Highly stable oxytocin derivatives

A compound of general formula I

• wherein
• Z1 (N-terminus) denotes NH2, H, or OH;
• Z9 (C-terminus) denotes NH2, or OH;
• or
• Z9 denotes NH if m denotes 2, 3, 4, 5, or 6;
• X1 and X2 independently from one another denote S, Se, or CH2;
• R21, R31, R71, and R81 independently from one another denote H, C1-6alkyl, halogen, or CF3;
• Rx denotes H or a group, optionally substituted by C6-10 aryl and/or optionally substituted by one or more identical or different Ra and/or Rb, selected from among C1-6 alkyl, C2-6 alkenyl, or C2-6 alkynyl;
• Ry denotes H or a group, optionally substituted by C6-10 aryl and/or optionally substituted by one or more identical or different Ra and/or Rb, selected from C1-6alkyl, C2-6alkenyl, or C2-6alkynyl;
• n1 denotes 0, 1, 2, or 3, and wherein n1 denotes 0 if R21 is different from H;
• n2 denotes 0, 1, 2, or 3, and wherein n2 denotes 0 if R31 is different from H;
• n3 denotes 0, 1, 2, or 3, and wherein n3 denotes 0 if R81 is different from H;
• n4 denotes 0 or 1;
• n8 denotes 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;
• m denotes 0, 1, 2, 3, 4, 5, or 6;
• W denotes O or S;
• X3 denotes N;
• or
• X3 denotes O or NH if m denotes 0;
• X4 denotes CH or N;
• Y denotes NH or O;
• R2 denotes Tyr together with the peptide backbone of residue 2;
• or
• R2 denotes H or a group, optionally substituted by one or more identical or different Ra and/or Rb, selected independently from among C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-8 cycloalkyl, C4-8 cycloalkylalkyl, C6-8 aryl, C7-8 arylalkyl, 3-8 membered heterocycloalkyl, 4-8 membered heterocycloalkylalkyl, 5-8 membered heteroaryl, and 6-8 membered heteroarylalkyl;
• R3 denotes Ile together with the peptide backbone of residue 3;
• or
• R3 denotes H or a group, optionally substituted by one or more identical or different Ra and/or Rb, selected independently from among C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-8 cycloalkyl, C4-8 cycloalkylalkyl, C6-8 aryl, C7-8 arylalkyl, 3-8 membered heterocycloalkyl, 4-8 membered heterocycloalkylalkyl, 5-8 membered heteroaryl, and 6-8 membered heteroarylalkyl;
• R7 denotes H or a group, optionally substituted by one or more identical or different Ra and/or Rb, selected independently from among C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-8 cycloalkyl, C4-8 cycloalkylalkyl, C6-8 aryl, C7-8 arylalkyl, 3-8 membered heterocycloalkyl, 4-8 membered heterocycloalkylalkyl, 5-8 membered heteroaryl, and 6-8 membered heteroarylalkyl;
• or
• R7 together with Rx forms an optionally substituted 3 to 6 membered heterocycloalkyl ring;
• R8 denotes —C(O)Rc, —C(Rc)═NORc, or a group, optionally substituted by one or more identical or different Ra and/or Rb, selected independently from among C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, 3-13 membered heterocycloalkyl, and 5-13 membered heteroaryl, and wherein R8 optionally comprises a terminal lipidation and/or PEGylation, and/or labeling;
• R9 denotes H or C1-5alkyl;
• each Ra independently of one another denotes H or a group, optionally substituted by one or more identical or different Rb and/or Rc, selected from among C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-8cycloalkyl, C4-8cycloalkylalkyl, C6-8 aryl, C7-8 arylalkyl, 3-8 membered heterocycloalkyl, 4-8 membered heterocycloalkylalkyl, 5-8 membered heteroaryl, and 6-8 membered heteroarylalkyl;
• each Rb is a suitable substituent and is selected in each case independently of one another from among ═O, —ORc, C1-3haloalkyloxy, —OCF3, ═S, —SRc, =NRc, =NORc, —NRcRc, —ONRcRc, —N(ORc)Rc, —N(Rg)NRcRc, halogen, —CF3, —CN, —NC, —OCN, —SCN, —NO, —NO2, =N2, —N3, —S(O)Rc, —S(O)ORc, —S(O)2Rc, —S(O)2ORc, —S(O)NRcRc, —S(O)2NRcRc, —OS(O)Rc, —OS(O)2Rc, —OS(O)2ORc, —OS(O)NRcRc, —OS(O)2NRcRc, —C(O)Rc, —C(O)ORc, —C(O)SRc, —C(O)NRcRc, —C(O)N(Rg)NRcRc, —C(O)N(Rg)ORc, —C(NRg)NRcRc, —C(NOH)Rc, —C(NOH)NRcRc, —OC(O)Rc, —OC(O)ORc, —OC(O)SRc, —OC(O)NRcRc, —OC(NRg)NRcRc, —SC(O)Rc, —SC(O)ORc, —SC(O)NRcRc, —SC(NR9)NRcRc, —N(Rg)C(O)Rc, and —N[C(O)Rc]2;
• each Re independently of one another denotes H or a group, optionally substituted by one or more identical or different Rd and/or Re, selected from among C1-6alkyl, C2-6alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, C4-8 cycloalkylalkyl, C6-8 aryl, C7-8 arylalkyl, 3-8 membered heterocycloalkyl, 4-8 membered heterocycloalkylalkyl, 5-8 membered heteroaryl and 6-8 membered heteroarylalkyl;
• each Rd denotes a suitable substituent and is selected in each case independently of one another from among ═O, —ORe, C1-3haloalkyloxy, —OCF3, ═S, —SRe, =NRe, =NORe, —NReRe, —ONReRe, —N(ORe)Re, —N(Rg)NReRe, halogen, —CF3, —CN, —NC, —OCN, —SCN, —NO, —NO2, =N2, —N3, —S(O)Re, —S(O)ORe, —S(O)2Re, —S(O)2ORe, —S(O)NReRe, —S(O)2NReRe, —OS(O)Re, —OS(O)2Re, —OS(O)2ORe, —OS(O)NReRe, —OS(O)2NReRe, —C(O)Re, —C(O)ORe, —C(O)SRe, —C(O)NReRe, —C(O)N(Rg)NRcRc, —C(O)N(Rg)ORe, —C(NRg)NReRe, —C(NOH)Re, —C(NOH)NReRe, —OC(O)Re, —OC(O)ORe, —OC(O)SRe, —OC(O)NReRe, —OC(NRg)NRcRc, —SC(O)Re, —SC(O)ORe, —SC(O)NReRe, —SC(NR9)NReRe, —N(Rg)C(O)Re, and —N[C(O)Re]2;
• and
• each Re independently of one another denotes H or a group selected from among C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-8 cycloalkyl, C6-8 aryl, 3-8 membered heterocycloalkyl, and 5-8 membered heteroaryl;
• and
• each Rg independently of one another denotes H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-8 cycloalkyl, C6-8 aryl, 3-8 membered heterocycloalkyl, or 5-8 membered heteroaryl;
• with the proviso that R8, n4, n8, and Y together with the peptide backbone of residue 8 is different from Leu, Ile, cyclopentyl-Gly (Cpg), Lys, Arg, or the enantiomers thereof;
• with the proviso that if R8 comprises a terminal lipidation and/or PEGylation and/or labeling, R2 together with the peptide backbone of residue 2 is different from Tyr, and/or R3 together with the peptide backbone of residue 3 is different from Ile, and/or one of X1 or X2 is different from S;
• and
• with the proviso that if R8, n4, n8, and Y together with the peptide backbone of residue 8 is Ala or Thr, then R2 together with the peptide backbone of residue 2 is different from Tyr, and/or R3 together with the peptide backbone of residue 3 is different from Ile, and/or one of X1 or X2 is different from S;
• optionally in the form of the tautomers, the racemates, the enantiomers, the diastereomers, hydrates, and mixtures thereof, and optionally the pharmacologically acceptable salts thereof.