Hz). MS: m / z = 650, MH <+>.
ESEMPIO 10: ciclo{Suc[1-(S)-(piperazin-1-il)]-Trp-Phe-[(R)-NH-CH(CH2-C6H5)-CH2NH]} EXAMPLE 10: cycle {Suc [1- (S) - (piperazin-1-yl)] - Trp-Phe - [(R) -NH-CH (CH2-C6H5) -CH2NH]}
(composto di formula generale I in cui R4 è piperazin-1-i! e gli altri sostituenti sono come descritto per il composto A) (compound of general formula I in which R4 is piperazin-1-i! and the other substituents are as described for compound A)
MS: m/z = 650, MH<+>. . MS: m / z = 650, MH <+>. .
ESEMPIO 11: ciclo{Suc[1-(R)-(4-metansolfonil-piperazin-1-il)]-Trp-Phe-[(R)-NH-CH(CH2-C6H5)-CH2NH]} . . EXAMPLE 11: cycle {Suc [1- (R) - (4-methanesulfonyl-piperazin-1-yl)] - Trp-Phe - [(R) -NH-CH (CH2-C6H5) -CH2NH]}. .
(composto di formula generale I in cui R4 è 4-metansolfonil-piperazin-I -il, C-R4 ha configurazione R e gli altri sostituenti sono come descritto per il composto A) (compound of general formula I where R4 is 4-methanesulfonyl-piperazin-I -yl, C-R4 has R configuration and the other substituents are as described for compound A)
Il composto descritto neH'E.sempio 9 è stato sciolto iri DMF anidra e trattato con TEA e metansolionil cloruro. Dopo tre ore sotto agitazione a temperatura ambiente, la miscela viene purificata per HPLC preparativo come descritto nell'Esempio 5. The compound described in Example 9 was dissolved in anhydrous DMF and treated with TEA and methanesolionyl chloride. After three hours under stirring at room temperature, the mixture is purified by preparative HPLC as described in Example 5.
1H-NMR (DMSO-d6, 500 MHz): d 2.41 (1H,t, J = 11.1 Hz); 2.66-2.81 (3H, m); 2.81-3.00 (5H, m); 2.92 (3H, s); 3.00-3.61 (m, sovrapposto al segnale dell'acqua); 3.96-4.07 (1H, m); 4.12 (1H, bs); 4.19 (1H, bs); 6.92 (1H, d, J = 8.6 Hz); 6.98 (1H, t, J = .7.4. Hz); 7.03-7.30 (12H, m); 7.45 (1H, d, J = 7.9 Hz); 7.50 (1H, bs); .8.00-8.60 (1 H, bs); 8.75 (1H, bs); 10.82 (1H, s). 1H-NMR (DMSO-d6, 500 MHz): d 2.41 (1H, t, J = 11.1 Hz); 2.66-2.81 (3H, m); 2.81-3.00 (5H, m); 2.92 (3H, s); 3.00-3.61 (m, superimposed on the water signal); 3.96-4.07 (1H, m); 4.12 (1H, bs); 4.19 (1H, bs); 6.92 (1H, d, J = 8.6 Hz); 6.98 (1H, t, J = .7.4. Hz); 7.03-7.30 (12H, m); 7.45 (1H, d, J = 7.9 Hz); 7.50 (1H, bs); 8.00-8.60 (1H, bs); 8.75 (1H, bs); 10.82 (1H, s).
MS: m/z = 728,.MH<+>MS: m / z = 728, .MH <+>
ESEMPIO 12: .ciclo{Suc[1-(S)-(4-metansoifonii-piperazin-1-il)]-Trp-Phe-[(R)-NH-CH(CH2-C6H5)-CH2NH]},EXAMPLE 12: {Suc [1- (S) - (4-metansoifonii-piperazin-1-yl)] cycle - Trp-Phe - [(R) -NH-CH (CH2-C6H5) -CH2NH]},
(composto di formula generale I in cui R4 è 4-metansolfonil-piperazin-1 -il e gli altri sostituenti sono come descritto per il composto A) MS: m/z = 728, MH<+>. (compound of general formula I in which R4 is 4-methanesulfonyl-piperazin-1 -yl and the other substituents are as described for compound A) MS: m / z = 728, MH <+>.
ESEMPIO 13: ciclo{Suc[1 -(R)-(2-furilmetil)amino]-Trp-Phe-[(R)-NH-CH(CH2-C6H5)-CH2NH]} EXAMPLE 13: {Suc [1 - (R) - (2-furylmethyl) amino] -Trp-Phe - [(R) -NH-CH (CH2-C6H5) -CH2NH] cycle
(composto di formula generale I in cui R4 è (2-furilmetil)amino, C-R4 ha configurazione R e gli altri sostituenti sono come descritto per il composto A) (compound of general formula I where R4 is (2-furylmethyl) amino, C-R4 has R configuration and the other substituents are as described for compound A)
Il composto è stato preparato utilizzando, una procedura analoga a quella descritta nell'Esempio 5, utilizzando còme reagente 2-furaldeide e lasciando reagire per 4 ore. Il prodotto grezzo così ottenuto è stato purificato per HPLC preparativo come descritto. nell'Esempio 9. The compound was prepared using a procedure similar to that described in Example 5, using 2-furaldehyde as reagent and letting it react for 4 hours. The crude product thus obtained was purified by preparative HPLC as described. in Example 9.
1H-NMR (DMSO-d6, 500 MHz): d 2.39-2.46 (1H, m); 2.69-2.96 (5H,m); 3.02-3.22 (2H, bs); 3.57-3.82 (IH, bs); 4.04, 4.16 e 4.30 (5H, bs); 6.50 (1H, bs); 6.59 (1H, bs); 6.84 (1H, d, J = 7.1 Hz); 6,99 (1H. m); 7.04-7.28 (14H, m); 7.35 (IH, d, J = 8.1 Hz); 7.48 (1H, d, J = 7.8 Hz); 7.74 (1H. bs); 8.81 (1H, bs); S.22-9.69 (1H, bs); 10.88 (1H, s). 1H-NMR (DMSO-d6, 500 MHz): d 2.39-2.46 (1H, m); 2.69-2.96 (5H, m); 3.02-3.22 (2H, bs); 3.57-3.82 (1H, bs); 4.04, 4.16 and 4.30 (5H, bs); 6.50 (1H, bs); 6.59 (1H, bs); 6.84 (1H, d, J = 7.1 Hz); 6.99 (1H. M); 7.04-7.28 (14H, m); 7.35 (1H, d, J = 8.1 Hz); 7.48 (1H, d, J = 7.8 Hz); 7.74 (1H. Bs); 8.81 (1H, bs); S.22-9.69 (1H, bs); 10.88 (1H, s).
MS: m/z = 661 , MH<+>. MS: m / z = 661, MH <+>.
ESEMPIO . 14: ciclo{Suc[1-(R)-(4-ietraidropiranil)amino]-Trp-Phe-[{R)-NH-CH(CH2-C6H5)-CH2NH]} EXAMPLE . 14: {Suc [1- (R) - (4-ietrahydropyranil) amino] -Trp-Phe - [{R) -NH-CH (CH2-C6H5) -CH2NH] cycle
{composto di formula generale I in cui R4 è (4-tetraidropiranil)amino, C-R4 ha configurazione R e gii altri sostituenti sono come descritto per il composto A) {compound of general formula I in which R4 is (4-tetrahydropyranil) amino, C-R4 has R configuration and the other substituents are as described for compound A)
50 mg di isomero dei composto A con il C-R4 avente configurazione R, preparato in modo analogo a come descritto nell’ esempio 1a-1h: vengono sciolti in 5 mi di metanolo. Si aggiungono in sequenza acido acètico (0.1 mi), tetraidro-4H-piran-4-one (18 mg sciolti in 1 mi di metanolo) ed infine sodio cianoboroidruro (12 mg). Si mantiene una notte sotto agitazione. Si acidifica con HCI 1N sino a pH=1-2, si diluisce con acqua e si evapora il metanolo; sì aggiunge NaHC03 e si estrae con etile acetato, lavando con salamoia ed essiccando su sodio solfato. Si concentra e si purifica per· HPLC preparativo (colonna: Deltapak RP18 100 À ,19 x 300 mm; flusso; -15 ml/min; I = 220, 270 nm; fase mobile: A= H2O 0.1% TFA, B = CH3CN 0.1% TFA, gradiente da A:B = 75:25 a A.B = 15:85 in 120 min. 50 mg of isomer of compound A with C-R4 having R configuration, prepared in the same way as described in example 1a-1h: they are dissolved in 5 ml of methanol. Acetic acid (0.1 ml), tetrahydro-4H-piran-4-one (18 mg dissolved in 1 ml of methanol) and finally sodium cyanoborohydride (12 mg) are added in sequence. It is kept under stirring overnight. It is acidified with 1N HCI up to pH = 1-2, diluted with water and the methanol evaporated; NaHC03 is added and it is extracted with ethyl acetate, washing with brine and drying over sodium sulphate. It is concentrated and purified by preparative HPLC (column: Deltapak RP18 100 A, 19 x 300 mm; flow; -15 ml / min; I = 220, 270 nm; mobile phase: A = H2O 0.1% TFA, B = CH3CN 0.1% TFA, gradient from A: B = 75:25 to A.B = 15:85 in 120 min.
1H-NMR (DMSO-d6, 500 MHz): d 1.57 .(2H, bs); 1.90-2.04 (2H, m); 2,38-2.47 (1H, m); 2.67-2.98 (5H,m); 3.06-3.25 (4H, m); 3.25-3.42 (m, sovrapposto al segnale dell'acqua); 3.72 (1H, bs); 3.82-3.95 (2H, m); 3.95-4.11 (2H, m); 4.25 (1H, bs); 4.33 (1H, m); 6.86 (1 H, d, J = 8^4 Hz); 6:97- 7.03 (1H, m); 7.04-7.31 (12H, m); 7.35 (1H, d, J = 8.1 Hz); 7.41-7.51 (1 H, bs); 7.43 (IH, d, J = 7.9 Hz); 8.82-9.11 (3H, m); 10.85 (IH, d, J = 1.0 Hz). 1H-NMR (DMSO-d6, 500 MHz): d 1.57. (2H, bs); 1.90-2.04 (2H, m); 2.38-2.47 (1H, m); 2.67-2.98 (5H, m); 3.06-3.25 (4H, m); 3.25-3.42 (m, superimposed on the water signal); 3.72 (1H, bs); 3.82-3.95 (2H, m); 3.95-4.11 (2H, m); 4.25 (1H, bs); 4.33 (1H, m); 6.86 (1 H, d, J = 8 ^ 4 Hz); 6: 97-7.03 (1H, m); 7.04-7.31 (12H, m); 7.35 (1H, d, J = 8.1 Hz); 7.41-7.51 (1H, bs); 7.43 (1H, d, J = 7.9 Hz); 8.82-9.11 (3H, m); 10.85 (1H, d, J = 1.0 Hz).
MS: m/z = 665, MH<+>MS: m / z = 665, MH <+>
ESEMPIO 15: ciclo{Suc[1-(R)-(1 -metil-piperidin-4-il)amino]-Trp-Phe-[(R)-NH-CH(CH2-C6H5)-CM2NH]} EXAMPLE 15: {Suc [1- (R) - (1 -methyl-piperidin-4-yl) amino] -Trp-Phe - [(R) -NH-CH (CH2-C6H5) -CM2NH] cycle
(composto di formula generale I in cui R4 è (1 -metil-piperiain-4-il)amino, C-R4 ha configurazione R e gli altri sostituenti sono come descritto per il composto A) (compound of general formula I where R4 is (1-methyl-piperiain-4-yl) amino, C-R4 has R configuration and the other substituents are as described for compound A)
Il composto viene ottenuto mediante la procedura descritta nell'Esempio 14 , ma utilizzando come reagente 1 -metil-4-piperidone. The compound is obtained by means of the procedure described in Example 14, but using 1-methyl-4-piperidone as reagent.
1 H-NMR (DMS0-d6, 500 MHz): d 1.75 (2H, bs); 2.Ί7 (1H, -bs); 2.25 (IH, bs); 2.34-2.38 (1 H, m); 2.69-3.05 (m sovrapposti a bs); 2.75 (s); 3.05-3.58 (m, sovrapposto al segnale dell'acqua); 3.70 (1 H, bs); 3.93-4.10 (2H, bs); 4.10-4.39 (2H, bs); 6.85 (1H, d, J = 8.4 Hz); 7.00 (1H, m); 7.05-7.36 (12H, m); 7.36. (1H, d, J = 8.1 Hz); 7.43 (1H, bs); 7.49 (1 H, d, J = 8.0 Hz); 8.94 (1H, bs); 9.26 (1H, bs); 9.72 (1H, bs); 10.90 (1 H, s). 1 H-NMR (DMS0-d6, 500 MHz): d 1.75 (2H, bs); 2.Ί7 (1H, -bs); 2.25 (1H, bs); 2.34-2.38 (1H, m); 2.69-3.05 (m superimposed on bs); 2.75 (s); 3.05-3.58 (m, superimposed on the water signal); 3.70 (1H, bs); 3.93-4.10 (2H, bs); 4.10-4.39 (2H, bs); 6.85 (1H, d, J = 8.4 Hz); 7.00 (1H, m); 7.05-7.36 (12H, m); 7.36. (1H, d, J = 8.1 Hz); 7.43 (1H, bs); 7.49 (1 H, d, J = 8.0 Hz); 8.94 (1H, bs); 9.26 (1H, bs); 9.72 (1H, bs); 10.90 (1 H, s).
MS: m/z = 678, MH<+>. MS: m / z = 678, MH <+>.
ESEMPIO 16: ciclo{Suc[1-(S)-(2-guanidinoacetil)amino]-Trp-Phe-[(R)-NH-CH(CH2-C6H5)-CH2NH]} EXAMPLE 16: {Suc [1- (S) - (2-guanidinoacetyl) amino] -Trp-Phe - [(R) -NH-CH (CH2-C6H5) -CH2NH] cycle
(compósto di formula generale I in cui R4 è (2-guanidinoacetil)amino e gli altri sostituenti sono come descritto per il composto A) (compound of general formula I in which R4 is (2-guanidinoacetyl) amino and the other substituents are as described for compound A)
Ad una soluzione di 80 mg di composto A, preparato come descritto in esempio 1 e 23. mg di BocGlyOH in 1 mi di DMF, si aggiungono 30 mg di EDCI.HCI e 21 mg di 1 idrossibenzotriazolo. Dopo 1h a temperatura ambiente sotto agitazione magnetica, si concentra la miscela di reazione sotto vuoto e la si diluisce con acqua. Per filtrazione ed essiccamento si ottengono 120 mg di prodotto grezzo che viene sciolto in 10 m| di diclorometano e trattato con 1 mi di acido trifluoroacetico. Dopo tre ore a temperatura ambiente, il solvente viene eliminato sotto vuoto a dare 127 mg di trifluoroacetato grezzo che viene sciolto in 700 mi di DMF. A questa soluzione, si aggiungono 65 ml di diisopropiletilammina e 28 mg di pìrazolocarbossiamidina. Si lascia sotto agitazione magnetica, a temperatura ambiente per 20 h, dopodiché si elimina il solvente sotto vuoto e si isola il composto voluto per H IPLC preparativo. To a solution of 80 mg of compound A, prepared as described in examples 1 and 23. mg of BocGlyOH in 1 ml of DMF, 30 mg of EDCI.HCI and 21 mg of 1 hydroxybenzotriazole are added. After 1 hour at room temperature under magnetic stirring, the reaction mixture is concentrated under vacuum and diluted with water. By filtration and drying 120 mg of crude product are obtained which is dissolved in 10 m | of dichloromethane and treated with 1 ml of trifluoroacetic acid. After three hours at room temperature, the solvent is removed under vacuum to give 127 mg of crude trifluoroacetate which is dissolved in 700 ml of DMF. To this solution, 65 ml of diisopropylethylamine and 28 mg of pìrazolocarboxiamidine are added. The mixture is left under magnetic stirring, at room temperature for 20 h, after which the solvent is removed under vacuum and the desired compound is isolated for preparative H IPLC.
1H-NMR (DMSO-dS, 500 MHz): d 10.83 (d, J =1.9, 1H); 9.87 (m, 1H); 8.85 (d, J = 4.8, 1H); 8.70 (s broad, 1H); 8.61 (d, J = 7.5, 1H); 7.96 (d, J = 8.6, 1 H); 6.90-7.60 (m, 21 H); 4.78 (m, 1H); 4.26 (m,1H); 4.01 (m, 2H); 2.40-3.36 (m, 10H).. 1H-NMR (DMSO-dS, 500 MHz): d 10.83 (d, J = 1.9, 1H); 9.87 (m, 1H); 8.85 (d, J = 4.8, 1H); 8.70 (broad s, 1H); 8.61 (d, J = 7.5, 1H); 7.96 (d, J = 8.6, 1H); 6.90-7.60 (m, 21H); 4.78 (m, 1H); 4.26 (m, 1H); 4.01 (m, 2H); 2.40-3.36 (m, 10H) ..
MS: m/z = 680 MH<+>. MS: m / z = 680 MH <+>.
ESEMPIO 17: ciclo{Suc[1 -(S)-2-(4mnorfolinoacetil)amino]-Trp-Phe-[(R)-NH-CH(CH2-C6H5)-CH2!\IH]} . EXAMPLE 17: {Suc [1 - (S) -2- (4mnorfolinoacetyl) amino] -Trp-Phe - [(R) -NH-CH (CH2-C6H5) -CH2! \ IH]} cycle.
(composto di formula generale I in cui R4 è 2-(4-morfoiinoacetil)amino e gli altri sostituenti sono come descritto per il composto A) (compound of general formula I where R4 is 2- (4-morfoiinoacetyl) amino and the other substituents are as described for compound A)
A 21 mg di acido 2-(4-morfolin)acetico, sciolti in 5 mi DMF, si aggiungono 40 mg di 1-idrossibenzotriazplo e 20 mg di EDCI.HCI. Si lascia sotto agitazione per circa 10 minuti, e si aggiungono 60 mg di ciclo{Suc[1-(S)-amino]-Trp-Phe-[{R)-NH-CH(CH2-C6H5)-CH2NH]y Dopo.4 ore si evapora e si purifica per HPLC preparativo col metodo descritto nell'Esempio 9. To 21 mg of 2- (4-morpholin) acetic acid, dissolved in 5 ml DMF, 40 mg of 1-hydroxybenzotriazplo and 20 mg of EDCI.HCI are added. It is left under stirring for about 10 minutes, and 60 mg of {Suc [1- (S) -amino] -Trp-Phe - [{R) -NH-CH (CH2-C6H5) -CH2NH] cycle are added. 4 hours it is evaporated and purified by preparative HPLC with the method described in Example 9.
1H-NMR (DMSOde, 500 MHz): d 2.57 (1H,dd, J = 4.4; 15.7 Hz); 2.662.85 (7H, m); 2.98-3.59 (bs, sovrapposto al segnale dell'acqua); 3.26 (dd, J = 4.4; 14.3 Hz);. 3.59-4.03 (6H, m); 4.03-4.15 (2H,m); 4.36 (1H, m); 4.77 (1 H,. bs); 6.84 (IH, bs); 6.94 (1 H, d, J = 2.0 Hz); 6.98 (1H, t, J = 7.2 Hz); 7.07 (1H, t, J = 7.2 Hz); 7.13-7.31 (9H, m); 7.33 (1 H,<'>d, J = 8;1 Hz); 7.41 (1H, d. J = 7.8Hz); 8.32 (1H, bs); 8.49 (1H, d, J = 4=8 Hz); 8.86-9.10 (IH, bs); 10.10-10.30 (1H, bs); 10.81 (1 H, d, J = 1.7 Hz). MS: m/z = 708, MH<+>. 1H-NMR (DMSOde, 500 MHz): d 2.57 (1H, dd, J = 4.4; 15.7 Hz); 2,662.85 (7H, m); 2.98-3.59 (bs, superimposed on the water signal); 3.26 (dd, J = 4.4; 14.3 Hz); 3.59-4.03 (6H, m); 4.03-4.15 (2H, m); 4.36 (1H, m); 4.77 (1 H ,. bs); 6.84 (1H, bs); 6.94 (1 H, d, J = 2.0 Hz); 6.98 (1H, t, J = 7.2 Hz); 7.07 (1H, t, J = 7.2 Hz); 7.13-7.31 (9H, m); 7.33 (1 H, <'> d, J = 8; 1 Hz); 7.41 (1H, d. J = 7.8Hz); 8.32 (1H, bs); 8.49 (1H, d, J = 4 = 8 Hz); 8.86-9.10 (1H, bs); 10.10-10.30 (1H, bs); 10.81 (1 H, d, J = 1.7 Hz). MS: m / z = 708, MH <+>.
Con analoga procedura sperimentale sono stati, ottenuti: With a similar experimental procedure, the following were obtained:
ESEMPIO 18: ciclo{Suc[1 -(R)-2-(4-morfolinoacetil)amino]-T rp-Phe-[(R)-NH-CH(CH2-C6H5)-CH2NH]} EXAMPLE 18: {Suc [1 - (R) -2- (4-morpholinoacetyl) amino] -T rp-Phe - [(R) -NH-CH (CH2-C6H5) -CH2NH] cycle
(composto di formula generale l in. cui R4 è 2-(4-morfolinoacetil)amino, C-R4 ha configurazione R e gli altri sostituenti sono come descritto per il composto A) (compound of general formula l where R4 is 2- (4-morpholinoacetyl) amino, C-R4 has R configuration and the other substituents are as described for compound A)
1H-NMR (DMSO-d6, 500 MHz): d 2.34 (1 H, dd, J = 8.3, 14.2 Hz); 2.71-2.90 (5H, m); 2.97 (1H, dd, J = 4.1, 14.2 Hz); 3.00-3.24 (4H, bs); 3.26-3.53 (m, sovrapposto al segnale dell'acqua); 3.79 (6H, bs); 4.00-4.10 (1H,m); 4.13-4.20 (1H, m); 4.20-4.27 (1H, m); 4.59-4.68 (IH, m); 6.79 (1 H, d, J = 8.1 Hz); 6.95-7.01 (1 H, m); 7.05-7.10 (1H, m); 7.15-7.20 (4H, m); 7.23-7.29 (7H, m); 7.35 (1H, d, J = 8.1 Hz); 7.47 (1 H, d, J = 7.8. Hz); 8.04 (1H, bs); 8.60 (1 H, d, J = 5.2 Hz); 8.53-8.70 (1H, bs); 10.70 (1H, s). 1H-NMR (DMSO-d6, 500 MHz): d 2.34 (1 H, dd, J = 8.3, 14.2 Hz); 2.71-2.90 (5H, m); 2.97 (1H, dd, J = 4.1, 14.2 Hz); 3.00-3.24 (4H, bs); 3.26-3.53 (m, superimposed on the water signal); 3.79 (6H, bs); 4.00-4.10 (1H, m); 4.13-4.20 (1H, m); 4.20-4.27 (1H, m); 4.59-4.68 (1H, m); 6.79 (1 H, d, J = 8.1 Hz); 6.95-7.01 (1H, m); 7.05-7.10 (1H, m); 7.15-7.20 (4H, m); 7.23-7.29 (7H, m); 7.35 (1H, d, J = 8.1 Hz); 7.47 (1 H, d, J = 7.8. Hz); 8.04 (1H, bs); 8.60 (1H, d, J = 5.2 Hz); 8.53-8.70 (1H, bs); 10.70 (1H, s).
MS: m/z = 708, MH<+>. MS: m / z = 708, MH <+>.
ESEMPIO . 19: ciclo{Suc[1-{R)-(4-guanidinobenzoil)amino]-Trp-Phe-[(R)-NH-CH(CH2-C6H5)-CH2NH]} EXAMPLE . 19: {Suc [1- {R) - (4-guanidinobenzoyl) amino] -Trp-Phe - [(R) -NH-CH (CH2-C6H5) -CH2NH] cycle
(composto di formula generale I in cui R4 è (4guanidinobenzoil)amino, C-R4 ha configurazione R e gli altri sostituenti sono come descritto per il composto A) (compound of general formula I where R4 is (4guanidinobenzoyl) amino, C-R4 has R configuration and the other substituents are as described for compound A)
1.H-NMR (DMSO-d6, 500 MHz): d 10.81 (s, 1H); 8.52 (d, J = 5.4, 1H); 8.47 (d, J = 7.9, 1 H); 8.26 (dd, J = 4.0, 8.3, 1H); 6.90-7.75 (m, 17H); 6.82 (d, J = 9.2, IH); 4.76 {m, 1H); 4.34 (m,.1H); 4,11 (m, 1H); 3.80-3.90 (m, 2H); 3.71 (m, 1H); 3.25-3.35 (m, 1H); 2.60-2.85 (m, 6H); 2.45-2.55 (m, 1H).. . 1.H-NMR (DMSO-d6, 500 MHz): d 10.81 (s, 1H); 8.52 (d, J = 5.4, 1H); 8.47 (d, J = 7.9, 1H); 8.26 (dd, J = 4.0, 8.3, 1H); 6.90-7.75 (m, 17H); 6.82 (d, J = 9.2, 1H); 4.76 {m, 1H); 4.34 (m, .1H); 4.11 (m, 1H); 3.80-3.90 (m, 2H); 3.71 (m, 1H); 3.25-3.35 (m, 1H); 2.60-2.85 (m, 6H); 2.45-2.55 (m, 1H) ...
MS: m/z = 680 MH<+>. MS: m / z = 680 MH <+>.
ESEMPIO 20: ciclo{Suc[1-(S)-decanoilamino]-Trp-Phe-[(R)-NH-CH(CH2-C6H5)-CH2NH]} EXAMPLE 20: cycle {Suc [1- (S) -decanoylamino] -Trp-Phe - [(R) -NH-CH (CH2-C6H5) -CH2NH]}
{composto di formula generale I in cui R4 è decanoiiamino e gli altri sostituenti sono come descritto per il composto A) {compound of general formula I in which R4 is decanoiiamino and the other substituents are as described for compound A)
1H-NMR (DMSO-d6, 500 MHz): d 10.81 (d, J = 2.2, 1H): 8.54 (d, J = 5.4, 1H); 8.13-8.21 (m, 2H); 6.75-7.45 (m, 17H); 4.70 (m, 1H); 4.33 (m,1H); 4.11 (m, 1H); 4.02 (m, 1 H); 3.96 (m, IH); 3.30 (m, 1H); 2.65-2.80 {m, 7H) 2.45-2.55 (m, IH); 2.01 (t, J = 7.32, 2H); 1.48. {m, 2H); 1.15-1.30 (m, 12H); 0.84 (t, J = 6.7, 3H). 1H-NMR (DMSO-d6, 500 MHz): d 10.81 (d, J = 2.2, 1H): 8.54 (d, J = 5.4, 1H); 8.13-8.21 (m, 2H); 6.75-7.45 (m, 17H); 4.70 (m, 1H); 4.33 (m, 1H); 4.11 (m, 1H); 4.02 (m, 1H); 3.96 (m, 1H); 3.30 (m, 1H); 2.65-2.80 {m, 7H) 2.45-2.55 (m, 1H); 2.01 (t, J = 7.32, 2H); 1.48. {m, 2H); 1.15-1.30 (m, 12H); 0.84 (t, J = 6.7, 3H).
MS: m/z = 735 MH+. MS: m / z = 735 MH +.
ESEMPIO 21: cicÌo{Suc[1-{S)-(2-tetrazol-1-il)acetilaming]-Trp'Phè-[(R)-NH-CH(CH2-C6H5)-CH2NH]} EXAMPLE 21: cyclo {Suc [1- {S) - (2-tetrazol-1-yl) acetylaming] -Trp'Phè - [(R) -NH-CH (CH2-C6H5) -CH2NH]}
(composto di formula generale I in cui R4 é (2-tetrazol-1-i!)acetilamino e gli altri sostituenti sono come descritto perii composto A) (compound of general formula I wherein R4 is (2-tetrazol-1-i!) acetylamino and the other substituents are as described for compound A)
1H-NMR (DMSO-d6, 500 MHz): d 10.80 (d, J> 2.0, 1H); 9.32 (s, 1H); 8.87 (d, J = 80, 1H); 8.52 (d, J= 5.3, 1H); 8.38 (dd; J = 4.0, 8.5 IH); 6.93-7.42 (m, 17H); 6.78 (d: J 9.3, 1H); 5.27 e.5.30 (spettro AB, J = 16.6, 2H); 4.76 (m, IH); 4.35 (m,1H); 4.01-4.13. (m, 2H); 3.73 (m, 1H); 3.25-3.35 (m, .IH); 2.54-2.86 (m, 8H). 1H-NMR (DMSO-d6, 500 MHz): d 10.80 (d, J> 2.0, 1H); 9.32 (s, 1H); 8.87 (d, J = 80, 1H); 8.52 (d, J = 5.3, 1H); 8.38 (dd; J = 4.0, 8.5 1H); 6.93-7.42 (m, 17H); 6.78 (d: J 9.3, 1H); 5.27 and.5.30 (spectrum AB, J = 16.6, 2H); 4.76 (m, 1H); 4.35 (m, 1H); 4.01-4.13. (m, 2H); 3.73 (m, 1H); 3.25-3.35 (m, .IH); 2.54-2.86 (m, 8H).
MS: m/z = 691 , MH<+>. MS: m / z = 691, MH <+>.
ESEMPIO 22: ciclo{Suc[1-(S)-(2-(5-mercapto-tetrazol-1-il)acetìlamino]-Trp-Phe-[(R)-NH-CH(CH2-C6H5)-CH2NH]} EXAMPLE 22: cycle {Suc [1- (S) - (2- (5-mercapto-tetrazol-1-yl) acetylamino] -Trp-Phe - [(R) -NH-CH (CH2-C6H5) -CH2NH] }
(composto di formula generale ! in cui R4 e (2-(5-mercapto-tetrazol-1-il)acetilamino e gli altri sostituenti sono come descritto per il composto A) (compound of general formula! wherein R4 and (2- (5-mercapto-tetrazol-1-yl) acetylamino and the other substituents are as described for compound A)
1H-NMR (DMSO-d6, 500 MHz): d 10.79 (d, J = 1.8, 1H); 8.79 (d, J-.= 7.9, 1H); 8.54 (d, J=- 5,2. 1H); 8.39 (dd, J = 5.4, 8.2 1H); 7.40 (d, J= 7.8, 1H); 6.96-7.34 (m, 15H); 6.95 (s, IH); 6.77 (d, J= 9.3, 1H); 4.98 e 5:01 (spettro AB, J = 16.7, 2H); 4.75 (m, 1H); 4.35 (m,1H); 4.01-4.12 (m, 2H); 3:74 (m, IH); 3.32-3.35 (m, 1H); 2.63-2:85 (m, 7H); 2.58 (dd, J = 4.8, 15.5, IH). 1H-NMR (DMSO-d6, 500 MHz): d 10.79 (d, J = 1.8, 1H); 8.79 (d, J -. = 7.9, 1H); 8.54 (d, J = - 5.2.1H); 8.39 (dd, J = 5.4, 8.2 1H); 7.40 (d, J = 7.8, 1H); 6.96-7.34 (m, 15H); 6.95 (s, 1H); 6.77 (d, J = 9.3, 1H); 4.98 and 5:01 (spectrum AB, J = 16.7, 2H); 4.75 (m, 1H); 4.35 (m, 1H); 4.01-4.12 (m, 2H); 3:74 (m, 1H); 3.32-3.35 (m, 1H); 2.63-2: 85 (m, 7H); 2.58 (dd, J = 4.8, 15.5, 1H).
MS: m/z = 723, MH<+>MS: m / z = 723, MH <+>
ESEMPIO 23: ciclo{Suc[1 -(S)-(3,4,5-triidrossi)benzoilamino]-Trp-Phe-[(R)-NH-CH(CH2-C6H5)-CH2NH]} EXAMPLE 23: cycle {Suc [1 - (S) - (3,4,5-trihydroxy) benzoylamino] -Trp-Phe - [(R) -NH-CH (CH2-C6H5) -CH2NH]}
(composto di formula generale I in cui R4 è (3,4,5-triidrossi)benzoilamino e gli altri sostituenti sono come descritto per il composto A) (compound of general formula I in which R4 is (3,4,5-trihydroxy) benzoylamino and the other substituents are as described for compound A)
1H-NMR (DMSO-d6, 500 MHz): d 10.80 (d, J = 2.0, 1.H); 9.02 (s broad, 1H); 8.71 (s broad, 1H); 8.61 (d, J - 5.4, ..1H); 8.32 (d, J= 7.8, 1 H); 7.88 (s broad, 1H); 7.58 (s. broad, 1H); 7/44 (d, J = 7.9, 1H); 7.15-7.35 (m, 10H); 6.90-7.09 (m, 7H); 4.82 (m, 1H); 4.30 (m,1H); 4.17 (m, 1H); 4.01 (m, 1 H); 3.61 (m, 1H); 3.25-3.32,(m, 1H); 2.71-2.93 (m, 7H); 2.54 (dd, J = 4.3, 14.9, 1 H). 1H-NMR (DMSO-d6, 500 MHz): d 10.80 (d, J = 2.0, 1.H); 9.02 (broad s, 1H); 8.71 (broad s, 1H); 8.61 (d, J - 5.4, ..1H); 8.32 (d, J = 7.8, 1H); 7.88 (broad s, 1H); 7.58 (broad s., 1H); 7/44 (d, J = 7.9, 1H); 7.15-7.35 (m, 10H); 6.90-7.09 (m, 7H); 4.82 (m, 1H); 4.30 (m, 1H); 4.17 (m, 1H); 4.01 (m, 1H); 3.61 (m, 1H); 3.25-3.32, (m, 1H); 2.71-2.93 (m, 7H); 2.54 (dd, J = 4.3, 14.9, 1H).
MS: m/z = 733, MH<+>MS: m / z = 733, MH <+>
ESEMPIO 24: ciclo{Suc[1-(S)-(2,6-diidrossipiridin-4-carbonil)amino]-Trp-Phe-[(R)-NH-CH(CH2-C6H5)-CH2NH]} EXAMPLE 24: {Suc [1- (S) - (2,6-dihydroxypyridine-4-carbonyl) amino] -Trp-Phe - [(R) -NH-CH (CH2-C6H5) -CH2NH] cycle
(composto di formula generale I in cui R4 è (2,6rdiidrossipiridin-4-carbonil)amino e gli altri sostituenti sono come descritto per il composto A) (compound of general formula I in which R4 is (2,6rdihydroxypyridine-4-carbonyl) amino and the other substituents are as described for compound A)
1H-NMR (DMSO-d6, 500 MHz): d 10.81 (d, J = 1.9, 1H); 8.76 (d, J = 7.7 1 H); 8.61 (d, J = 5.3, 1H); 7.97 (s broad, 1H); 7.95 (s, 1H); 7.53 (s broad, 1H); 6.90-7.45 (m, 16H); 6.25 (s broad, 1H); 4.80 (m,.1H); 4.31 (m, 1H); 4.17 (m, 1H); 4.02 (rri, 1H); 3.62 (m, -1 H); 3.28 (dd, J = 4.8, 1.4:1 , 1 H); 2.89 (m, 1H): 2..70-2.87 (m, 6H); 2.56 (dd, J = 4.3, 15.0, 1 H). MS: m/z = 718, MH<+>. 1H-NMR (DMSO-d6, 500 MHz): d 10.81 (d, J = 1.9, 1H); 8.76 (d, J = 7.7 1 H); 8.61 (d, J = 5.3, 1H); 7.97 (broad s, 1H); 7.95 (s, 1H); 7.53 (broad s, 1H); 6.90-7.45 (m, 16H); 6.25 (broad s, 1H); 4.80 (m, .1H); 4.31 (m, 1H); 4.17 (m, 1H); 4.02 (rri, 1H); 3.62 (m, -1H); 3.28 (dd, J = 4.8, 1.4: 1, 1H); 2.89 (m, 1H); 2..70-2.87 (m, 6H); 2.56 (dd, J = 4.3, 15.0, 1H). MS: m / z = 718, MH <+>.
ESEMPIO 25: ciclo{Suc[1 (S)-(6-oxo-1,6-diidropiridazin-3-carbonil)amino]-Trp-Phe-[(R)-NH-CH(CH2-C6H5)-CH2NH]} (composto di formula generale I in cui R4 è (6rOxo-1,6-diidropiridazin-3-carbonil)amino e gli altri sostituenti· sono come descritto per il composto A) EXAMPLE 25: cycle {Suc [1 (S) - (6-oxo-1,6-dihydropyridazin-3-carbonyl) amino] -Trp-Phe - [(R) -NH-CH (CH2-C6H5) -CH2NH] } (compound of general formula I in which R4 is (6rOxo-1,6-dihydropyridazin-3-carbonyl) amino and the other substituents are as described for compound A)
1H-NMR (DMSO-d6, 500 MHz): d 13.50 (s, IH) 10.80 (d, J = 2.0, 1 H); 8.48 (d, J = 5.2, IH); 8.41 (d, J = 7.9, 1H); 8.16 (dd, J = 4.7, 7.5, 1H); 7.84 (d, J = 9.9, .1 H); 7.46 (d, J = 8.8, 1H); 7.43 (d, J = 7.9, 1H); 7.32 (d,. J = 8.1, 1H); -7.15-7.30 (m, 9H); 6.94-7.08 (m, 5H); 4.83 (m, 1H); 4.33 (m, 1 H); 4.11 (m, 1H); 4.04 (m, 1H); 3.63. (m, 1H); 3.28 (dd, J = 5.0, 14.0, 1 H); 2.58-2.95 (m, 8H). 1H-NMR (DMSO-d6, 500 MHz): d 13.50 (s, 1H) 10.80 (d, J = 2.0, 1 H); 8.48 (d, J = 5.2, 1H); 8.41 (d, J = 7.9, 1H); 8.16 (dd, J = 4.7, 7.5, 1H); 7.84 (d, J = 9.9, .1H); 7.46 (d, J = 8.8, 1H); 7.43 (d, J = 7.9, 1H); 7.32 (d ,. J = 8.1, 1H); -7.15-7.30 (m, 9H); 6.94-7.08 (m, 5H); 4.83 (m, 1H); 4.33 (m, 1H); 4.11 (m, 1H); 4.04 (m, 1H); 3.63. (m, 1H); 3.28 (dd, J = 5.0, 14.0, 1H); 2.58-2.95 (m, 8H).
MS. m/z = 703, MH<+>. MS. m / z = 703, MH <+>.
ESEMPIO 26: ciclo{Suc[1-(R)--(6-oxo-1,6-diidropiridazin-3-carbonil)amino]-frp-Phe"[(R)-NH-CH(CH2-C6H5)-CH2NH]} (composto di formula generale i in cui R4 è (6-oxo-l,6-diidropiridazin-3-carbonil)amino, C-R4 ha configurazione R e gli altri sostituenti sono come descritto per il composto A) EXAMPLE 26: {Suc [1- (R) - (6-oxo-1,6-dihydropyridazin-3-carbonyl) amino] -frp-Phe "[(R) -NH-CH (CH2-C6H5) - cycle CH2NH]} (compound of general formula i in which R4 is (6-oxo-1,6-dihydropyridazin-3-carbonyl) amino, C-R4 has R configuration and the other substituents are as described for compound A)
1H-NMR (DMSO-d6, 500 MHz): d 13.41 (d, J = 2.1, 1H) 10.81 (s broad, 1H); 8.78 (d, J = 5.2, 1H); 8.50 (d, J = 8,9, IH); 7.88 (dd, J = 1·7, 9.8, 1 H); 7.79 (t broad, 1H); 7.68 (d broad, 1 H); 7.43 (d, J = 7.8, 1 H); 7.33 (d, J = 8.1, IH); 7.14-7.31 (m, 10H); 6.96-7.09 (m, 4H); 6.70 (d, J = 9.2, 1H) 4.78 (m 1H); 4..26 (m, 1H);^4.19 (m, 1H); 4.04 (m, 1H); 3.52 (m, 1H); 3.28 (dd, J = Α.Ό, 14.4, 1H); 3.12 (m,2H); 2.67-2:79 (m, 3H); 2.50 (m sovrapposto al segnale del solvente, 1H. 1H-NMR (DMSO-d6, 500 MHz): d 13.41 (d, J = 2.1, 1H) 10.81 (s broad, 1H); 8.78 (d, J = 5.2, 1H); 8.50 (d, J = 8.9, 1H); 7.88 (dd, J = 1 · 7, 9.8, 1H); 7.79 (broad t, 1H); 7.68 (d broad, 1H); 7.43 (d, J = 7.8, 1H); 7.33 (d, J = 8.1, 1H); 7.14-7.31 (m, 10H); 6.96-7.09 (m, 4H); 6.70 (d, J = 9.2, 1H) 4.78 (m 1H); 4..26 (m, 1H); ^ 4.19 (m, 1H); 4.04 (m, 1H); 3.52 (m, 1H); 3.28 (dd, J = Α.Ό, 14.4, 1H); 3.12 (m, 2H); 2.67-2: 79 (m, 3H); 2.50 (m superimposed on the solvent signal, 1H.
MS: m/z = 703, MH<+>. MS: m / z = 703, MH <+>.
ESEMPIO 27: ciclo{Suc[1-(S)-N-metil-N-(6-oxo-1 ,6-diidropiridazin-3-carbonil)amino]-Trp-Phe-[(R)-NH-CH(CH2-C6H5)-CH2NH]} (composto di formula generale I in cui R4 è N-metil-N-(6-oxo-1,6-diidropiridazin-3-carbonil)amino e gli altri sostituenti sono come descritto per il composto A) EXAMPLE 27: {Suc [1- (S) -N-methyl-N- (6-oxo-1,6-dihydropyridazin-3-carbonyl) amino cycle] -Trp-Phe - [(R) -NH-CH ( CH2-C6H5) -CH2NH]} (compound of general formula I in which R4 is N-methyl-N- (6-oxo-1,6-dihydropyridazin-3-carbonyl) amino and the other substituents are as described for the compound TO)
MS: m/z = 717, MH+. MS: m / z = 717, MH +.
ESEMPIO 28: clcio{Suc{1-(S)-[2-(1,3-dimetil-2,6-dioxo-1 ,2,3,6-tetraidropurin-7-il)-aceti!amino]}-Trp-Phe-[(R)-NH-CH(CH2-C6H5)-CH2NH]} EXAMPLE 28: clcium {Suc {1- (S) - [2- (1,3-dimethyl-2,6-dioxo-1, 2,3,6-tetrahydropurin-7-yl) -aceti! Amino]} - Trp-Phe - [(R) -NH-CH (CH2-C6H5) -CH2NH]}
(composto di formula generale I in cui R4 è 2-(1,3-dimeti!-2,6-dioxo-1,2,3,6-tetraidropurin-7-il)-acetilamino e gli altri sostituenti sono come descritto per il composto A) (compound of general formula I wherein R4 is 2- (1,3-dimeth! -2,6-dioxo-1,2,3,6-tetrahydropurin-7-yl) -acetylamino and the other substituents are as described for compound A)
1H-NMR (DMS0-d6, 500 MHz): d 11.30 (s, 1 H); 10.81 (d, J> 2.0, 1 H); 10.78 (d, J = 4.1 , 1 H); 9.10 (d, J = 6.3, 1 H); 8.60 (d, J = 5.3, 1 H); 8.11 (s broad, 1H); 7.50 (d, J = 6.0, 1H); 7.43 (d, J = 7.8, 1H); 7.33 (d, J = 8.1, 1 H); 7.13-7.31 (m, 10H); 6.37-7.10 (m, 4H); 6.17 (s, IH); 4.79 (m, IH); 4.3† (m, 1H); 4.16 (m, 1H); 4.03 (m, 1H); 3.64 (m, 1H); 3.26 (dd, J = 4.6, 14.1, ,1H); 2.83-2.90 (m, 2H); 2.70-2..80 (m, 5.H); 2.58 (dd, J = 4.2, 15.1, ΊΗ). 1H-NMR (DMS0-d6, 500 MHz): d 11.30 (s, 1H); 10.81 (d, J> 2.0, 1H); 10.78 (d, J = 4.1, 1H); 9.10 (d, J = 6.3, 1H); 8.60 (d, J = 5.3, 1H); 8.11 (broad s, 1H); 7.50 (d, J = 6.0, 1H); 7.43 (d, J = 7.8, 1H); 7.33 (d, J = 8.1, 1H); 7.13-7.31 (m, 10H); 6.37-7.10 (m, 4H); 6.17 (s, 1H); 4.79 (m, 1H); 4.3 † (m, 1H); 4.16 (m, 1H); 4.03 (m, 1H); 3.64 (m, 1H); 3.26 (dd, J = 4.6, 14.1,, 1H); 2.83-2.90 (m, 2H); 2.70-2..80 (m, 5.H); 2.58 (dd, J = 4.2, 15.1, ΊΗ).
MS: m/z = 719, MH<+>. MS: m / z = 719, MH <+>.
ESEMPIO 29: ciclo{Suc[1-(R)-carbossimetilossicarbonilamino]-Trp-Phe-[(R)-NH-CH(CH2-C6H5)-CH2NH]} EXAMPLE 29: cycle {Suc [1- (R) -carboxymethyloxycarbonylamino] -Trp-Phe - [(R) -NH-CH (CH2-C6H5) -CH2NH]}
(composto di formula generale l in cui R4 è carbossimetilossicarbonilamino, C-R4 ha onfigurazione R e gli altri sostituenti sono come descritto per il composto A) (compound of general formula l in which R4 is carboxymethyloxycarbonylamino, C-R4 has an R configuration and the other substituents are as described for compound A)
A 290 mg di isomero de! composto A con il C-R4 avente configurazione R sciolti in 15 mi. di acetonitrile si aggiungono 65 mg di 1,4-diossano-2,6-dione. Si agita per 2 ore a temperatura ambiente. Si evapora e si purifica il residuo per HPLC preparativo con i metodi già descritti. At 290 mg of isomer de! compound A with C-R4 having R configuration dissolved in 15 ml. of acetonitrile, 65 mg of 1,4-dioxane-2,6-dione are added. It is stirred for 2 hours at room temperature. The residue is evaporated and purified by preparative HPLC with the methods already described.
1H-NMR (DMSO-d6, 500 MHz): d 2.35 (1H,dd, J = 8.0, 14.0 Hz); 2,67-2.82 (5H, m); 2.90(1 H, dd, J = 4.4, 14.0 Hz); 3.21-3.27 (1H, m); 3.30-3.50 (m, sovrapposto ai segnale dell'acqua); 3.95-4.10 (1H, m); 4.03 (2H, s); 4.15 (2H, s); 4.14-4.26 (1H. m); 4.67 (1 H, m); 6.77 (1H, d, J = 9.0 Hz); 6.95-7.00 (1H, m); 7.02-7.09 (2H, rri); 7.14-7.29 (10H, m); 7.32 (1 H, d, J = 8.1 Hz); 7.43 (1H, d, J = 7.9Hz); 7.47 (1H, bs); 7.95 (1H, bs); 8.04 (1Ή, d, J = 8.5 Hz); 3.76 (1H,d, J = 5.0 Hz); 10.81 (1H, d, J = 2.3 Hz); 12.7-12.9 (IH, bs). 1H-NMR (DMSO-d6, 500 MHz): d 2.35 (1H, dd, J = 8.0, 14.0 Hz); 2.67-2.82 (5H, m); 2.90 (1 H, dd, J = 4.4, 14.0 Hz); 3.21-3.27 (1H, m); 3.30-3.50 (m, superimposed on the water mark); 3.95-4.10 (1H, m); 4.03 (2H, s); 4.15 (2H, s); 4.14-4.26 (1H. M); 4.67 (1H, m); 6.77 (1H, d, J = 9.0 Hz); 6.95-7.00 (1H, m); 7.02-7.09 (2H, rri); 7.14-7.29 (10H, m); 7.32 (1 H, d, J = 8.1 Hz); 7.43 (1H, d, J = 7.9Hz); 7.47 (1H, bs); 7.95 (1H, bs); 8.04 (1Ή, d, J = 8.5 Hz); 3.76 (1H, d, J = 5.0 Hz); 10.81 (1H, d, J = 2.3 Hz); 12.7-12.9 (1H, bs).
MS: m/z - 697, MH<+>. MS: m / z - 697, MH <+>.
ESEMPIO 30: ciclo{Suc[1-(S)-(N,N-bis-(2-idrossietil)aminocarbonil]-Trp-Phe-[(R)-NH-CH(CH2-C6H5)-CH2NH]} (composto di formula generale I in cui R4 è N,N-bis-(2-idrossietil)aminocarbonil e gli altri sostituenti sono come descritto per il composto A) ed ESEMPIO 31: ciclo{Suc[1-(R)-(N,N-bis-(2-idrossietil)aminocarbonil]-Trp-Phe-[(R)-NH-CH(CH2-C6H5)-CH2NH]} (isomero con C-R4 avente la configurazione EXAMPLE 30: cycle {Suc [1- (S) - (N, N-bis- (2-hydroxyethyl) aminocarbonyl] -Trp-Phe - [(R) -NH-CH (CH2-C6H5) -CH2NH]} ( compound of general formula I wherein R4 is N, N-bis- (2-hydroxyethyl) aminocarbonyl and the other substituents are as described for compound A) and EXAMPLE 31: cycle {Suc [1- (R) - (N, N-bis- (2-hydroxyethyl) aminocarbonyl] -Trp-Phe - [(R) -NH-CH (CH2-C6H5) -CH2NH]} (isomer with C-R4 having the configuration
<R)><R)>
31.2. mg di ciclo{Suc[1-COOH]-Trp-Phe-[(R)-NH-CH(CH2-C6H5)-CH2NH]}, (ottenuto come miscela di diastereoisomeri in una sintesi analoga a quella per ottenere il composto A, ma utilizzando al posto dell’ acido aspartico, acido carbossi-succinico opportunamente protetto) vengono sciolti in 1 mi DMF anidra. Si aggiungono 80 mg di PyBOP, 5.7 mi di dietanoiammina e 0.2 mi di TEA. Si lascia sotto agitazione a temperatura ambiente per una notte, si evapora - la oluzione e si riprende il residuo. in etile acetato; si lava con KHSO4 5%, poi con NaHCOs 5% e infine con salamoia. Si essicca la fase organica su. magnesio solfato. Evaporando il solvente si ottiene un residuo che pesa 60 mg. Si purifica per HPLC preparativo (colonna: Jupiter RP 18 15 μ 300 A, 250 x 21.2 mm; flusso: 20 ml/min; 1 = 220, 270 nm; fase; mobile: A= H2O 0.1% TFA, B = CH3CN 0.1% TFA, gradiente da A:B = 90:10 a A:B - 30:70 in 120 min). diastereoisomero A ftR = 54.5 mini 31.2. mg of cycle {Suc [1-COOH] -Trp-Phe - [(R) -NH-CH (CH2-C6H5) -CH2NH]}, (obtained as a mixture of diastereoisomers in a synthesis similar to that to obtain compound A , but using suitably protected carboxy-succinic acid instead of aspartic acid) are dissolved in 1 ml anhydrous DMF. 80 mg of PyBOP, 5.7 ml of dietanoiamine and 0.2 ml of TEA are added. The mixture is left under stirring at room temperature for one night, the solution is evaporated and the residue is taken up. in ethyl acetate; it is washed with 5% KHSO4, then with 5% NaHCOs and finally with brine. The organic phase is dried up. magnesium sulfate. Evaporating the solvent, a residue weighing 60 mg is obtained. It is purified by preparative HPLC (column: Jupiter RP 18 15 μ 300 A, 250 x 21.2 mm; flow: 20 ml / min; 1 = 220, 270 nm; phase; mobile: A = H2O 0.1% TFA, B = CH3CN 0.1 % TFA, gradient from A: B = 90:10 to A: B - 30:70 in 120 min). diastereomer A ftR = 54.5 mini
1H-NMR (DMSO-d6, 500 MHz): d 2.23 (1H, t, J = 12.4 Hz); 2.63-2.77 (3H, m); 2.80-2.91 (2H, m); 2,97 (1H, dd, J = 11.0, 13.9 Hz); 3.13-3.20 (1H, m); 3.20-3.68 (m, sovrapposto al segnale dell'acqua); 3.87 (1H, ; dd, J = 3.0, 12.1 Hz); 3.90-4.02 (2H, m); 4.25-4.37 (1H, m); 4.64 (1H, t, J = 5.2 Hz); 4.91 (-1H, t, J ~ 5.2 Hz); 6.94-7.31 (15H, m); 7.35 (1H, d, J = 8.0 Hz);.7.48 (1H, d, J = 7.9 Hz); 8.65 (1H, d, J = 5.0 Hz); 8.94 (1H, , m); 10.87 (1H, bsj. 1H-NMR (DMSO-d6, 500 MHz): d 2.23 (1H, t, J = 12.4 Hz); 2.63-2.77 (3H, m); 2.80-2.91 (2H, m); 2.97 (1H, dd, J = 11.0, 13.9 Hz); 3.13-3.20 (1H, m); 3.20-3.68 (m, superimposed on the water mark); 3.87 (1H,; dd, J = 3.0, 12.1 Hz); 3.90-4.02 (2H, m); 4.25-4.37 (1H, m); 4.64 (1H, t, J = 5.2 Hz); 4.91 (-1H, t, J ~ 5.2 Hz); 6.94-7.31 (15H, m); 7.35 (1H, d, J = 8.0 Hz); 7.48 (1H, d, J = 7.9 Hz); 8.65 (1H, d, J = 5.0 Hz); 8.94 (1H,, m); 10.87 (1H, bsj.
MS: m/z = 697, MH<+>MS: m / z = 697, MH <+>
diastereoisomero B (tR = 58.2 min) diastereomer B (tR = 58.2 min)
MS: m/z = 697,. MH<+>. MS: m / z = 697 ,. MH <+>.
ESEMPIO 32: ciclo{Suc[(lR,2Rj-1,2-diacetossi]-Trp-Phe-[(R)-NH-CH(CH2-C6H5)-CH2NH]} EXAMPLE 32: cycle {Suc [(1R, 2Rj-1,2-diacetoxy] -Trp-Phe - [(R) -NH-CH (CH2-C6H5) -CH2NH]}
(composto di formula generale I in cui R4. = R5 = acetitossi, C-R4 e C-R5 hanno configurazione R, e gli altri. sostituenti sono come descritto per il composto A). (compound of general formula I wherein R4. = R5 = acetytoxy, C-R4 and C-R5 have R configuration, and the other substituents are as described for compound A).
A 535 mg di 1H-Trp-Phe-[(R)-NH-(CH(CH2-C6H5)-CH2NH -Z], preparato come descritto in esempio id, sciolti in 7 mi di DMF anidra si aggiungono 210 mg di anidride (+)-di-0-acetil-L-tartarica. Si mantiene la soluzione un'ora sotto agitazione. Si concentra, si riprende il residuo con acqua e si estrae con etile acetato, lavando con salamoia ed essiccando su sodio solfato. Evaporando il solvente si ottiene un residuo solido che viene trattato con etile acetato (5 ml) tenuto sotto, agitazione, filtrato e lavato con il medesimo solvente (5 mi). Si ottene un solido dei peso di 357 mg [HPLC: tR=16.08 min (colonna Symmetry 5mm, 018, 100A, 150 x 3.9 mm; flusso: 1ml/min; fase mobile: A = H20 0.1%TFA, B = CH3CN 0.1% TFA, gradiente da A:B = 80:20 a A:B = 20;80 in 20 min)] che viene sciolto in 40 ml di metanolo, trattato con 60 mg di Pd/C al 10% e mantenuto sotto .agitazione, sotto atmosfera di idrogeno, per 4 ore. Si filtra, si lava con metanolo e si porta a secco ottenendo un solido del peso di 258 mg (HPLC, condizioni descritte sopra, tR=9.76 min). Il prodotto così ottenuto viene sciolto in DMF anidra. Si aggiungono 148 mg di 1-idròssibenzotriazolo e 103 mg di EDCI.HCI; si mantiene 2 ore sotto agitazione. Si evapora il solvente, si tratta il residuo con acido citrico 10% e si estrae in etile acetato. La fase organica viene lavata con salamoia, con NaHC03 5% e di nuovo con salamoia. Si essicca su sodio solfato e si concentra, ottenendo un prodotto solido del peso di 225 mg che viene purificato per HPLC preparativo (colonna: Deltapak RP18 100 A ,19 x 300 mm; flusso; 15 ml/min; I = 220, 270 nm; fase mobile: gradiente da acetonitrile:acqua 25:75 v/v a acetonitrile:acqua 85:15 v/v in 120 minuti). To 535 mg of 1H-Trp-Phe - [(R) -NH- (CH (CH2-C6H5) -CH2NH -Z], prepared as described in example id, dissolved in 7 ml of anhydrous DMF, 210 mg of anhydride are added (+) - di-0-acetyl-L-tartaric. The solution is kept for one hour under stirring. The mixture is concentrated, the residue is taken up with water and extracted with ethyl acetate, washing with brine and drying over sodium sulphate. Evaporating the solvent a solid residue is obtained which is treated with ethyl acetate (5 ml) kept under stirring, filtered and washed with the same solvent (5 ml). A solid weight of 357 mg is obtained [HPLC: tR = 16.08 min (Symmetry column 5mm, 018, 100A, 150 x 3.9 mm; flow: 1ml / min; mobile phase: A = H20 0.1% TFA, B = CH3CN 0.1% TFA, gradient from A: B = 80:20 to A: B = 20; 80 in 20 min)] which is dissolved in 40 ml of methanol, treated with 60 mg of Pd / C at 10% and kept under stirring, under a hydrogen atmosphere, for 4 hours. It is filtered, washed with methanol and dried to obtain a solid weighing 258 mg (HPLC, conditions described above, tR = 9.76 min). The product thus obtained is dissolved in anhydrous DMF. 148 mg of 1-hydroxybenzotriazole and 103 mg of EDCI.HCI are added; it is kept under stirring for 2 hours. The solvent is evaporated, the residue is treated with 10% citric acid and extracted in ethyl acetate. The organic phase is washed with brine, with 5% NaHC03 and again with brine. It is dried on sodium sulphate and concentrated, obtaining a solid product weighing 225 mg which is purified by preparative HPLC (column: Deltapak RP18 100 A, 19 x 300 mm; flow; 15 ml / min; I = 220, 270 nm mobile phase: gradient from acetonitrile: water 25:75 v / v to acetonitrile: water 85:15 v / v in 120 minutes).
1H-NMR (DMSO-d6, 500 MHz): d 1.92 (3H, s); 2.11 (3H, s); 2.69-2.77 (2H, m); 2.77-2.87 (2H, m); 2.9 (1 H, dd, J = 11.4, 15.0 Hz); 3.22-3.28 (1H, m); 3.35-3.40 (1H; m); 3.37 (1H, dd, J = 4.2, 14.1 Hz); 4.01 (1H,m); 4.08 (1H, m); 4.24 (1H, m); 4.94 (1H, d; J = 8.9 Hz); 5.28 (1H, d, J = 8.9 Hz); 6.76 (IH, d, J = 8.9 Hz); 6.99 (1H, t, J = 7.0 Hz); 7.05-7.11 (1H, m); 7.14-7.22 (4H, m) 7.22-7.31 (6H, m); 7.34 (1H, d, J = 8.1 Hzj; 7.44 (1H, d, J = 7.9 Hz); 7.72 (1H, bs); 8.24 (1H, bs); 8.65 (1H, d, J = 5.1 Hz); 10.89 (1H, d, J = 2.1 Hz). 1H-NMR (DMSO-d6, 500 MHz): d 1.92 (3H, s); 2.11 (3H, s); 2.69-2.77 (2H, m); 2.77-2.87 (2H, m); 2.9 (1 H, dd, J = 11.4, 15.0 Hz); 3.22-3.28 (1H, m); 3.35-3.40 (1H; m); 3.37 (1H, dd, J = 4.2, 14.1 Hz); 4.01 (1H, m); 4.08 (1H, m); 4.24 (1H, m); 4.94 (1H, d; J = 8.9 Hz); 5.28 (1H, d, J = 8.9 Hz); 6.76 (1H, d, J = 8.9 Hz); 6.99 (1H, t, J = 7.0 Hz); 7.05-7.11 (1H, m); 7.14-7.22 (4H, m) 7.22-7.31 (6H, m); 7.34 (1H, d, J = 8.1 Hzj; 7.44 (1H, d, J = 7.9 Hz); 7.72 (1H, bs); 8.24 (1H, bs); 8.65 (1H, d, J = 5.1 Hz); 10.89 (1H, d, J = 2.1 Hz).
MS: m/z = 682, MH<+>. MS: m / z = 682, MH <+>.
ESEMPIO 33: ciclo{Suc[(1 R,2R)-1 i2-diidrossi]-Trp-Phe-[(R)-NH-CH(CH2-C6H5)-CH2NH]} EXAMPLE 33: cycle {Suc [(1 R, 2R) -1 i2-dihydroxy] -Trp-Phe - [(R) -NH-CH (CH2-C6H5) -CH2NH]}
(composto di formula generale I in cui R4 = R5 = idrossi, C-R4 e C-R5 hanno configurazione. R, e gli altri sostituenti sono come descritto per il composto A) (compound of general formula I in which R4 = R5 = hydroxy, C-R4 and C-R5 have configuration. R, and the other substituents are as described for compound A)
A 157 mg del prodotto ottenuto neii'Esempio 31 sciolti in. 6.5 mi- di metanolo si aggiungono sotto agitazione 4.5 ml di una' soluzione acquosa 0.1 M di K2CO3. Si mantiene 2 ore sotto agitazione. Si aggiungono 0.1 ml di acido acetico glaciale, si concentra a piccolo volume e si estrae con etile acetato. La. fase organica, dopo lavaggio con salamoia, con NaHC03 5% e di nuovo con . salamoia, viene essiccata e concentrata ottenendo un prodotto solido che pesa 110 mg. Il prodotto viene purificato per HPLC preparativo (colonna: Deltapak RP18 100 A, 19 x 300 mm; flusso: 15 mi/min; I = 220, 270 nm; fase mobile: gradiente da acetonitrile:acqua 25:75 v/v a acetonitrile.acqua 85:15 v/v in 120 minuti). At 157 mg of the product obtained in Example 31 dissolved in. 6.5 ml of methanol are added under stirring 4.5 ml of a 0.1 M aqueous solution of K2CO3. It is kept under stirring for 2 hours. 0.1 ml of glacial acetic acid are added, concentrated to a small volume and extracted with ethyl acetate. The organic phase, after washing with brine, with 5% NaHC03 and again with. brine, is dried and concentrated to obtain a solid product weighing 110 mg. The product is purified by preparative HPLC (column: Deltapak RP18 100 A, 19 x 300 mm; flow: 15 ml / min; I = 220, 270 nm; mobile phase: gradient from acetonitrile: water 25: 75 v / v to acetonitrile. water 85:15 v / v in 120 minutes).
1H-NMR (DMSO-d6, 500 MHz)::d 2.64-2.90 (5H,.m); 2.97-3.07 (1H,.m); 3.41 (1 H, dd, J = 3.8, 14.3 Hz); 3.52-3.60.(1 H,m); 3.89 (1H, t, J = 5.1 Hz); 3.96-4.03 (2H, m); 4.03-4.09 (1H, m); 4.38 (1H, m); 5.94 (,1H, d, J = 5.2.HZ); 6.16 (1H, d, J = 5.5 Hz); 6.87 (1H, d, J = 9.3 Hz); 6.95-7.05 (1H, m); 7.05-7.10 (1H, m) 7.12 (1H, s); 7.14-7.31 (10H, m); 7.35 (1H, d, J = 8.1. Hz); 7.46 (1 H, d, J = 7.9 Hz); 7.65 (1H, bs); 7.87 (1H, bs); 7.95 (1H, d, J = 3,7 Hz); 10.87 (1H, d, J = 2.1 Hz). 1H-NMR (DMSO-d6, 500 MHz): d 2.64-2.90 (5H, .m); 2.97-3.07 (1H, .m); 3.41 (1 H, dd, J = 3.8, 14.3 Hz); 3.52-3.60. (1 H, m); 3.89 (1H, t, J = 5.1 Hz); 3.96-4.03 (2H, m); 4.03-4.09 (1H, m); 4.38 (1H, m); 5.94 (, 1H, d, J = 5.2.HZ); 6.16 (1H, d, J = 5.5 Hz); 6.87 (1H, d, J = 9.3 Hz); 6.95-7.05 (1H, m); 7.05-7.10 (1H, m) 7.12 (1H, s); 7.14-7.31 (10H, m); 7.35 (1H, d, J = 8.1. Hz); 7.46 (1H, d, J = 7.9 Hz); 7.65 (1H, bs); 7.87 (1H, bs); 7.95 (1H, d, J = 3.7 Hz); 10.87 (1H, d, J = 2.1 Hz).
MS: m/z = 598, MH+. MS: m / z = 598, MH +.
Con procedure analoghe a quelle descritte negli Esempi 32 è 33 sono stati preparati: With procedures similar to those described in Examples 32 and 33, the following were prepared:
ESEMPIO 34: ciclo{Suci(1S,2S)-1,2-diidrossi]-Trp-Phe-[(R)-NHCH(CH2-C6H5)-CH2NH]} EXAMPLE 34: cycle {Suci (1S, 2S) -1,2-dihydroxy] -Trp-Phe - [(R) -NHCH (CH2-C6H5) -CH2NH]}
(composto di formula generale I in cui R4 = R5 = idrossi, C-R4 e C-R5 hanno configurazione S e gli altri sostituenti sono come descritto per il composto A) (compound of general formula I in which R4 = R5 = hydroxy, C-R4 and C-R5 have S configuration and the other substituents are as described for compound A)
MS: m/z = 598, MH<+>. MS: m / z = 598, MH <+>.
ESEMPIO 35: ciclo{Suc[( 1 R,2R)-1 >diacetossi]-Trp-Phe-[NH-CH2-CH2NH]} EXAMPLE 35: cycle {Suc [(1 R, 2R) -1> diacetoxy] -Trp-Phe- [NH-CH2-CH2NH]}
(composto di formula generale I in cui R4 = R5 = acetilossi, C-R4 e C-R5 hanno configurazione R, R3 è un idrogenò e gii altri sostituenti sono come. descritto per il composto. A) (compound of general formula I wherein R4 = R5 = acetyloxy, C-R4 and C-R5 have R configuration, R3 is a hydrogen and the other substituents are as described for the compound. A)
MS: m/z = 592, MH<+>MS: m / z = 592, MH <+>
ESEMPIO 36: ciclc{Suc[(1 S,2S)-1 2-diacetossi]-Trp-Phe-[(R)-NH-CH(CH2-C6H5)-CH2NH]} EXAMPLE 36: cyclc {Suc [(1 S, 2S) -1 2-diacetoxy] -Trp-Phe - [(R) -NH-CH (CH2-C6H5) -CH2NH]}
(composto di formula generale I in cui R4 = R5 = acetilossi, C-R4 e C-R5 hanno configurazione S, e gli altri sostituenti sono come descritto per il composto A) (compound of general formula I in which R4 = R5 = acetyloxy, C-R4 and C-R5 have S configuration, and the other substituents are as described for compound A)
MS: m/z = 682, MH<+>MS: m / z = 682, MH <+>
ESEMPIO 37: cido(Trp-Phe-D-b-HPhe-L-b-HCys(b-D-Gal)) (composto di formula generale I in cui R4 è b-D-Gal-S-CH2, X3 = NH-CO- e gli altri sostituenti sono come descritto per il composto A) a) H-Trp-Phe-OtBu EXAMPLE 37: cido (Trp-Phe-D-b-HPhe-L-b-HCys (b-D-Gal)) (compound of general formula I in which R4 is b-D-Gal-S-CH2, X3 = NH-CO- and the other substituents are as described for compound A) a) H-Trp-Phe-OtBu
A 3.6 g (16.3 mmoli) di (S)-Fenilanina t-butilestere in 100 mi DMF anidra si aggiungono in successione N-benzilossicarbònil-(S)-triptofano (5.5 g, . 16.3 mmoli), 1-idrossibenzotriazolo. (6.61 g, 48.9 mmoli) e EDCI.HC! (3.22 g 16.8 mmoli). Si agita per 20 ore a temperatura ambiente e si ripartisce la miscela di reazione fra etile acetato e acqua (100/100 mi). Si separano le due fasi, si estrae ancora con etile acetato e si lava la fase organica con acqua, potassio bisolfato 5% aq. e sodio bicarbonato aq. 5%.. Si essicca su sodio solfato, si evapora il solvente sotto vuoto ottenendo un olio che solidifica per trattamento con una miscela .1:1 v/v di etere di petrolio .40-60° e etère etilico. Il solvente viene, evaporato, e il residuo' solido lavato nuovamente con etere di petrolio, filtrato e essiccato sotto vuoto a dare 7.85 g di prodotto solido bianco, p. f. 126-129°C. Il prodotto viene sciolto in 110.ml.di metanolo in presenza di 1.60 mg di Pd/C al 10 %. La soluzione è idrogenata per 5 ore sotto, agitazione magnetica a pressione e temperatura ambiente; si filtra e si porta a secco, ottenendo un olio che trattato alcune volte con . etere etilico dà un solido bianco schiumoso del peso di 5.65. g. To 3.6 g (16.3 mmoles) of (S) -Phenylanine t-butyl ester in 100 ml anhydrous DMF, N-benzyloxycarbonyl- (S) -tryptophan (5.5 g,. 16.3 mmol), 1-hydroxybenzotriazole are added in succession. (6.61 g, 48.9 mmol) and EDCI.HC! (3.22 g 16.8 mmol). The mixture is stirred for 20 hours at room temperature and the reaction mixture is partitioned between ethyl acetate and water (100/100 ml). The two phases are separated, extracted again with ethyl acetate and the organic phase is washed with water, potassium bisulfate 5% aq. and sodium bicarbonate aq. 5% .. It is dried on sodium sulphate, the solvent is evaporated under vacuum to obtain an oil which solidifies by treatment with a mixture .1: 1 v / v of petroleum ether .40-60 ° and ethyl ether. The solvent is evaporated and the solid residue washed again with petroleum ether, filtered and dried under vacuum to give 7.85 g of white solid product, e.g. f. 126-129 ° C. The product is dissolved in 110 ml of methanol in the presence of 1.60 mg of 10% Pd / C. The solution is hydrogenated for 5 hours under magnetic stirring at room temperature and pressure; it is filtered and dried, obtaining an oil that is treated a few times with. ethyl ether gives a frothy white solid weighing 5.65. g.
HPLC: tR = 10.5 min (colonna Symmetry C18 (5 mm, 100A, 150 x 3.9 mm); MeCN 0.1% TFA / H2O 0. 1% TFA, 20/80 > 80/20 in20'; flusso = Tml/min, I = 220, 270 nm). HPLC: tR = 10.5 min (Symmetry C18 column (5 mm, 100A, 150 x 3.9 mm); MeCN 0.1% TFA / H2O 0. 1% TFA, 20/80> 80/20 in20 '; flow = Tml / min, I = 220, 270 nm).
b) Boc-b-HCys(b-D-Ga!(Ac)4)-OH b) Boc-b-HCys (b-D-Ga! (Ac) 4) -OH
2.8 g (12.4 immoli) di S-benzil-b-omocisteinà, preparata come descritto in:. K. Baìenovic, D. Fies J. Org. Chem. 17 (1952), 347-349, sono sospèsi in 60 mi di butanolo; alla sospensione, riscaldata allebollizione, si aggiungono a piccole porzioni 2.8 g di sodio. La miscela viene scaldata a riflusso fino a che tutto il sodio è passato in soluzione, raffreddata poi a temperatura ambiente e. estratta per tre volte con acqua. La fase acquosa, raffreddata in un bagno a ghiaccio e agitata vigorosamente, viene neutralizzata e filtrata, li filtrato viene ossidato in corrente d’aria, in presenza di FeCl3 catalitico; come descritto in W. I. Patterson, V. du Vigneaud J. S/o/. Chem. 111 (1935), 393-398. Si ottengono 1.1 g di b-omocistina, che viene trattata con tbutossicarbonilazide in DMF acquosa in presenza di idrossido di sodio come descritto in J.J. Ferrare, Biochém. Prep. (1971), 13, 39-41, ottenendo 1.63 g di bis-N-Boc-b-omocistina, (Boc-b-HCys-OH)2. Il prodotto sciolto in 50 mi di tetraidrofurano acqua 9:1 v/v e trattato con 450 mg di tri et i [fosfina, come descritto in F. Urpi, J. Vilarrasa, Tetrahedron Lett. 38 (1986), 4623, ottenendo 1.50. g di Boc-bòmocisfeina (Boc-b-HCys-OH).. Il prodotto di reazione viene sciolto in 50 mi di tetràidrofurano e trattato con 306 mg di sodio idruro, poi con 2.62 g di 2,3,4, 6-tetra-O-acetil-a-D-galattopiranosil bromuro, come descritto in M. Gerz et al. Angew. Chem. 32 (1993), 269-271. Si ottengono . 2.16 g di N-Boc - S (2,3,4,6-tetra-O-acetil-b-D-galattopiranosiO-b-omocisteina. MS (LC-MS, ioni positivi): 566 (MH<+>). c) Boc-b-HCys(b-D-Gal(Ac)4)-Trp-PheTOtBu 2.8 g (12.4 immoles) of S-benzyl-b-homocysteine, prepared as described in :. K. Baìenovic, D. Fies J. Org. Chem. 17 (1952), 347-349, are suspended in 60 ml of butanol; to the suspension, heated to boiling, 2.8 g of sodium are added in small portions. The mixture is refluxed until all the sodium has dissolved, then cooled to room temperature e. extracted three times with water. The aqueous phase, cooled in an ice bath and vigorously stirred, is neutralized and filtered, the filtered is oxidized in an air stream, in the presence of catalytic FeCl3; as described in W. I. Patterson, V. du Vigneaud J. S / o /. Chem. 111 (1935), 393-398. 1.1 g of b-homocystine are obtained, which is treated with tbutoxycarbonylazide in aqueous DMF in the presence of sodium hydroxide as described in J.J. Ferrare, Biochém. Prep. (1971), 13, 39-41, obtaining 1.63 g of bis-N-Boc-b-homocystine, (Boc-b-HCys-OH) 2. The product dissolved in 50 ml of tetrahydrofuran water 9: 1 v / v and treated with 450 mg of trieth i [phosphine, as described in F. Urpi, J. Vilarrasa, Tetrahedron Lett. 38 (1986), 4623, obtaining 1.50. g of Boc-bòmocisfeina (Boc-b-HCys-OH) .. The reaction product is dissolved in 50 ml of tetràhydrofuran and treated with 306 mg of sodium hydride, then with 2.62 g of 2,3,4,6-tetra -O-acetyl-a-D-galactopyranosyl bromide, as described in M. Gerz et al. Angew. Chem. 32 (1993), 269-271. They are obtained. 2.16 g of N-Boc - S (2,3,4,6-tetra-O-acetyl-b-D-galactopyranosis O-b-homocysteine. MS (LC-MS, positive ions): 566 (MH <+>). C ) Boc-b-HCys (b-D-Gal (Ac) 4) -Trp-PheTOtBu
A 1 g (1.77 mmoli) di N-Boc S-(2,3,4,6-tetra-0-acetil-b-D-galattopiranosil)-b-omocisteiria in 50 ml di DMF anidra, si aggiungono 720 mg di 1-idrossibenzotriazolo (5.3 mmoli), 370 mg di EDCI.HCI (1.93 mmoli) e 720 mg di H-Trp-Phe-OtBu. La soluzione è lasciata sotto agitazione a. temperatura ambiente per una notte; si concentra a piccolo volume, si diluisce con etile acetato, e si lava con acido citrico 10% poi con NaHC03 5% e infine con acqua. La fase organica, essiccata su sodio solfato, viene filtrata e portata a secco ottenendo. un prodotto solido del peso di 1.27 g, MS (LC-MS, ioni positivi): 955 (MH<+>). 720 mg of 1- hydroxybenzotriazole (5.3 mmol), 370 mg of EDCI.HCI (1.93 mmol) and 720 mg of H-Trp-Phe-OtBu. The solution is left under stirring a. room temperature for one night; it is concentrated to a small volume, diluted with ethyl acetate, and washed with 10% citric acid then with 5% NaHC03 and finally with water. The organic phase, dried over sodium sulphate, is filtered and dried to obtain. a solid product weighing 1.27 g, MS (LC-MS, positive ions): 955 (MH <+>).
d) Boc-D-b-HPhe-b-HCys(b-D-Gal(Ac)4)-Trp-Phe-OtBu d) Boc-D-b-HPhe-b-HCys (b-D-Gal (Ac) 4) -Trp-Phe-OtBu
Il prodotto dell'esempio 37c viene sciolto . nella minima quantità di diclorometano e la soluzione raffreddata a. 0°C. Si aggiungono, ad intervalli nefcorso di 4 ore sotto agitazione alla stessa temperatura, 1.2 mi di HCI 4 M in diossano. Si mantiene per 24 ore a 5°C. Si concentra sotto vuoto. Si tratta i! residuo con NaHC03 5%, si estrae con etile acetato e si lava più volte con acqua. Si essicca su sodio solfato e si porta.a secco, ottenendo un prodotto solido che pesa 680 mg. MS (LC-MS; ioni positivi):. 855 (MH<+>). Il prodotto viene aggiunto ad una soluzionè in 40 mi di DMF anidra di 325 mg di 1-idrossibenzotriazolo (2.4 immoli), 175 mg di EDCl.HCI (0.91 immoli) e 270 mg di N-Boc-D-bomofenilalanina (Boc-D-b-HPhe-QH, preparata come descritto in M. A. .Ondetti, S. L. Engel J. Meci. Chem. 18 (1975), 761 ). Si lascia sotto agitazione a temperatura ambiente per una notte; si concentra , a piccolo volume, si diluisce con etile acetato, e si lava con acido citrico 10% poi con NaHCO 3 5% e infine con acqua. La fase organica, essiccata su sodio solfato, viene filtrata e portata a secco ottenendo. un prodotto solido del peso di 648 mg, MS (LC-MS, ioni positivi): 1116 (MH<+>). The product of Example 37c is dissolved. in the minimum amount of dichloromethane and the cooled solution a. 0 ° C. 1.2 ml of 4 M HCl in dioxane are added at intervals of 4 hours under stirring at the same temperature. It is kept for 24 hours at 5 ° C. It is concentrated in a vacuum. This is i! residue with 5% NaHC03, it is extracted with ethyl acetate and washed several times with water. It is dried on sodium sulphate and dried, obtaining a solid product weighing 680 mg. MS (LC-MS; positive ions) :. 855 (MH <+>). The product is added to a solution in 40 ml of anhydrous DMF of 325 mg of 1-hydroxybenzotriazole (2.4 immoles), 175 mg of EDCl.HCI (0.91 immoles) and 270 mg of N-Boc-D-bomophenylalanine (Boc-D-b -HPhe-QH, prepared as described in M. A.. Ondetti, S. L. Engel J. Meci. Chem. 18 (1975), 761). It is left under stirring at room temperature for one night; it is concentrated to a small volume, diluted with ethyl acetate, and washed with 10% citric acid then with 5% NaHCO 3 and finally with water. The organic phase, dried over sodium sulphate, is filtered and dried to obtain. a solid product weighing 648 mg, MS (LC-MS, positive ions): 1116 (MH <+>).
e) ciclo(Trp-Phe-D-b-HPhe-L-b-HCys(b-D-Gal)) e) cycle (Trp-Phe-D-b-HPhe-L-b-HCys (b-D-Gal))
Il prodotto dell'esempio 37d) viene aggiunto a piccole porzioni ad una soluzione formata da 10 mi di acido trifluoroacetico e 170 μl di 1,2-etanditìolo; si agita per un'ora a temperatura ambiente, - Dopo vaporazione sotto vuoto si ottiene un olio che viene trattato alcune volte con etere etilico. Il residuo semisolido ottenuto viene sciolto in 30 mi di DMF anidra; si aggiungono 0.11 mi di N-etildiisopropilammina, 240 mg di- 1-idrossibenzotriazolo (1,78 mmoli) e 130 mg di EDCI.HC! (0.68 mmoli). Si lascia sotto agitazione a temperatura ambiente per 24 ore; si concentra a piccolo volume, si diluisce con etile acetato, e si lava con acido citrico 10% poi con NaHC03 5% e infine con acqua. La fase organica, essiccata su sodio solfato, viene filtrata e portata a secco ottenendo un prodotto che pesa 305 mg, MS (LC-MS, ioni positivi): 942 (MH<+>). Il prodotto viene sciolto in metanolo anidro (250 ml). Si aggiunge una soluzione di metossido di sodio in metanolo (1.5 ml di una soluzione contenente 5 g/l di sodio in metanolo) e si agita fino a. completamento delia reazione (ca. 2 ore), controllando per HPLC. A fine reazione si evapora il solvente e si purifica il residuo per HPLC preparativo. (colonna: DeltaPak RP-18, 15μ, 100A, 19 x 300 mm; flusso: 20 ml/min; H20/CH3CN 0.1% TFA, gradiente da.10% a 90% CH3CN) ottenendo 168 mg dei prodotto voluto. MS (LC-MS, ioni positivi): 774 (MH<+>). The product of example 37d) is added in small portions to a solution formed by 10 ml of trifluoroacetic acid and 170 μl of 1,2-ethanedityl; it is stirred for one hour at room temperature, - After vaporization under vacuum an oil is obtained which is treated a few times with ethyl ether. The semisolid residue obtained is dissolved in 30 ml of anhydrous DMF; 0.11 ml of N-ethyldiisopropylamine, 240 mg of-1-hydroxybenzotriazole (1.78 mmoles) and 130 mg of EDCI.HC are added! (0.68 mmol). It is left under stirring at room temperature for 24 hours; it is concentrated to a small volume, diluted with ethyl acetate, and washed with 10% citric acid then with 5% NaHC03 and finally with water. The organic phase, dried over sodium sulphate, is filtered and dried to obtain a product weighing 305 mg, MS (LC-MS, positive ions): 942 (MH <+>). The product is dissolved in anhydrous methanol (250 ml). A solution of sodium methoxide in methanol (1.5 ml of a solution containing 5 g / l of sodium in methanol) is added and stirred up to. completion of the reaction (approx. 2 hours), checking by HPLC. At the end of the reaction the solvent is evaporated and the residue is purified by preparative HPLC. (column: DeltaPak RP-18, 15μ, 100A, 19 x 300 mm; flow: 20 ml / min; H20 / CH3CN 0.1% TFA, gradient from 10% to 90% CH3CN) obtaining 168 mg of the desired product. MS (LC-MS, positive ions): 774 (MH <+>).
ESEMPIO .38: ciclo{Suc[1 -(b-D-Gal)tiometil]-Trp-Phe-[(R)-NH-CH(CH2-C6H5)-CH2NH]}. EXAMPLE .38: {Suc [1 - (b-D-Gal) thiomethyl] -Trp-Phe - [(R) -NH-CH (CH2-C6H5) -CH2NH]} cycle.
(composto di formula generale I in cui X4 = -GO-NH- e gli altri sostituenti sono come descritto per il composto dell'. esempio 37) a) Boc-Trp-Phe-[(R)-NH-CHCH2-C6H5)-CH2NH 2] (compound of general formula I in which X4 = -GO-NH- and the other substituents are as described for the compound of Example 37) a) Boc-Trp-Phe - [(R) -NH-CHCH2-C6H5) -CH2NH 2]
420 mg (1.47 mmoli) di (R)-1-benzilossicarbonil-3-feni!-propan-1,2-diammina, 400 mg (1.51 mmoli). di N-Bpc-fenilalanina e 610 mg (4.49 mmoli) 1 -idrossibenzotriazoio vengono sciolti sotto azoto in 20 mi. di THF anidro. Si raffredda a 0°C, si aggiungono 290 mg (1.52 mmoli) di EDCI HCI e si agita per 24 h, lasciando tornare a temperatura ambiente. Si evapora il solvente, si riprende il residuo con etile acetato lavando con una soluzione acquosa satura di NaCI, con NaHC03 aq. saturo, con acido citrico 10%. Si essicca su solfato di sodio e si evapora, ottenendo 740 mg di prodotto solido bianco, che viene sciolto in 20 mi di cloruro di metilene e 4 mi di acido trifluoroacetico, Dopo un'ora si evapora il solvente, si ridiscioglie il residuo in cloruro di metilene e si lava più volte con NaHC03 aq. saturo. Si essicca su solfato di sodio e si evapora il solvente sotto vuoto, ottenendo 570 mg di prodotto solido bianco che viene sciolto in 25 ml THF anidro. Si aggiungono 425 mg di Boc-triptofano e 540 mg di 1-idrossibenzotriazolo; Si raffredda a 0°C,. si aggiungono 275 mg di EDCI.HCI e si agita per 24 h, lasciando tornare a temperatura ambiente. Si aggiungono lentamente, sotto agitazione, 75 mi di acqua. Si filtra sotto vuoto il prodotto solido ottenuto, lavandolo- sul filtro con acqua. Si ottengono, dopo essiccamento sotto vuoto in presenza di cloruro di calcio, 895 mg di prodotto solido bianco. Il prodotto viene sciolto in 10 mi di DMF e 50 mi di metanolo. Si aggiungono 250 mg di Pd/C 10% e si idrogena per circa 24 ore. Si filtra, si , evapora il solvente e si solidifica il residuo oleoso ottenuto per addizione di etere etilico a freddo. Cristallizzando da etile acetato e etanolo si ottengono 690 mg di prodotto solido bianco. MS (LC-MS, ioni positivi): 584 (MH<+>). 420 mg (1.47 mmol) of (R) -1-benzyloxycarbonyl-3-phenyl -propan-1,2-diamine, 400 mg (1.51 mmol). of N-Bpc-phenylalanine and 610 mg (4.49 mmoles) 1-hydroxybenzotriazoium are dissolved under nitrogen in 20 ml. of anhydrous THF. The mixture is cooled to 0 ° C, 290 mg (1.52 mmoles) of EDCI HCI are added and the mixture is stirred for 24 h, allowing it to return to room temperature. The solvent is evaporated, the residue is taken up with ethyl acetate, washing with a saturated aqueous solution of NaCl, with NaHC03 aq. saturated, with 10% citric acid. It is dried over sodium sulphate and evaporated, obtaining 740 mg of white solid product, which is dissolved in 20 ml of methylene chloride and 4 ml of trifluoroacetic acid, After one hour the solvent is evaporated, the residue is redissolved in chloride of methylene and washed several times with NaHC03 aq. saturated. It is dried over sodium sulphate and the solvent is evaporated under vacuum, obtaining 570 mg of white solid product which is dissolved in 25 ml anhydrous THF. 425 mg of Boc-tryptophan and 540 mg of 1-hydroxybenzotriazole are added; It is cooled to 0 ° C. 275 mg of EDCI.HCI are added and the mixture is stirred for 24 h, allowing it to return to room temperature. 75 ml of water are slowly added under stirring. The solid product obtained is filtered under vacuum, washing it on the filter with water. After drying under vacuum in the presence of calcium chloride, 895 mg of white solid product are obtained. The product is dissolved in 10 ml of DMF and 50 ml of methanol. 250 mg of 10% Pd / C are added and hydrogenated for about 24 hours. The solvent is filtered, evaporated and the oily residue obtained by cold addition of ethyl ether solidifies. By crystallizing from ethyl acetate and ethanol 690 mg of white solid product are obtained. MS (LC-MS, positive ions): 584 (MH <+>).
b) acido 2-(b-D-tetraaceti!galattosil)tiometilsuccinico 4-allil estere 3.64 g dell'anidride dell'acido S-acetil tioitamalico (anidride 3-(acetiìtiometil)succinics, preparata da anidride itaconica e addio tiolacetico come descritto in !. M. Klotz et al. Biochim. Biophys. Acta 100 (1965), 104) sono sciolti in alcol allilico e la soluzione lasciata sotto agitazione a temperatura ambiente per 5 giorni. L'alcol allilico in eccesso viene allontanato quasi totalmente per evaporazione sotto vuoto; il residuo, dopo aggiunta di etere di petrolio, viene posto in frigorifero per una notte: Ripetute cristallizzazioni a freddo danno 1.67 g di acido . 2-acetiltiometiisuccinico 4-alìil estere. Concentrando : le acque madri si recuperano 0.86 g dell'isomero acido 2-acetìltiometilsuccinico 1-allil estere. L'acido 2-acetiltiometilsuccinico 4-allil estere (1.67 g) viene sciolto sotto azoto in NaOH 0.2N. Dopo 5 minuti la soluzione viene acidificata con acido solforico, ossidata con iodio e estratta con etile acetato, come descritto in L. Zervas et al. J.. Am. Chem. Soc. 85 (1963), 1337: Si lava con acqua fino a neutralità, si essicca su sodio solfato e si evapora, ottenendo 0.62 g di acido 2-(3-allilossicarbonil-2-carbossi-propildisulfanilmetil)succinico 4-alìil estere. Il prodotto, grezzo viene trattato con trietìlfosfina in tetraidrofuranoacqua, poi con sodio idruro e 2,3,4,6-tetra-0-acetiPa-D-galattopiranosil bromuro, come descritto nell'Esempio 36b per Boc-b-omocisteina, ottenendo 0.9 g di acido 2-(b-D-tetraacetilgalattosil)tiometilsuccinico 4-allil estere, MS.(LC-MS, ioni positivi): 535 (MH<+>). b) 2- (b-D-tetraacetyl galactosyl) thiomethylsuccinic acid 4-allyl ester 3.64 g of S-acetyl thioitamalic acid anhydride (3- (acethyomethyl) succinics anhydride, prepared from itaconic anhydride and thiolacetic addio as described in!. M. Klotz et al. Biochim. Biophys. Acta 100 (1965), 104) are dissolved in allyl alcohol and the solution left under stirring at room temperature for 5 days. The allyl alcohol in excess is removed almost completely by evaporation under vacuum; the residue, after addition of petroleum ether, is placed in the refrigerator for one night: Repeated cold crystallizations give 1.67 g of acid. 2-acetylthiomethysuccinic 4-allyl ester. By concentrating: the mother liquors 0.86 g of the 2-acetylthiomethylsuccinic acid isomer 1-allyl ester are recovered. The 2-acetylthiomethylsuccinic acid 4-allyl ester (1.67 g) is dissolved under nitrogen in 0.2N NaOH. After 5 minutes the solution is acidified with sulfuric acid, oxidized with iodine and extracted with ethyl acetate, as described in L. Zervas et al. J .. Am. Chem. Soc. 85 (1963), 1337: It is washed with water until neutral, dried on sodium sulphate and evaporated, obtaining 0.62 g of 2- (3-allyloxycarbonyl-2-carboxy-propyldisulfanylmethyl) succinic 4-allyl ester. The crude product is treated with triethylphosphine in tetrahydrofuran water, then with sodium hydride and 2,3,4,6-tetra-0-acetiPa-D-galactopyranosyl bromide, as described in Example 36b for Boc-b-homocysteine, obtaining 0.9 g of 2- (b-D-tetraacetylgalactosyl) thiomethylsuccinic acid 4-allyl ester, MS. (LC-MS, positive ions): 535 (MH <+>).
c) ciclo{Suc[1-(b-D-Gal)tiometil]-Trp-Phe-[(R)-NH-CH(CH2-C6H5)-CH2NH]} c) cycle {Suc [1- (b-D-Gal) thiomethyl] -Trp-Phe - [(R) -NH-CH (CH2-C6H5) -CH2NH]}
975 mg . (1.67 mmoli) di Boc-Trp-Phe-[(R)-NH-CH(CH2-C6H5)CH2NH2] (Esempio 38a), 0.9 g di acido 2-(b-D-tetraacetilgalattosii)tiometilsuccinico 4-allil estere (1.67 mmoli; Esempio 38b) e 677 mg (5.0 mmoli)· l-idrossibenzotriazolo vengono sciolti sotto azoto in 25 mi di THF anidro. Si raffredda a 0°C, si aggiungono 330 mg (1.72 .mmoli) di EDCÌ.HCI e si agita per 24 h, lasciando tornare a temperatura ambiente. Si evapora il solvente, si riprende il residuo con etile acetato lavando con una soluzione acquosa satura di NaCI, con NaHC03 aq. saturo, con acido citrico 10%. Si essicca sp solfato di sodio e si evapora, ottenendo 1.43 g di solido bianco, MS (LC-MS, ioni positivi): 1100 (MH<+>). 975 mg. (1.67 mmoles) of Boc-Trp-Phe - [(R) -NH-CH (CH2-C6H5) CH2NH2] (Example 38a), 0.9 g of 2- (b-D-tetraacetylgalactosii) thiomethylsuccinic 4-allyl ester (1.67 mmoles ; Example 38b) and 677 mg (5.0 mmol) 1-hydroxybenzotriazole are dissolved under nitrogen in 25 ml of anhydrous THF. The mixture is cooled to 0 ° C, 330 mg (1.72 mmoles) of EDCI.HCI are added and the mixture is stirred for 24 h, allowing it to return to room temperature. The solvent is evaporated, the residue is taken up with ethyl acetate, washing with a saturated aqueous solution of NaCl, with NaHC03 aq. saturated, with 10% citric acid. Sodium sp sulphate is dried and evaporated, obtaining 1.43 g of white solid, MS (LC-MS, positive ions): 1100 (MH <+>).
Il prodotto viene sciolto a temperatura ambiente in 250 mi THF. Si aggiungono 520 mg di Pd(dba)2 (1.30 moli) e 513 mg di trifenilfosfina (1.95 mmoli).. Dopo 5' si aggiungono 110 mi di acido acetico glaciale (1.95 mmoli) e si agita alla stessa temperatura fino a scomparsa del prodotto di partenza (TLC CH2CI2/CH3OH 10:1 v/v): Si evapora il solvente, si riprende il residuo con etere etilico e si filtra il solido, ottenuto sotto azoto, lavandolo più volte sul filtro con etere etilico e essiccandolo sotto vuoto. Si ottengono 798 mg di prodotto solido bianco, MS (LC-MS, ioni positivi): 1060 (MH<+>). Il prodotto viene sciolto in 25 mi di cloruro di metilene e 5 mi di acido trifluoroacetico.. Dopo un'ora si evapora il solvente, si ridiscioglie il residuo in etile acetato e si lava più volte con NaHC03 aq. saturo. Si essicca su solfato di sodio e si evapora il solvente sette vuoto, ottenendo 624 mg di prodotto solido bianco, MS (LC-MS, ioni positivi): 960 (MH<+>). Il prodotto viene sciolto sotto azoto in DMF anidra. Si aggiungono 265 mg (1.95 mmoli) di 1 -idrossibenzotriazolo. Si raffredda a 0°C, si aggiungono 125 mg (0.65 mmoli) di EDCI.HCI e si agita per 24 h, lasciando tornare a temperatura ambiente. Si evapora i! solvente, si riprende il residuo con etile acetato lavando con una soluzione acquosa satura di NaCI, con NaHC03 aq. saturo, con acido citrico 10%. La fase organica, essiccata su sòdio solfato, viene filtrata e portata a secco ottenendo un prodotto solido bianco che pesa 337 mg. MS (LC-MS, ioni positivi): 942 (MH<+>). Il prodotto viene sciolto in metanolo anidro (300 mi). Si aggiunge una soluzióne di metossido di sodio in metanolo (1.66 mi di una soluzione -contenente 5 g/l di sodio in metanòlo) e si agita fino a completamento della reazione (ca. 2 ore), controllando per HPLC. A fine reazione si evapora il solvente. I due prodotti epimeri vengono separati per HPLC preparativo (colonna: DeltaPak RP-18, 15μ, 100A, 19 x 300 mm; flusso: 20 ml/min; H2O/CH3CN 0.1% TFA,. gradiente da 10% a 90% CH3CN) ottenendo i due prodotti: The product is dissolved at room temperature in 250 ml THF. 520 mg of Pd (dba) 2 (1.30 moles) and 513 mg of triphenylphosphine (1.95 mmoles) are added. After 5 minutes, 110 ml of glacial acetic acid (1.95 mmoles) are added and the mixture is stirred at the same temperature until the starting product (TLC CH2CI2 / CH3OH 10: 1 v / v): The solvent is evaporated, the residue is taken up with ethyl ether and the solid obtained is filtered under nitrogen, washing it several times on the filter with ethyl ether and drying it under vacuum . 798 mg of white solid product are obtained, MS (LC-MS, positive ions): 1060 (MH <+>). The product is dissolved in 25 ml of methylene chloride and 5 ml of trifluoroacetic acid. After one hour the solvent is evaporated, the residue is redissolved in ethyl acetate and washed several times with NaHC03 aq. saturated. It is dried over sodium sulphate and the solvent is evaporated empty, obtaining 624 mg of white solid product, MS (LC-MS, positive ions): 960 (MH <+>). The product is dissolved under nitrogen in anhydrous DMF. 265 mg (1.95 mmol) of 1-hydroxybenzotriazole are added. The mixture is cooled to 0 ° C, 125 mg (0.65 mmoles) of EDCI.HCI are added and the mixture is stirred for 24 h, allowing it to return to room temperature. It evaporates i! solvent, the residue is taken up with ethyl acetate, washing with a saturated aqueous solution of NaCl, with NaHC03 aq. saturated, with 10% citric acid. The organic phase, dried on sodium sulphate, is filtered and dried to obtain a white solid product weighing 337 mg. MS (LC-MS, positive ions): 942 (MH <+>). The product is dissolved in anhydrous methanol (300 ml). A solution of sodium methoxide in methanol (1.66 ml of a solution containing 5 g / l of sodium in methanol) is added and stirred until completion of the reaction (about 2 hours), checking by HPLC. At the end of the reaction the solvent is evaporated. The two epimer products are separated by preparative HPLC (column: DeltaPak RP-18, 15μ, 100A, 19 x 300 mm; flow: 20 ml / min; H2O / CH3CN 0.1% TFA, 10% to 90% CH3CN gradient) obtaining the two products:
ciclo{Suc[1(R)-(b-D-Gal)tiometil]-Trp-Phe-[(R)-NH-CH(CH2-C6H5)-CH2NH]}, tR = 12.3 min, MS (LC-MS, ioni positivi): 774 (MH<+>). ciclo{Suc[1(S)-(b-D-Gal)tiomelil]-Trp-Phe-[(R)-NH-CH(CH2-C6H5)-CH2NH]}, tR = 14.1 min, MS (LC-MS, ioni positivi): 774 (MH<+>). cycle {Suc [1 (R) - (b-D-Gal) thiomethyl] -Trp-Phe - [(R) -NH-CH (CH2-C6H5) -CH2NH]}, tR = 12.3 min, MS (LC-MS, positive ions): 774 (MH <+>). {Suc [1 (S) - (b-D-Gal) thiomelyl] -Trp-Phe - [(R) -NH-CH (CH2-C6H5) -CH2NH]} cycle, tR = 14.1 min, MS (LC-MS, positive ions): 774 (MH <+>).
ESEMPIO 39: ciclo{Suc[2-(b-D-Gal)tiometil]-Trp-Phe-[(R)-NH-CH(CH2-C6H5)-CH2NH]} EXAMPLE 39: {Suc [2- (b-D-Gal) thiomethyl] -Trp-Phe - [(R) -NH-CH (CH2-C6H5) -CH2NH] cycle
(composto di formula generale I in cui R5 è b-D-GaLS-CH2, R4 è idrogeno e gli altri sostituenti sono come descritto per il composto A) Con la stessa procedura descritta nell'Esempio 37; ma utilizzando il monoallilestere isomero [acido 2-(2-allilossicarbonil-3-carbossi-propil-. (compound of general formula I in which R5 is b-D-GaLS-CH2, R4 is hydrogen and the other substituents are as described for compound A) With the same procedure described in Example 37; but using the isomer monoallyl ester [2- (2-allyloxycarbonyl-3-carboxy-propyl-.
disulfanilmetil)succinico 1-ailil estere] si ottengono i due composti epimeri: disulfanylmethyl) succinic 1-aylyl ester] the two epimer compounds are obtained:
cicl.o{Suc[2(R)-(b-P-Gal)tiometil]-Trp-Phe-[(R)-NH-CH(CH2-C6H5)-CH2NH]}, MS (LC-MS, ioni positivi): 942 (MH<+>). cycl.o {Suc [2 (R) - (b-P-Gal) thiomethyl] -Trp-Phe - [(R) -NH-CH (CH2-C6H5) -CH2NH]}, MS (LC-MS, positive ions) : 942 (MH <+>).
ciclo{Suc[2(SHb-D-Gal)tiometil]-Trp-Phe-[(R)-NH-CH(CH2-C6H5)-CH2NH]}, MS (LC-MS, ioni positivi): 942 (MH<+>). {Suc [2 (SHb-D-Gal) thiomethyl] -Trp-Phe - [(R) -NH-CH (CH2-C6H5) -CH2NH]} cycle, MS (LC-MS, positive ions): 942 (MH <+>).
ESEMPIO 40: . ciclo{Suc[1-(R)-cianometilamino]-Trp-Phe-[(R)-NH-CH(CH2-C6H5)-CH2NH]} EXAMPLE 40:. cycle {Suc [1- (R) -cyanomethylamino] -Trp-Phe - [(R) -NH-CH (CH2-C6H5) -CH2NH]}
(composto di formula generale I in cui R4 è cianometilammino , C-R4 ha configurazione R e gli altri sostituenti sono come descritto per il composto A) (compound of general formula I where R4 is cyanomethylamino, C-R4 has R configuration and the other substituents are as described for compound A)
A 50 mg di ciclo{Suc[1-(R)-amino]-Trp-Phe-[(R)-NH-CH(CH2-C6H5)-. CH2NH]}, preparato come descritto per l isomero composto A, sciolti in 1 mi di DMF, si aggiungono 12 μΙ di TEA e 6,5 μl di cloroacetonitrile; si aggiungono 15 mg di Mal e si agita per circa 16. ore a temperatura ambiente. Si filtra e si purifica per HPLC preparativo (colonna: Symmetry RP 18, .7 μ,100 A, 300 x 19 mm; flusso .15 mi/min; I = 220, 270 nm; fase mobile: A= H2O 0.1% TFA, B = CH3CN 0.1% TFA, gradiente da A:B = 25:75 a A:B - 15:85 in 120 min). At 50 mg of cycle {Suc [1- (R) -amino] -Trp-Phe - [(R) -NH-CH (CH2-C6H5) -. CH2NH]}, prepared as described for compound isomer A, dissolved in 1 ml of DMF, 12 μΙ of TEA and 6.5 μl of chloroacetonitrile are added; 15 mg of Mal are added and the mixture is stirred for about 16 hours at room temperature. Filter and purify by preparative HPLC (column: Symmetry RP 18, .7 μ, 100 A, 300 x 19 mm; flow .15 ml / min; I = 220, 270 nm; mobile phase: A = H2O 0.1% TFA , B = CH3CN 0.1% TFA, gradient from A: B = 25:75 to A: B - 15:85 in 120 min).
1H-NMR (DMSO-d6, 500 MHz): d 2.34 (1 H, dd, J = 7.4, 13.6 Hz);.2.71-2.84 (5H, m); 2.91 (1H, dd, J = 4.3, 13.6 Hz); 3,16-3.27 (2H, m); 3,27-3.60 (m, sovrapposto al segnale dell'acqua); 3.66 e 3.74 (2H, ABq; J = 17.5, Hz); 3.96-4.11 (1H, m); 4.11-4.27 (2H, m); 6.77 (IH, d, J = 9.0 Hz); 6.98 (1 H, m); 7.03-7.10 (2H m); 7.4-7.21 (3H, m) 7.21-7.30 (5H, m); 7.34 (1H, d, J = 8.1 Hz); 7.44 (IH, d<'>, J = 7.9 Hz); 7.64 (1H, bs); 7.88 (1 H, bs); 8.75 (TH, d, J = 4.9 Hz); 10.83 (1H, d, J = 1.6 Hz). 1H-NMR (DMSO-d6, 500 MHz): d 2.34 (1 H, dd, J = 7.4, 13.6 Hz); 2.71-2.84 (5H, m); 2.91 (1H, dd, J = 4.3, 13.6 Hz); 3.16-3.27 (2H, m); 3.27-3.60 (m, superimposed on the water mark); 3.66 and 3.74 (2H, ABq; J = 17.5, Hz); 3.96-4.11 (1H, m); 4.11-4.27 (2H, m); 6.77 (1H, d, J = 9.0 Hz); 6.98 (1H, m); 7.03-7.10 (2H m); 7.4-7.21 (3H, m) 7.21-7.30 (5H, m); 7.34 (1H, d, J = 8.1 Hz); 7.44 (1H, d <'>, J = 7.9 Hz); 7.64 (1H, bs); 7.88 (1H, bs); 8.75 (TH, d, J = 4.9 Hz); 10.83 (1H, d, J = 1.6 Hz).
MS: m/z = 620, MH<+>MS: m / z = 620, MH <+>
ESEMPIO 41 : ciclo{Suc[1-(S)-N-metil-(4-metilbenzen)solfonilaminoj-Trp-Phe-[(R)-NH-CH(CH2-C6H5)-CH2NH]} EXAMPLE 41: cycle {Suc [1- (S) -N-methyl- (4-methylbenzen) sulfonylaminoj-Trp-Phe - [(R) -NH-CH (CH2-C6H5) -CH2NH]}
(composto di formula generale I in cui R4 è N-metil-4-metilbenzensolfonilamino e gli altri sostituenti sono come descritto per ii composto A) (compound of general formula I in which R4 is N-methyl-4-methylbenzenesulfonylamino and the other substituents are as described for compound A)
MS: m/z = 749, MH<+>. MS: m / z = 749, MH <+>.
ESEMPIO 42: cìclo{Suc[1.-(R)-(4-tetraidrotiopiranil)amino]-Trp-Phe-[(R)-NH-CH(CH2-C6H5)-CH2NH]} EXAMPLE 42: cycl {Suc [1 .- (R) - (4-tetrahydrothiopyranil) amino] -Trp-Phe - [(R) -NH-CH (CH2-C6H5) -CH2NH]}
(composto di formula , generale I in cui R4 è (4-tetraidrotiopiranil)amìno, C-R4 ha configurazione R e gli altri sostituenti sono come descritto per il composto A) MS: m/z = 681 , ΜΗ<+ >Abbreviazioni: (compound of formula, general I where R4 is (4-tetrahydrothiopyranil) amine, C-R4 has R configuration and the other substituents are as described for compound A) MS: m / z = 681, ΜΗ <+> Abbreviations:
Per la nomenclatura e le abbreviazioni degli amminoacidi si fa riferimento alle raccomandazioni della IUPAC-1UB Joint Commìssìon on Biochemical Nomencìatiire(Eur. J. Biochem. 1984, 138, 9); gli amminoacidi si intendono nella configurazione S se non altrimenti specificato: For the nomenclature and abbreviations of amino acids, reference is made to the recommendations of the IUPAC-1UB Joint Commission on Biochemical Nomencìatiire (Eur. J. Biochem. 1984, 138, 9); amino acids are intended in the S configuration unless otherwise specified:
Le altre abbreviazioni usate sono: The other abbreviations used are:
aq. = soluzione aquosa; Bzl = benzile; EDCI = 1-(3-dimetilamminopropil)3-etilcarbodiimide; Gal = galattosio; (S)-b-HCys-OH = (S)-b-omocisteina, ((S) H2N-CH(CH2SH)-CH2QOOH); PyBOP = benzotriazol-1-il-ossi-tris-pirrolidìno-fosfonio esafluorofosfato; TEA = trietìlammina; TFA = acido trifluoroacetico; Z = Cbz = Nbenzilossicarbonil, BOC = iert-butossicarbonil; -Sue- = succinil; DIEA -Ν,Ν-diisopropiletilammina; DMF = Ν,Ν-dimetilformammide; NKA = neurochinina A; HOBt = 1-idrossibenzotriazolo. La numerazione dei sostituenti sul gruppo succinico è come segue: aq. = aqueous solution; Bzl = benzyl; EDCI = 1- (3-dimethylaminopropyl) 3-ethylcarbodiimide; Gal = galactose; (S) -b-HCys-OH = (S) -b-homocysteine, ((S) H2N-CH (CH2SH) -CH2QOOH); PyBOP = benzotriazol-1-yl-oxy-tris-pyrrolidine-phosphonium hexafluorophosphate; TEA = triethylamine; TFA = trifluoroacetic acid; Z = Cbz = Nbenzyloxycarbonyl, BOC = iert-butoxycarbonyl; -Sue- = succinyl; DIEA -Ν, Ν-diisopropylethylamine; DMF = Ν, Ν-dimethylformamide; NKA = neurokinin A; HOBt = 1-hydroxybenzotriazole. The numbering of the substituents on the succinic group is as follows:
-Suc(1-NH2)- = -CO-CH(NH2)-CH2-CO-; -Suc (1-NH2) - = -CO-CH (NH2) -CH2-CO-;
-Suc(2-NH2)- = -CO-CH2-CH(NH2)-CO-Attività biologica -Suc (2-NH2) - = -CO-CH2-CH (NH2) -CO-Biological activity
I composti descritti nella presente invenzione agiscono come antagonisti al recettore NK-2 delle tachichinine. L'attività biologica è stata valutata in due test funzionali in vitro, usando arteria polmonare di coniglio (RPA) e trachea di criceto (HT), secondo i metodi descritti da Maggi C.A. et al: Br. J. Pharmacol. 1990, 100, 588 e D'Orleans-Jusfe P. et; al. Eur. J. Pharmacol. 1986, 125, 37. L'affinità dei composti per il recettore NK-2 umano è stata valutata in un test di binding utilizzando membrane di cellule CHO (Chinese hamster ovary) transfettate con il recettore NK-2 di ileo umano ed il radioligando [125|]NKA (Amersham, attività àspecifica 2000 Ci/mmol) alla concentrazione di 100 pM in studi di competizione: Le sostanze in esame sono state testate in un range di concentrazione da 0.01 nM a 10mM: Al termine dell' incubazione (30 min., 20°C) i campioni sono stati filtrati su filtri Whatman GF/B impiegando il sistema di filtrazione automatico Brandel. La radioattività è stata determinata usando un gamma-counter. (Cobra, Canberra Packard). The compounds described in the present invention act as antagonists to the tachykinin NK-2 receptor. Biological activity was evaluated in two functional tests in vitro, using rabbit pulmonary artery (RPA) and hamster trachea (HT), according to the methods described by Maggi C.A. et al: Br. J. Pharmacol. 1990, 100, 588 and D'Orleans-Jusfe P. et; to the. Eur. J. Pharmacol. 1986, 125, 37. The affinity of the compounds for the human NK-2 receptor was evaluated in a binding test using membranes of CHO (Chinese hamster ovary) cells transfected with the human ileus NK-2 receptor and radioligand [ 125 |] NKA (Amersham, specific activity 2000 Ci / mmol) at a concentration of 100 pM in competition studies: The test substances were tested in a concentration range from 0.01 nM to 10mM: At the end of incubation (30 min ., 20 ° C) the samples were filtered on Whatman GF / B filters using the Brandel automatic filtration system. Radioactivity was determined using a gamma counter. (Cobra, Canberra Packard).
I dati derivati dagli studi funzionali sono stati espressi come pA2 (Amnlakshana O. and Schild H.O., Br. J. Pharmacol. Chemother. Data derived from functional studies were expressed as pA2 (Amnlakshana O. and Schild H.O., Br. J. Pharmacol. Chemother.
1.959, 14, 45) e quelli dagli studi di binding come pKi (-iog Ki calcolata con il programma LIGAND: Munson P.J. et ai. Anal. Biochem. 1980, 107, 220). 1.959, 14, 45) and those from binding studies such as pKi (-iog Ki calculated with the LIGAND program: Munson P.J. et ai. Anal. Biochem. 1980, 107, 220).
I composti dell'invenzione si sono dimostrati attivi nel test di cui sopra, con valori di pA2 tra 5 e 9 e di pKi fra 5 e 10 The compounds of the invention proved to be active in the above test, with pA2 values between 5 and 9 and pKi between 5 and 10
Claims (12)
Priority Applications (11)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IT1998FI000186A IT1304888B1 (en) | 1998-08-05 | 1998-08-05 | MONOCYCLIC ACTION COMPOUNDS NK-2 ANTAGONIST AND FORMULATIONS THAT CONTAIN |
| TW088112671A TW491857B (en) | 1998-08-05 | 1999-07-27 | Monocyclic compounds having NK-2 antagonist action and compositions containing them |
| PCT/EP1999/005459 WO2000008046A1 (en) | 1998-08-05 | 1999-07-30 | Monocyclic compounds having nk-2 antagonist action and compositions containing them |
| JP2000563679A JP2002522450A (en) | 1998-08-05 | 1999-07-30 | Monocyclic compounds having NK-2 antagonistic activity and compositions containing them |
| TR2001/00354T TR200100354T2 (en) | 1998-08-05 | 1999-07-30 | Monocyclic compounds and formations with NK-2 Antagonist action. |
| EP99941479A EP1102789A1 (en) | 1998-08-05 | 1999-07-30 | Monocyclic compounds having nk-2 antagonist action and compositions containing them |
| AU55079/99A AU5507999A (en) | 1998-08-05 | 1999-07-30 | Monocyclic compounds having nk-2 antagonist action and compositions containing them |
| CA002339638A CA2339638A1 (en) | 1998-08-05 | 1999-07-30 | Monocyclic compounds having nk-2 antagonist action and compositions containing them |
| PE1999000784A PE20001002A1 (en) | 1998-08-05 | 1999-08-04 | SINGLE CYCLIC COMPOUNDS WITH ANTAGONIST NK2 ACTION AND THE COMPOSITION THAT CONTAINS THEM |
| CO99049466A CO5080789A1 (en) | 1998-08-05 | 1999-08-05 | MONOCICLIC COMPOUNDS WITH ANTAGONIST ACTION NK2 AND COMPOSITION THAT CONTAINS THEM |
| ARP990103922A AR021751A1 (en) | 1998-08-05 | 1999-08-05 | MONOCICLIC COMPOUNDS, PHARMACEUTICAL COMPOSITIONS CONTAINING THEM AND THEIR USE AS AN ANTAGONIST OF NK2 TAQUIQUININE RECEIVER IN THE TREATMENT OF DEPATOLOGIES WHERE THERE IS RELEASE OF TACHIQUININS |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IT1998FI000186A IT1304888B1 (en) | 1998-08-05 | 1998-08-05 | MONOCYCLIC ACTION COMPOUNDS NK-2 ANTAGONIST AND FORMULATIONS THAT CONTAIN |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| ITFI980186A1 true ITFI980186A1 (en) | 2000-02-05 |
| IT1304888B1 IT1304888B1 (en) | 2001-04-05 |
Family
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| IT1998FI000186A IT1304888B1 (en) | 1998-08-05 | 1998-08-05 | MONOCYCLIC ACTION COMPOUNDS NK-2 ANTAGONIST AND FORMULATIONS THAT CONTAIN |
Country Status (11)
| Country | Link |
|---|---|
| EP (1) | EP1102789A1 (en) |
| JP (1) | JP2002522450A (en) |
| AR (1) | AR021751A1 (en) |
| AU (1) | AU5507999A (en) |
| CA (1) | CA2339638A1 (en) |
| CO (1) | CO5080789A1 (en) |
| IT (1) | IT1304888B1 (en) |
| PE (1) | PE20001002A1 (en) |
| TR (1) | TR200100354T2 (en) |
| TW (1) | TW491857B (en) |
| WO (1) | WO2000008046A1 (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IT1307809B1 (en) * | 1999-10-21 | 2001-11-19 | Menarini Ricerche Spa | BASIC MONOCYCLIC COMPOUNDS WITH NK-2 ANTAGONIST ACTION, MANUFACTURING PROCESSES AND FORMULATIONS CONTAINING THEM. |
| PL217630B1 (en) | 2003-04-24 | 2014-08-29 | Incyte Corp | Aza spiro alkane derivatives as inhibitors of metalloproteases |
| UY38485A (en) | 2018-11-27 | 2020-06-30 | Novartis Ag | CYCLIC TETRAMER COMPOUNDS AS PROPROTEIN CONVERTASE SUBTILISIN / KEXIN TYPE 9 (PCSK9) INHIBITORS, METHOD OF TREATMENT, USE AND PREPARATION |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4703034A (en) * | 1986-04-28 | 1987-10-27 | Merck & Co., Inc. | Novel cyclic tetrapeptide |
| AU2387592A (en) * | 1991-08-08 | 1993-03-02 | A. Menarini Industrie Farmaceutiche Riunite S.R.L. | Cyclic hexapeptides as tachyquinin antagonists, their preparation and pharmaceutical compositions thereof |
| ATE155486T1 (en) * | 1991-08-13 | 1997-08-15 | Takeda Chemical Industries Ltd | CYCLIC PEPTIDES AND THEIR USE |
| IT1277835B1 (en) * | 1995-03-13 | 1997-11-12 | Menarini Farma Ind | BICYCLE COMPOUNDS, THEIR PREPARATION AND USE IN PHARMACEUTICAL COMPOSITIONS |
| IT1291776B1 (en) * | 1997-02-07 | 1999-01-21 | Menarini Ricerche Spa | MONOCYCLIC COMPOUNDS WITH FOUR BIFUNCTIONAL RESIDUES, HAVING NK-2 ANTAGONIST ACTION |
-
1998
- 1998-08-05 IT IT1998FI000186A patent/IT1304888B1/en active
-
1999
- 1999-07-27 TW TW088112671A patent/TW491857B/en active
- 1999-07-30 CA CA002339638A patent/CA2339638A1/en not_active Abandoned
- 1999-07-30 TR TR2001/00354T patent/TR200100354T2/en unknown
- 1999-07-30 WO PCT/EP1999/005459 patent/WO2000008046A1/en not_active Application Discontinuation
- 1999-07-30 AU AU55079/99A patent/AU5507999A/en not_active Abandoned
- 1999-07-30 EP EP99941479A patent/EP1102789A1/en not_active Withdrawn
- 1999-07-30 JP JP2000563679A patent/JP2002522450A/en active Pending
- 1999-08-04 PE PE1999000784A patent/PE20001002A1/en not_active Application Discontinuation
- 1999-08-05 AR ARP990103922A patent/AR021751A1/en unknown
- 1999-08-05 CO CO99049466A patent/CO5080789A1/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| AR021751A1 (en) | 2002-08-07 |
| JP2002522450A (en) | 2002-07-23 |
| WO2000008046A1 (en) | 2000-02-17 |
| CO5080789A1 (en) | 2001-09-25 |
| AU5507999A (en) | 2000-02-28 |
| IT1304888B1 (en) | 2001-04-05 |
| CA2339638A1 (en) | 2000-02-17 |
| EP1102789A1 (en) | 2001-05-30 |
| PE20001002A1 (en) | 2000-10-16 |
| TW491857B (en) | 2002-06-21 |
| TR200100354T2 (en) | 2001-05-21 |
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