BACKBONE-CYCLIZED PEPTIDOMIMETICS WITH GLP-1R MODULATING ACTIVITY

Abstract

Novel backbone-cyclized peptidomimetics of the general formula

cyclo[-P.sup.1-P.sup.2-P.sup.3-P.sup.4-P.sup.5-P.sup.6-P.sup.7-P.sup.8-T.sup.1-T.sup.2-] (I)

wherein the single elements T or P are -amino acid residues connected in either direction which, depending on their positions in the chain, are as defined in the description and the claims, and salts thereof, have the property to modulate the GLP-1 receptor. They can be used as medicaments to treat, prevent, or delay the onset of diseases, disorders or conditions in which modulation of the human GLP-1 receptor is beneficial, such as type 2 diabetes.

These backbone-cyclized peptidomimetics can be manufactured by a process which is based on a mixed solidand solution phase synthetic strategy.

Claims

1. A compound of the general formula (I)
cyclo[-P.sup.1-P.sup.2-P.sup.3-P.sup.4-P.sup.5-P.sup.6-P.sup.7-P.sup.8-T.sup.1-T.sup.2-](I) wherein the single elements T or P are connected in either direction from the carbonyl (CO) point of attachment to the nitrogen (N) of the next element and wherein T.sup.1 is a D -amino acid residue of formula ##STR00011## T.sup.2 is an L or D -amino acid residue of one of the formulae ##STR00012## P.sup.1 is Phe; Tyr; 3Pal; 2Thi; or 3Thi; P.sup.2 is Asp; Asn; Glu; Hgl; Gln; hGln; Cit; or an L -amino acid residue of formula ##STR00013## P.sup.3 is Leu; Nle; Cha; Chg; Asn; Gln; hGln; or Cit; P.sup.4 is Leu; Nle; Val; or an L -amino acid residue of formula ##STR00014## P.sup.5 is Ala; Aib; or Abu; P.sup.6 is Trp; Trp(5OH); Tpi; or Trp(1Me); P.sup.7 is Asp; Asn; Glu; Hgl; Gln; hGln; or Cit; P.sup.8 is Arg; hArg; Agp; Lys; hLys; Orn; or an L -amino acid residue of formula ##STR00015## with the proviso that if P.sup.3 is Asn; Gln; hGln; or Cit; then P.sup.2 is an L -amino acid residue of formula AA5; P.sup.7 is Asp; Glu; Hgl; or Cit; or if P.sup.3 is Leu; Nle; Cha; or Chg; and P.sup.2 is Asn; Gln; hGln; Cit; or an L -amino acid residue of formula AA5; then P.sup.7 is Glu; or Hgl; R.sup.Ar is, with the proviso of containing less than 26 carbon- and/or heteroatoms, (CR.sup.20R.sup.22).sub.nR.sup.27; (CH.sub.2).sub.nO(CH.sub.2).sub.mR.sup.27; (CH.sub.2).sub.nS(CH.sub.2).sub.mR.sup.27; or (CH.sub.2).sub.nNR.sup.25(CH.sub.2).sub.mR.sup.27; R.sup.1, R.sup.2 and R.sup.3 are independently H; CF.sub.3; or CH.sub.3; R.sup.4, R.sup.5 and R.sup.6 are independently H; F; CF.sub.3; C.sub.1-8-alkyl; C.sub.2-8-alkenyl; C.sub.2-8-alkynyl; cycloalkyl; heterocycloalkyl; (CHR.sup.12).sub.oOR.sup.15; -O(CO)R.sup.15; (CHR.sup.12).sub.oSR.sup.15; (CHR.sup.12).sub.oNR.sup.15R.sup.16; (CHR.sup.12).sub.oOCONR.sup.15R.sup.16; (CHR.sup.12).sub.oNR.sup.1CONR.sup.15R.sup.16; (CHR.sup.12).sub.oNR.sup.1COOR.sup.15; (CHR.sup.12).sub.oNR.sup.1COR.sup.15; (CHR.sup.12).sub.oCOOR.sup.15; (CHR.sup.12).sub.oCONR.sup.15R.sup.16; (CHR.sup.12).sub.oPO(OR.sup.1).sub.2; (CHR.sup.12).sub.oSO.sub.2R.sub.15; (CHR.sup.12).sub.oNR.sup.1SO.sub.2R.sup.15; or (CHR.sup.12).sub.oSO.sub.2NR.sup.15R.sup.16; R.sup.4 and R.sup.2; or R.sup.5 and R.sup.6 taken together can form: O; or (CHR.sup.1).sub.p; R.sup.4 and R.sup.5; or R.sup.6 and R.sup.7taken together can form: (CHR.sup.1).sub.p; (CH.sub.2).sub.tO(CH.sub.2).sub.u; (CH.sub.2).sub.tS(CH.sub.2).sub.u; or (CH.sub.2).sub.tNR.sup.1(CH.sub.2).sub.u; R.sup.7 is H; F; CF.sub.3; C.sub.1-8-alkyl; C.sub.2-8-alkenyl; C.sub.2-8-alkynyl; cycloalkyl; heterocycloalkyl; (CHR.sup.12).sub.rOR.sup.15; O(CO)R.sup.15; (CHR.sup.12).sub.rSR.sup.15; (CHR.sup.10).sub.rNR.sup.15R.sup.16; (CHR.sup.12).sub.rOCONR.sup.15R.sup.16; (CHR.sup.12).sub.rNR.sup.1CONR.sup.15R.sup.16; (CHR.sup.12).sub.rNR.sup.1COOR.sup.15; (CHR.sup.12).sub.rNR.sup.1COR.sup.15; (CHR.sup.12).sub.oCOOR.sup.15; (CHR.sup.12).sub.oCONR.sup.15R.sup.16; (CHR.sup.12).sub.rPO(OR.sup.1).sub.2; (CHR.sup.12).sub.rSO.sub.2R.sup.15; (CHR.sup.12).sub.rNR.sup.1SO.sub.2R.sup.15; or (CHR.sup.12).sub.rSO.sub.2NR.sup.15R.sup.16; R.sup.8 and R.sup.9 are, with the proviso of containing combined less than 26 carbon- and/or heteroatoms, independently C.sub.1-8-alkyl; C.sub.2-8-alkenyl; C.sub.2-8-alkynyl; cycloalkyl-C.sub.1-4-alkyl; heterocycloalkyl-C.sub.1-4-alkyl; (CHR.sup.1).sub.sOCF.sub.3; (CHR.sup.1).sub.sOR.sup.18; (CHR.sup.1).sub.sSCF.sub.3; or (CHR.sup.1).sub.sSR.sup.18; Z is, with the proviso of containing less than 26 carbon- and/or heteroatoms, (CR.sup.2R.sup.12).sub.q; (CR.sup.2R.sup.12).sub.kO(Cr.sup.2R.sup.12).sub.l; or (CR.sup.2R.sup.12).sub.kS(CR.sup.2R.sup.12).sub.l; or a group of one of the formulae ##STR00016## A is O; NR.sup.17; S; SO; or SO.sub.2; X is CR.sup.19; or N; R.sup.10 and R.sup.11 are independently H; F; Cl; Br; I; CF.sub.3; OCF.sub.3; OCHF.sub.2; C.sub.1-4-alkyl; C.sub.2-4-alkenyl; or C.sub.2-4-alkynyl; R.sup.12, R.sup.13 and R.sup.14 are independently H; F; CF.sub.3; or CH.sub.3; R.sup.15 and R.sup.16 are independently H; C.sub.1-8-alkyl; C.sub.2-8-alkenyl; C.sub.2-8-alkynyl; C.sub.1-6-alkoxy; cycloalkyl; heterocycloalkyl; cycloalkyl-C.sub.1-6-alkyl; or heterocycloalkyl-C.sub.1-6-alkyl; or the structural element NR.sup.15R.sup.16 can form heterocycloalkyl; R.sup.17 is H; C.sub.1-4-alkyl; C.sub.2-4-alkenyl; or C.sub.2-4-alkynyl; R.sup.18 is C.sub.1-4-alkyl; C.sub.2-4-alkenyl; or C.sub.2-4-alkynyl; R.sup.19 is H; F; Cl; Br; I; CN; CF.sub.3; OCHF.sub.2; OCF.sub.3; C.sub.1-4-alkyl; C.sub.2-4-alkenyl; or C.sub.2-4 alkynyl; R.sup.20 and R.sup.21 are independently H; CF.sub.3; C.sub.1-8-alkyl; C.sub.2-8-alkenyl; C.sub.2-8-alkynyl; or aryl-C.sub.1-6-alkyl; R.sup.22 is H; F; CF.sub.3; C.sub.1-8-alkyl; C.sub.2-8-alkenyl; C.sub.2-8-alkynyl; cycloalkyl; heterocycloalkyl; aryl; heteroaryl; aryl-C.sub.1-6-alkyl; heteroaryl-C.sub.1-6-alkyl; (CHR.sup.23).sub.oOR.sup.25; O(CO)R.sup.25; (CHR.sup.23).sub.oSR.sup.25; (CHR.sup.23).sub.oNR.sup.25R.sup.26; (CHR.sup.23).sub.oOCONR.sup.25R.sup.26; (CHR.sup.23).sub.oNR.sup.20CONR.sup.25R.sup.26; (CHR.sup.23).sub.oNR.sup.20COOR.sup.25; (CHR.sup.23).sub.oNR.sup.20COR.sup.25; (CHR.sup.23).sub.oCOOR.sup.25; (CHR.sup.23).sub.oCONR.sup.25R.sup.26; (CHR.sup.23).sub.oPO(OR.sup.20).sub.2; (CHR.sup.23).sub.oSO.sub.2R.sup.25; (CHR.sup.23).sub.oNR.sup.20SO.sub.2R.sup.25; (CHR.sup.23).sub.oSO.sub.2NR.sup.25R.sup.26; (CR.sup.20R.sup.23).sub.oR.sup.27; or (CHR.sup.20).sub.nO(CHR.sup.21).sub.mR.sup.27; R.sup.23 is H; F; CF.sub.3; C.sub.1-8-alkyl; C.sub.2-8-alkenyl; C.sub.2-8-alkynyl; cycloalkyl; heterocycloalkyl; cycloalkyl-C.sub.1-6-alkyl; heterocycloalkyl-C.sub.1-6-alkyl; aryl; heteroaryl; aryl-C.sub.1-6-alkyl; heteroaryl-C.sub.1-6-alkyl; (CHR.sup.20).sub.oOR.sup.25; OCOR.sup.20; (CHR.sup.20)NR.sup.25R.sup.26; COOR.sup.25; CONR.sup.25R.sup.26; SO.sub.2R.sup.25; or SO.sub.2NR.sup.25R.sup.26; R.sup.24 is H; CF.sub.3; C.sub.1-8-alkyl; C.sub.2-8-alkenyl; C.sub.2-8-alkynyl; cycloalkyl; heterocycloalkyl; cycloalkyl-C.sub.1-6-alkyl; heterocycloalkyl-C.sub.1-6-alkyl; aryl; heteroaryl; aryl-C.sub.1-6-alkyl; heteroaryl-C.sub.1-6-alkyl; cycloalkyl-aryl; heterocycloalkyl-aryl; cycloalkyl-heteroaryl; heterocycloalkyl-heteroaryl; aryl-cycloalkyl; aryl-heterocycloalkyl; heteroaryl-cycloalkyl; heteroaryl-heterocycloalkyl; (CHR.sup.20).sub.oOR.sup.25; (CHR.sup.20).sub.oSR.sup.25; (CHR.sup.20).sub.oNR.sup.25R.sup.26; (CHR.sup.20).sub.oCOOR.sup.25; (CHR.sup.20).sub.oCONR.sup.25R.sup.26; or (CHR.sup.20).sub.oSO.sub.2R.sup.25; R.sup.25 and R.sup.26 are independently H; C.sub.1-8-alkyl; C.sub.2-8-alkenyl; C.sub.2-8-alkynyl; C.sub.1-6-alkoxy; cycloalkyl; heterocycloalkyl; cycloalkyl-C.sub.1-6-alkyl; heterocycloalkyl-C.sub.1-6-alkyl; aryl; heteroaryl; aryl-C.sub.1-6-alkyl; heteroaryl-C.sub.1-6-alkyl; cycloalkyl-aryl; heterocycloalkyl-aryl; cycloalkyl-heteroaryl; heterocycloalkyl-heteroaryl; aryl-cycloalkyl; aryl-heterocycloalkyl; heteroaryl-cycloalkyl; or heteroaryl-heterocycloalkyl; or the structural element R.sup.25R.sup.26 can independently form: heterocycloalkyl; aryl-heterocycloalkyl; or heteroaryl-heterocycloalkyl; R.sup.27 is an aryl group of one of the formulae ##STR00017## or a heteroaryl group of one of the formulae ##STR00018## ##STR00019## X, X, X and X are independently CR.sup.28; or N; R.sup.28 and R.sup.29 are independently H; F; Cl; Br; I; OH; NH.sub.2; NO.sub.2; CN; CF.sub.3; OCHF.sub.2; OCF.sub.3; C.sub.1-8-alkyl; C.sub.2-8-alkenyl; C.sub.2-8-alkynyl; aryl; heteroaryl; aryl-C.sub.1-6-alkyl; heteroaryl-C.sub.1-6-alkyl; (CH.sub.2).sub.oR.sup.30; (CH.sub.2).sub.oOR.sup.25; O(CO)R.sup.25;O(CH.sub.2).sub.oR.sup.30; (CH.sub.2).sub.oSR.sup.25; (CH.sub.2).sub.oNR.sup.25R.sup.26; (CH.sub.2).sub.oOCONR.sup.25R.sup.26; (CH.sub.2).sub.oNR.sup.20CONR.sup.25R.sup.26; (CH.sub.2).sub.oNR.sup.20COR.sup.25; (CH.sub.2).sub.oCOOR.sup.25; (CH.sub.2).sub.oCONR.sup.25R.sup.26; (CH.sub.2).sub.oPO(OR.sup.20).sub.2; (CH.sub.2).sub.oS.sub.2R.sup.24; or (CH.sub.2).sub.oCOR.sup.25; R.sup.30 is an aryl group of the formula ##STR00020## R.sup.31, R.sup.32 and R.sup.33 are independently H; F; Cl; Br; I; OH; NH.sub.2; NO.sub.2; CN; CF.sub.3; OCHF.sub.2; OCF.sub.3; C.sub.1-8-alkyl; C.sub.2-8-alkenyl; C.sub.2-8-alkynyl; (CH.sub.2).sub.oOR.sup.25; O(CO)R.sup.25; (CH.sub.2).sub.oNR.sup.20R.sup.25; (CH.sub.2).sub.oCOOR.sup.25; or (CH.sub.2).sub.oCONR.sup.20R.sup.25; R.sup.34 is H; Ac; C.sub.1-8-alkyl; or aryl-C.sub.1-6-alkyl; k and l are independently an integer of 1-5 with the proviso that k+l6; t and u are independently an integer of 0-3 with the proviso that t+u1 and t+u3; n and m are independently an integer of 0-5 with the proviso that n+m6; o is 0-4; p is 2-4; q is 3-7; r is 1-3; s is 1-4; or a pharmaceutically acceptable salt thereof.

2. A compound according to claim 1 wherein P.sup.1 is Phe; Tyr; 3Pal; 2Thi; or 3Thi; P.sup.2 is Asp; Asn; Glu; Hgl; Gln; hGln; Cit; Bbta; 2Pal; 3Pal; 4Pal; h2Pal; h3Pal; h4Pal; Ala(2Furyl); Ala(3Furyl); Ala(1Im); Ala(2Im); hAla(1Im); hAla(2Im); Ala(Pyrazinyl); Ala(1Pyrazolyl); Ala(3Pyrazolyl); Ala(2Pyrimidin); Ala(4Pyrimidin); Ala(5Pyrimidin); Ala(2Quin); Ala(3Quin); Ala(4Quin); Phe; Phe(4NH.sub.2); Phe(mC(NH.sub.2)NH); Phe(pC(NH.sub.2)NH); Phe(2Cl); Phe(3Cl); Phe(4Cl); Phe(3,4Cl.sub.2); Phe(2F); Phe(3F); Phe(4F); Phe(3CN); Phe(4CN); Phe(2CF.sub.3); Phe(3CF.sub.3); Phe(4CF.sub.3); Phe(3,4(CF.sub.3).sub.2); Phe(4COOMe); hPhe; Phg; 1Nal; 2Nal; Nle(6OBn); Ser(Bn); Thr(Bn); Trp; Trp(7Aza); Trp(5Br); Trp(6Br); Trp(6CF.sub.3); Trp(5Cl); Trp(6Cl); Trp(5,6Cl); Trp(5OH); hTrp; His; His(Me); His(Bn); hHis; 2Thi; 3Thi; Tyr; Tyr(3F); Tyr(Bn); Tyr(Me); Tyr(Ph); Tyr(4OHPh); hTyr; or Tza; P.sup.3 is Leu; Nle; Cha; Chg; Asn; Gln; hGln; or Cit; P.sup.4 is Leu; Nle; Val; Bbta; 2Pal; 3Pal; 4Pal; h2Pal; h3Pal; h4Pal; Ala(2Furyl); Ala(3Furyl); Ala(1Im); Ala(2Im); hAla(1Im); hAla(2Im); Ala(Pyrazinyl); Ala(1Pyrazolyl); Ala(3Pyrazolyl); Ala(2Pyrimidin); Ala(4Pyrimidin); Ala(5Pyrimidin); Ala(2Quin); Ala(3Quin); Ala(4Quin); Phe; Phe(4NH.sub.2); Phe(mC(NH.sub.2)NH); Phe(pC(NH.sub.2)NH); Phe(2Cl); Phe(3Cl); Phe(4Cl); Phe(3,4Cl.sub.2); Phe(2F); Phe(3F); Phe(4F); Phe(3CN); Phe(4CN); Phe(2CF.sub.3); Phe(3CF.sub.3); Phe(4CF.sub.3); Phe(3,4(CF.sub.3).sub.2); Phe(4COOMe); hPhe; Phg; 1Nal; 2Nal; Nle(6OBn); Ser(Bn); Thr(Bn); Trp; Trp(7Aza); Trp(5Br); Trp(6Br); Trp(6CF.sub.3); Trp(5Cl); Trp(6Cl); Trp(5,6Cl);Trp(5OH); hTrp; His; His(Me); His(Bn); hHis; 2Thi; 3Thi; Tyr; Tyr(3F); Tyr(Bn); Tyr(Me); Tyr(Ph); Tyr(4OHPh); hTyr; or Tza; P.sup.5 is Ala; Aib; or Abu; P.sup.6 is Trp; Trp(5OH); Tpi; or Trp(1Me); P.sup.7 is Asp; Asn; Glu; Hgl; Gln; hGln; or Cit; P.sup.8 is Bbta; 2Pal; 3Pal; 4Pal; h2Pal; h3Pal; h4Pal; Ala(2Furyl); Ala(3Furyl); Ala(1Im); Ala(2Im); hAla(1Im); hAla(2Im); Ala(Pyrazinyl); Ala(1Pyrazolyl); Ala(3Pyrazolyl); Ala(2Pyrimidin); Ala(4Pyrimidin); Ala(5Pyrimidin); Ala(2Quin); Ala(3Quin); Ala(4Quin); Phe; Phe(4NH.sub.2); Phe(mC(NH.sub.2)NH); Phe(pC(NH.sub.2)NH); Phe(2Cl); Phe(3Cl); Phe(4Cl); Phe(3,4Cl.sub.2); Phe(2F); Phe(3F); Phe(4F); Phe(3CN); Phe(4CN); Phe(2CF.sub.3); Phe(3CF.sub.3); Phe(4CF.sub.3); Phe(3,4(CF.sub.3).sub.2); Phe(4COOMe); hPhe; Phg; 1Nal; 2Nal; Nle(6OBn); Ser(Bn); Thr(Bn); Trp; Trp(7Aza); Trp(5Br);Trp(6Br); Trp(6CF.sub.3); Trp(5Cl); Trp(6Cl); Trp(5,6Cl); Trp(5OH); hTrp; His; His(Me); His(Bn); hHis; 2Thi; 3Thi; Tyr; Tyr(3F); Tyr(Bn); Tyr(Me); Tyr(Ph); Tyr(4OHPh); hTyr; Tza; Arg; hArg; Agp; Lys; hLys; or Orn; with the proviso that if P.sup.3 is Asn; Gln; hGln; or Cit; then P.sup.2 is Bbta; 2Pal; 3Pal; 4Pal; h2Pal; h3Pal; h4Pal; Ala(2Furyl); Ala(3Furyl); Ala(1Im); Ala(2Im); hAla(1Im); hAla(2Im); Ala(Pyrazinyl); Ala(1Pyrazolyl); Ala(3Pyrazolyl); Ala(2Pyrimidin); Ala(4Pyrimidin); Ala(5Pyrimidin); Ala(2Quin); Ala(3Quin); Ala(4Quin); Phe; Phe(4NH.sub.2); Phe(mC(NH.sub.2)NH); Phe(pC(NH.sub.2)NH); Phe(2Cl); Phe(3Cl); Phe(4Cl); Phe(3,4Cl.sub.2); Phe(2F); Phe(3F); Phe(4F); Phe(3CN); Phe(4CN); Phe(2CF.sub.3); Phe(3CF.sub.3); Phe(4CF.sub.3); Phe(3,4(CF.sub.3).sub.2); Phe(4COOMe); hPhe; Phg; 1Nal; 2Nal; Nle(6OBn); Ser(Bn); Thr(Bn); Trp; Trp(7Aza); Trp(5Br); Trp(6Br); Trp(6CF.sub.3); Trp(5Cl); Trp(6Cl); Trp(5,6Cl); Trp(5OH); hTrp; His; His(Me); His(Bn); hHis; 2Thi; 3Thi; Tyr; Tyr(3F); Tyr(Bn); Tyr(Me); Tyr(Ph); Tyr(4OHPh); hTyr; or Tza; P.sup.7 is Asp; Glu; Hgl; or Cit; or if P.sup.3 is Leu; Nle; Cha; or Chg; then P.sup.2 is Asp; Asn; Glu; Hgl; Gln; hGln; Cit; Bbta; 2Pal; 3Pal; 4Pal; h2Pal; h3Pal; h4Pal; Ala(2Furyl); Ala(3Furyl); Ala(1Im); Ala(2Im); hAla(1Im); hAla(2Im); Ala(Pyrazinyl); Ala(1Pyrazolyl); Ala(3Pyrazolyl); Ala(2Pyrimidin); Ala(4Pyrimidin); Ala(5Pyrimidin); Ala(2Quin); Ala(3Quin); Ala(4Quin); Phe; Phe(4NH.sub.2); Phe(mC(NH.sub.2)NH); Phe(pC(NH.sub.2)NH); Phe(2Cl); Phe(3Cl); Phe(4Cl); Phe(3,4Cl.sub.2); Phe(2F); Phe(3F); Phe(4F); Phe(3CN); Phe(4CN); Phe(2CF.sub.3); Phe(3CF.sub.3); Phe(4CF.sub.3); Phe(3,4(CF.sub.3).sub.2); Phe(4COOMe); hPhe; Phg; 1Nal; 2Nal; Nle(6OBn); Ser(Bn); Thr(Bn); Trp; Trp(7Aza); Trp(5Br); Trp(6Br); Trp(6CF.sub.3); Trp(5Cl); Trp(6Cl); Trp(5,6Cl); Trp(5OH); hTrp; His; His(Me); His(Bn); hHis; 2Thi; 3Thi; Tyr; Tyr(3F); Tyr(Bn); Tyr(Me); Tyr(Ph); Tyr(4OHPh); hTyr; or Tza; and with the further proviso that if P.sup.2 is Asn; Gln; hGln; Cit; Bbta; 2Pal; 3Pal; 4Pal; h2Pal; h3Pal; h4Pal; Ala(2Furyl); Ala(3Furyl); Ala(1Im); Ala(2Im); hAla(1Im); hAla(2Im); Ala(Pyrazinyl); Ala(1Pyrazolyl); Ala(3Pyrazolyl); Ala(2Pyrimidin); Ala(4Pyrimidin); Ala(5Pyrimidin); Ala(2Quin); Ala(3Quin); Ala(4Quin); Phe; Phe(4NH.sub.2); Phe(mC(NH.sub.2)NH); Phe(pC(NH.sub.2)NH);Phe(2Cl); Phe(3Cl); Phe(4Cl); Phe(3,4Cl.sub.2); Phe(2F); Phe(3F); Phe(4F); Phe(3CN); Phe(4CN); Phe(2CF.sub.3); Phe(3CF.sub.3); Phe(4CF.sub.3); Phe(3,4(CF.sub.3).sub.2); Phe(4COOMe); hPhe; Phg; 1Nal; 2Nal; Nle(6OBn); Ser(Bn); Thr(Bn); Trp; Trp(7Aza); Trp(5Br); Trp(6Br); Trp(6CF.sub.3); Trp(5Cl); Trp(6Cl); Trp(5,6Cl); Trp(5OH); hTrp; His; His(Me); His(Bn); hHis; 2Thi; 3Thi; Tyr; Tyr(3F); Tyr(Bn); Tyr(Me); Tyr(Ph); Tyr(4OHPh); hTyr; or Tza; then P.sup.7 is Glu; or Hgl; or a pharmaceutically acceptable salt thereof.

3. A compound according to claim 1 or 2 wherein P.sup.1 is Phe; 3Pal; 2Thi; or 3Thi; P.sup.2 is Glu; Hgl; Gln; Cit; Phe; Phe(4NH.sub.2); Phe(4F); Phe(4Cl); 3Pal; 4Pal; Tyr; Tyr(Me); Tyr(Ph); Tyr(Bn); His; His(Bn); Trp; or Trp(5OH); P.sup.3 is Leu; Nle; Cha; Chg; Gln; or Cit; P.sup.4 is Leu; Nle; Val; Phe; hPhe; Phe(4NH.sub.2); Phe(4Cl); Phe(4CN); 4Pal; Tyr; Tyr(Me); Tyr(Ph); His; or 2Thi; P.sup.5 is Ala; Aib; or Abu; P.sup.6 is Trp; or Trp(1Me); P.sup.7 is Asp; Glu; Hgl; Gln; or Cit; P.sup.8 is Phe; Phg; hPhe; Phe(4NH.sub.2); Phe(3Cl); Phe(4Cl); Phe(4CN); 3Pal; Tyr; Tyr(Me); Tyr(Bn); His; His(Bn); 2Thi; 3Thi; Trp; Trp(5OH); Arg; or Lys; with the proviso that if P.sup.3 is Gln; or Cit; then P.sup.2 is Phe; Phe(4NH.sub.2); Phe(4F); Phe(4Cl); 3Pal; 4Pal; Tyr; Tyr(Me); Tyr(Ph); Tyr(Bn); His; His(Bn); Trp; or Trp(5OH); P.sup.7 is Asp; Glu; Hgl; or Cit; or if P.sup.3 is Leu; Nle; Cha; or Chg; then P.sup.2 is Glu; Hgl; Gln; Cit; His; or Trp; and with the further proviso that if P.sup.2 is Gln; Cit; His; or Trp; then P.sup.7 is Glu; or Hgl; or a pharmaceutically acceptable salt thereof.

4. A compound according to any one of claims 1 to 3 wherein P.sup.1 is Phe; P.sup.2 is Glu; Gln; Phe; Phe(4NH.sub.2); 3Pal; 4Pal; Tyr; Tyr(Me); Tyr(Ph); Tyr(Bn); His; His(Bn); Trp; or Trp(5OH); P.sup.3 is Leu; or Gln; P.sup.4 is Leu; Phe; Phe(4CN); Tyr; or Tyr(Me); P.sup.5 is Ala; P.sup.6 is Trp; P.sup.7 is Glu; Hgl; Gln; or Cit; P.sup.8 is Phe; Phg; Phe(4NH.sub.2); 3Pal; Tyr; Tyr(Me); Tyr(Bn); His; His(Bn); Trp; Trp(5OH); or Arg; with the proviso that if P.sup.3 is Gln; then P.sup.2 is Phe; Phe(4NH.sub.2); 3Pal; 4Pal; Tyr; Tyr(Me); Tyr(Ph); Tyr(Bn); His; His(Bn); Trp or Trp(5OH); P.sup.7 is Glu; Hgl; or Cit; or if P.sup.3 is Leu; then P.sup.2 is Glu; Gln; His; or Trp; and with the further proviso that if P.sup.2 is Gln; His; or Trp; then P.sup.7 is Glu; or Hgl; or a pharmaceutically acceptable salt thereof.

5. A compound according to any one of claims 1 to 4 wherein T.sup.1 is .sup.DPro; .sup.DAzt; .sup.DPro(5,5Me.sub.2); .sup.DPro((4S)NH.sub.2); .sup.DPro((4R)NH.sub.2); .sup.DPro((3R)OH); .sup.DPro((3S)OH); .sup.DPro((4R)OH); or .sup.DPro((4S)OH); T.sup.2 is Aib; Deg; Dpg; Ac4c; 3,3-AC-OXT; Cyp; Chx; Chx(4oxo); 4,4-AC-THP; Ac7c; Ac8c; Atc; or Ind; or pharmaceutically acceptable salts thereof.

6. A compound according to any one of claims 1 to 5 wherein T.sup.1is .sup.DPro; or .sup.DPro(5,5Me.sub.2); T.sup.2 is Aib; Deg; Dpg; Ac4c; 3,3-AC-OXT; Cyp; Chx; 4,4-AC-THP; Ac7c; Ac8c; or Ind; or a pharmaceutically acceptable salt thereof.

7. A compound according to claim 1 or 6 wherein T.sub.1is .sup.DPro; T.sup.2 is Aib; Deg; Dpg; Cyp; Chx; Ac7c; Ac8c; or Ind; or a pharmaceutically acceptable salt thereof.

8. A compound according to any one of claims 1 to 7 which is selected from cyclo(-Phe-Phe-Gln-Tyr-Ala-Trp-Glu-Tyr-.sup.DPro-Chx-); cyclo(-Phe-3Pal-Gln-Tyr-Ala-Trp-Glu-Tyr-.sup.DPro-Chx-); cyclo(-Phe-Phe(4NH.sub.2)-Gln-Tyr-Ala-Trp-Glu-Tyr-.sup.DPro-Chx-); cyclo(-Phe-His(Bn)-Gln-Tyr-Ala-Trp-Glu-Tyr-.sup.DPro-Chx-); cyclo(-Phe-Tyr(Bn)-Gln-Tyr-Ala-Trp-Glu-Tyr-.sup.DPro-Chx-); cyclo(-Phe-Tyr(Ph)-Gln-Tyr-Ala-Trp-Glu-Arg-.sup.DPro-Chx-); cyclo(-Phe-Tyr(Ph)-Gln-Tyr-Ala-Trp-Glu-Tyr-.sup.DPro-Chx-); cyclo(-Phe-Trp-Gln-Tyr(Me)-Ala-Trp-Glu-Tyr-.sup.DPro-Chx-); cyclo(-Phe-Trp-Gln-Tyr-Ala-Trp-Glu-Tyr(Me)-.sup.DPro-Chx-); cyclo(-Phe-Phe-Gln-Tyr-Ala-Trp-Glu-Arg-.sup.DPro-Chx-); cyclo(-Phe-Tyr(Ph)-Gln-Tyr-Ala-Trp-Glu-Arg-.sup.DPro-Aib-); cyclo(-Phe-Trp-Leu-Tyr-Ala-Trp-Glu-Tyr-.sup.DPro-Chx-); cyclo(-Phe-Glu-Leu-Tyr-Ala-Trp-Glu-Tyr-.sup.DPro-Ind-); cyclo(-Phe-Tyr-Gln-Tyr-Ala-Trp-Glu-Tyr-.sup.DPro-Chx-); cyclo(-Phe-Trp-Gln-Tyr-Ala-Trp-Glu-His(Bn)-.sup.DPro-Chx-); cyclo(-Phe-Glu-Leu-Tyr-Ala-Trp-Glu-Trp-.sup.DPro-Chx-); cyclo(-Phe-Trp-Gln-Tyr-Ala-Trp-Glu-Trp-.sup.DPro-Chx-); cyclo(-Phe-Trp-Gln-Tyr-Ala-Trp-Glu-Trp(5OH)-.sup.DPro-Chx-); cyclo(-Phe-3Pal-Gln-Tyr-Ala-Trp-Glu-Arg-.sup.DPro-Chx-); cyclo(-Phe-His-Leu-Tyr-Ala-Trp-Glu-Tyr-DPro-Chx-); cyclo(-Phe-Phe(4NH.sub.2)-Gln-Tyr-Ala-Trp-Glu-Arg-.sup.DPro-Chx-); cyclo(-Phe-Trp-Gln-Tyr-Ala-Trp-Glu-Tyr(Bn)-.sup.DPro-Chx-); cyclo(-Phe-Trp-Gln-Tyr(Me)-Ala-Trp-Glu-Arg-.sup.DPro-Chx-); cyclo(-Phe-Trp-Gln-Tyr-Ala-Trp-Glu-Phe-.sup.DPro-Chx-); cyclo(-Phe-Glu-Leu-Tyr-Ala-Trp-Glu-Trp(5OH)-.sup.DPro-Chx-); cyclo(-Phe-Glu-Leu-Leu-Ala-Trp-Glu-Phe-.sup.DPro-Dpg-); cyclo(-Phe-Trp-Gln-Phe-Ala-Trp-Glu-Tyr-.sup.DPro-Chx-); cyclo(-Phe-Glu-Leu-Tyr-Ala-Trp-Trp(5OH)-Tyr-.sup.DPro-Chx-); cyclo(-Phe-Glu-Leu-Tyr(Me)-Ala-Trp-Glu-Tyr-.sup.DPro-Chx-); cyclo(-Phe-Trp-Gln-Tyr-Ala-Trp-Glu-Phe(4NH.sub.2)-.sup.DPro-Chx-); cyclo(-Phe-Glu-Leu-Tyr-Ala-Trp-Glu-Phe-.sup.DPro-Chx-); cyclo(-Phe-Tyr(Me)-Gln-Tyr-Ala-Trp-Glu-Tyr-.sup.DPro-Chx-); cyclo(-Phe-4Pal-Gln-Tyr-Ala-Trp-Glu-Tyr-.sup.DPro-Chx-); cyclo(-Phe-Glu-Leu-Tyr(Me)-Ala-Trp-Glu-Tyr(Me)-.sup.DPro-Chx-); cyclo(-Phe-Trp(5OH)-Gln-Tyr-Ala-Trp-Glu-Tyr-.sup.DPro-Chx-); cyclo(-Phe-Glu-Leu-Tyr-Ala-Trp-Glu-His(Bn)-.sup.DPro-Chx-); cyclo(-Phe-Glu-Leu-Phe(4CN)-Ala-Trp-Glu-Tyr-.sup.DPro-Chx-); cyclo(-Phe-Glu-Leu-Tyr-Ala-Trp-Cit-Tyr-.sup.DPro-Chx-); cyclo(-Phe-Glu-Leu-Tyr-Ala-Trp-Glu-His-.sup.DPro-Chx-); cyclo(-Phe-Gln-Leu-Tyr-Ala-Trp-Glu-Tyr-.sup.DPro-Chx-); cyclo(-Phe-Glu-Leu-Tyr-Ala-Trp-Glu-3Pal-.sup.DPro-Chx-); cyclo(-Phe-Glu-Leu-Tyr-Ala-Trp-Glu-Arg-.sup.DPro-Chx-); cyclo(-Phe-Glu-Leu-Leu-Ala-Trp-Glu-Phe-.sup.DPro-Chx-); cyclo(-Phe-Glu-Leu-Leu-Ala-Trp-Glu-Phe-.sup.DPro-Cyp-); cyclo(-Phe-Glu-Leu-Leu-Ala-Trp-Glu-Phe-.sup.DPro-Aib-); cyclo(-Phe-Trp-Gln-Leu-Ala-Trp-Glu-Phe-.sup.DPro-Cyp-); cyclo(-Phe-Glu-Leu-Leu-Ala-Trp-Glu-Phe-.sup.DPro-Deg-); cyclo(-Phe-Glu-Leu-Tyr-Ala-Trp-Glu-Phe-.sup.DPro-Cyp-); cyclo(-Phe-Gln-Leu-Tyr-Ala-Trp-Hgl-Tyr-.sup.DPro-Chx-); cyclo(-Phe-Glu-Leu-Tyr-Ala-Trp-Glu-Phg-.sup.DPro-Chx-); cyclo(-Phe-His-Leu-Tyr-Ala-Trp-Gln-Tyr-.sup.DPro-Aib-); cyclo(-Phe-Glu-Leu-Leu-Ala-Trp-Glu-Phe-.sup.DPro-Ind-); cyclo(-Phe-Glu-Leu-Leu-Ala-Trp-Glu-Phe-.sup.DPro-Ac7c-); cyclo(-Phe-Glu-Leu-Leu-Ala-Trp-Glu-Phe-.sup.DPro-Ac8c-); or a pharmaceutically acceptable salt thereof.

9. A compound according to claim 8 which is selected from cyclo(-Phe-Phe-Gln-Tyr-Ala-Trp-Glu-Tyr-.sup.DPro-Chx-); cyclo(-Phe-3Pal-Gln-Tyr-Ala-Trp-Glu-Tyr-.sup.DPro-Chx-); cyclo(-Phe-Phe(4NH.sub.2)-Gln-Tyr-Ala-Trp-Glu-Tyr-.sup.DPro-Chx-); cyclo(-Phe-His(Bn)-Gln-Tyr-Ala-Trp-Glu-Tyr-.sup.DPro-Chx-); cyclo(-Phe-Tyr(Bn)-Gln-Tyr-Ala-Trp-Glu-Tyr-.sup.DPro-Chx-); cyclo(-Phe-Tyr(Ph)-Gln-Tyr-Ala-Trp-Glu-Arg-.sup.DPro-Chx-); cyclo(-Phe-Tyr(Ph)-Gln-Tyr-Ala-Trp-Glu-Tyr-.sup.DPro-Chx-); cyclo(-Phe-Trp-Gln-Tyr(Me)-Ala-Trp-Glu-Tyr-.sup.DPro-Chx-); cyclo(-Phe-Trp-Gln-Tyr-Ala-Trp-Glu-Tyr(Me)-.sup.DPro-Chx-); cyclo(-Phe-Phe-Gln-Tyr-Ala-Trp-Glu-Arg-.sup.DPro-Chx-); cyclo(-Phe-Tyr(Ph)-Gln-Tyr-Ala-Trp-Glu-Arg-.sup.DPro-Aib-); cyclo(-Phe-Trp-Leu-Tyr-Ala-Trp-Glu-Tyr-.sup.DPro-Chx-); cyclo(-Phe-Glu-Leu-Tyr-Ala-Trp-Glu-Tyr-.sup.DPro-Ind-); cyclo(-Phe-Tyr-Gln-Tyr-Ala-Trp-Glu-Tyr-.sup.DPro-Chx-); cyclo(-Phe-Trp-Gln-Tyr-Ala-Trp-Glu-His(Bn)-.sup.DPro-Chx-); cyclo(-Phe-Glu-Leu-Tyr-Ala-Trp-Glu-Trp-.sup.DPro-Chx-); cyclo(-Phe-Trp-Gln-Tyr-Ala-Trp-Glu-Trp-.sup.DPro-Chx-); cyclo(-Phe-Trp-Gln-Tyr-Ala-Trp-Glu-Trp(5OH)-.sup.DPro-Chx-); cyclo(-Phe-3Pal-Gln-Tyr-Ala-Trp-Glu-Arg-.sup.DPro-Chx-); cyclo(-Phe-His-Leu-Tyr-Ala-Trp-Glu-Tyr-DPro-Chx-); cyclo(-Phe-Phe(4NH.sub.2)-Gln-Tyr-Ala-Trp-Glu-Arg-.sup.DPro-Chx-); cyclo(-Phe-Trp-Gln-Tyr-Ala-Trp-Glu-Tyr(Bn)-.sup.DPro-Chx-); cyclo(-Phe-Trp-Gln-Tyr(Me)-Ala-Trp-Glu-Arg-.sup.DPro-Chx-); cyclo(-Phe-Trp-Gln-Tyr-Ala-Trp-Glu-Phe-.sup.DPro-Chx-); cyclo(-Phe-Glu-Leu-Tyr-Ala-Trp-Glu-Trp(5OH)-.sup.DPro-Chx-); cyclo(-Phe-Trp-Gln-Phe-Ala-Trp-Glu-Tyr-.sup.DPro-Chx-); cyclo(-Phe-Glu-Leu-Tyr(Me)-Ala-Trp-Glu-Tyr-.sup.DPro-Chx-); cyclo(-Phe-Trp-Gln-Tyr-Ala-Trp-Glu-Phe(4NH.sub.2)-.sup.DPro-Chx-); cyclo(-Phe-Glu-Leu-Tyr-Ala-Trp-Glu-Phe-.sup.DPro-Chx-); cyclo(-Phe-Tyr(Me)-Gln-Tyr-Ala-Trp-Glu-Tyr-.sup.DPro-Chx-); cyclo(-Phe-4Pal-Gln-Tyr-Ala-Trp-Glu-Tyr-.sup.DPro-Chx-); cyclo(-Phe-Glu-Leu-Tyr(Me)-Ala-Trp-Glu-Tyr(Me)-.sup.DPro-Chx-); cyclo(-Phe-Glu-Leu-Tyr-Ala-Trp-Glu-His(Bn)-.sup.DPro-Chx-); cyclo(-Phe-Glu-Leu-Phe(4CN)-Ala-Trp-Glu-Tyr-.sup.DPro-Chx-); cyclo(-Phe-Glu-Leu-Tyr-Ala-Trp-Cit-Tyr-.sup.DPro-Chx-); cyclo(-Phe-Glu-Leu-Tyr-Ala-Trp-Glu-3Pal-.sup.DPro-Chx-); cyclo(-Phe-Glu-Leu-Tyr-Ala-Trp-Glu-Phe-.sup.DPro-Cyp-); cyclo(-Phe-Glu-Leu-Leu-Ala-Trp-Glu-Phe-.sup.DPro-Ind-); or a pharmaceutically acceptable salt thereof.

10. A compound according to claim 8 or 9 which is selected from cyclo(-Phe-Phe-Gln-Tyr-Ala-Trp-Glu-Tyr-.sup.DPro-Chx-); cyclo(-Phe-His(Bn)-Gln-Tyr-Ala-Trp-Glu-Tyr-.sup.DPro-Chx-); cyclo(-Phe-Phe(4NH.sub.2)-Gln-Tyr-Ala-Trp-Glu-Tyr-.sup.DPro-Chx-); cyclo(-Phe-Tyr(Bn)-Gln-Tyr-Ala-Trp-Glu-Tyr-.sup.DPro-Chx-); cyclo(-Phe-Tyr(Ph)-Gln-Tyr-Ala-Trp-Glu-Arg-.sup.DPro-Chx-); cyclo(-Phe-3Pal-Gln-Tyr-Ala-Trp-Glu-Tyr-.sup.DPro-Chx-); cyclo(-Phe-Trp-Gln-Tyr(Me)-Ala-Trp-Glu-Tyr-.sup.DPro-Chx-); cyclo(-Phe-Phe-Gln-Tyr-Ala-Trp-Glu-Arg-.sup.DPro-Chx-); or a pharmaceutically acceptable salt thereof.

11. A compound according to any one of claims 1 to 10 having modulating activity at the GLP-1 receptor.

12. A pharmaceutical composition containing a compound or a mixture of compounds according to any one of claims 1 to 11 and at least one pharmaceutically inert carrier.

13. A pharmaceutical composition according to claim 12 in a form suitable for oral, topical, transdermal, injection, buccal, transmucosal, rectal, pulmonary or inhalation administration, especially in the form of tablets, dragees, capsules, solutions, liquids, gels, plaster, creams, ointments, syrup, slurries, suspensions, depot preparations, spray, nebulizer or suppositories.

14. A compound of formula (I) according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, for use as a medicament.

15. The use of a compound according to any one of claims 1 to 11, or a composition according to claim 12 or 13, for the treatment or prevention of diseases, disorders or conditions related to diabetes, particularly type 2 diabetes, or prediabetes; or complications or comorbidities associated with diabetes or prediabetes; or metabolic syndrome, insulin resistance, hypertension, hyperglycemia, cardiovascular diseases or disorders, atherosclerosis-related diseases, neurodegenerative diseases, or cognitive disorders; or for the treatment of traumatic brain injuries, satiety disorders, mood disorders or obesity.

16. The use of a compound according to any one of claims 1 to 11 for the manufacture of a medicament to treat or prevent diseases, disorders, or conditions associated with the GLP-1 receptor, particularly diseases, disorders or conditions related to diabetes, such as type 2 diabetes and type 1 diabetes; or prediabetes, such as impaired glucose tolerance; or diabetes-related complications and comorbidities, such as diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, impaired wound healing, dyslipidemia, and vascular diseases and obesity; or hyperglycemia; or metabolic syndrome; or hypertension; or insulin resistance; or obesity; or cognitive disorders, such as cognitive deficits; or mood disorders; or neurodegenerative diseases, such as Alzheimer's disease; or traumatic brain injuries; or stroke; or insufficient satiety; or cardiovascular disorders and diseases, such as coronary heart disease and myocardial infarction; or atherosclerosis; or gastric ulcers; or inflammatory bowel syndrome.

17. A method of treating or preventing a disease, disorder, or condition associated with the GLP-1 receptor, particularly diseases, disorders or conditions related to diabetes, such as type 2 diabetes or type 1 diabetes; or prediabetes, such as impaired glucose tolerance; or diabetes-related complications and comorbidities, such as diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, impaired wound healing, dyslipidemia, and vascular diseases and obesity; or hyperglycemia; or metabolic syndrome; or hypertension; or insulin resistance; or obesity; or cognitive disorders, such as cognitive deficits; or mood disorders; or neurodegenerative diseases, such as Alzheimer's disease; or traumatic brain injuries; or stroke; or insufficient satiety; or cardiovascular disorders and diseases, such as coronary heart disease and myocardial infarction; or atherosclerosis; or gastric ulcers; or inflammatory bowel syndrome; comprising administering to a subject in need thereof a pharmaceutically acceptable amount of a compound according to any one of claims 1 to 11, or a composition according to claim 12 or 13.

18. A process for the preparation of a compound according to any one of claims 1 to 11 which comprises (a) coupling an appropriately functionalized solid support with an appropriately N-protected derivative of that amino acid which in the desired end-product is in position T.sup.1 or T.sup.2 or P.sup.1 to P.sup.8 as defined above; any functional group which may be present in said N-protected amino acid derivative being likewise appropriately protected; (b) removing the N-protecting group from the product obtained in step (a); (c) coupling the product thus obtained with an appropriately N-protected derivative of that amino acid which in the desired end-product is in the position of the next element (T or P), following counterclockwise or clockwise the sequence according to general formula (I) in COOH to NH.sub.2 orientation; any functional group which may be present in said N-protected amino acid derivative being likewise appropriately protected; (d) removing the N-protecting group from the product thus obtained; (e) repeating steps (c) and (d) until all amino acid residues have been introduced; (f) detaching the product thus obtained from the solid support; (g) cyclizing the product cleaved from the solid support; (h) removing any protecting groups present on functional groups of any members of the chain of amino acid residues and, if desired, any protecting group(s) which may in addition be present in the molecule; (i) if desired, converting the product thus obtained into a pharmaceutically acceptable salt or converting a pharmaceutically acceptable, or unacceptable, salt thus obtained into the corresponding free compound of formula (I) or into a different, pharmaceutically acceptable salt.

Description

EXAMPLES

[0594] 1. Peptide Synthesis

[0595] 1.1 General Synthetic Procedures

[0596] A general method for the synthesis of the peptidomimetics of the present invention is exemplified in the following. This is to demonstrate the principal concept and does not limit or restrict the present invention in any way. A person skilled in the art is easily able to modify these procedures, especially, but not limited to, choosing a different starting position within the ring system, to still achieve the preparation of the claimed cyclic peptidomimetic compounds of the present invention.

[0597] Coupling of the First Protected Amino Acid Residue to the Resin

[0598] In a dried flask, 2-chlorotritylchloride resin (polystyrene, 1% crosslinked; loading: 1.4 mmol/g) was swollen in dry CH.sub.2Cl.sub.2 for 30 min (7 ml CH.sub.2Cl.sub.2 per g resin). A solution of 0.8 eq of the Fmoc-protected amino acid and 6 eq of DIPEA in dry CH.sub.2Cl.sub.2/DMF (4/1, v/v) (10 ml per g resin) was added. After shaking for 2-4 h at rt the resin was filtered off and washed successively with CH.sub.2Cl.sub.2, DMF, CH.sub.2Cl.sub.2, DMF and CH.sub.2Cl.sub.2. Then a solution of dry CH.sub.2Cl.sub.2/MeOH/DIPEA (17:2:1, v/v/v) was added (10 ml per g resin). After shaking for 330 min the resin was filtered off in a pre-weighed sinter funnel and washed successively with CH.sub.2Cl.sub.2, DMF, CH.sub.2Cl.sub.2, MeOH, CH.sub.2Cl.sub.2, MeOH, CH.sub.2Cl.sub.2 (2) and Et.sub.2O (2). The resin was dried under high vacuum overnight. The final mass of resin was calculated before the qualitative control.

[0599] The following preloaded resins were prepared: Fmoc-Ala-2-chlorotrityl resin and Fmoc-Leu-2-chlorotrityl resin.

[0600] Synthesis of the Fully Protected Peptide Fragment

[0601] The synthesis was carried out on a Syro-peptide synthesizer (MultiSynTech GmbH) using 24 to 96 reaction vessels. In each vessel were placed approximately 80 mg of the above resin (weight of the resin before loading). The following reaction cycles were programmed and carried out:

TABLE-US-00001 Step Reagent Time 1 CH.sub.2Cl.sub.2, wash and swell (manual) 1 3 min 2 DMF, wash and swell 2 30 min 3 20% piperidine/DMF 1 5 min and 1 15 min 4 DMF, wash 5 1 min 5 3.5 eq. Fmoc amino acid/3.5 eq. 1 40 min HOAt in DMF or NMP + 3.5 eq. PyBOP/7 eq DIPEA or 3.5 eq. DIC 6 3.5 eq. Fmoc amino acid/3.5 eq. 1 40 min HOAt in DMF or NMP + 3.5 eq. HATU or PyBOP or HCTU + 7 eq. DIPEA 7 DMF, wash 5 1 min 8 20% piperidine/DMF 1 5 min and 1 15 min 9 DMF, wash 5 1 min 10 CH.sub.2Cl.sub.2, wash 3 1 min (at the end of the synthesis)

[0602] Steps 5 to 9 are repeated to add each amino-acid residue.

[0603] After the synthesis of the fully protected peptide fragment had been terminated, the cleavage, cyclization and work up procedures, as described herein below, were used for the preparation of the final compounds.

[0604] Cleavage, Backbone Cyclization and Deprotection of the Peptide

[0605] After assembly of the linear peptide, the resin was suspended in 1 ml of 1% TFA in CH.sub.2Cl.sub.2 (v/v; 0.14 mmol) for 3 minutes and filtered, and the filtrate was neutralized with 1 ml of 20% DIPEA in CH.sub.2Cl.sub.2 (v/v; 1.15 mmol). This procedure was repeated four times to ensure completion of the cleavage. The resin was washed three times with 1 ml of CH.sub.2Cl.sub.2. The CH.sub.2Cl.sub.2 layers containing product were evaporated to dryness.

[0606] The fully protected linear peptide was solubilised in 8 ml of dry DMF. Then 2 eq. of HATU and 2. eq. of HOAt in dry DMF (1-2 ml) and 4 eq. of DIPEA in dry DMF (1-2 ml) were added to the peptide, followed by stirring for ca. 16 h. The volatiles were removed by evaporation. The crude cyclic peptide was dissolved in 7 ml of CH.sub.2Cl.sub.2 and washed three times with 4.5 ml 10% acetonitrile in water (v/v). The CH.sub.2Cl.sub.2 layer was then evaporated to dryness.

[0607] To fully deprotect the peptide, 4-7 ml of cleavage cocktail TFA/TIS/H.sub.2O (95:2.5:2.5, v/v/v) was added, and the mixture was kept for 2.5-4 h at room temperature until the reaction was completed. The reaction mixture was evaporated close to dryness and the peptide precipitated with 7 mL of cold Et.sub.2O/pentane (1:1, v/v). The precipitate was washed three times with 3 mL of cold Et.sub.2O/pentane (1:1, v/v), and was subsequently purified by preparative reverse phase LC-MS.

[0608] After lyophilisation the products were obtained typically as white to off-white powders and analysed by HPLC-ESI-MS methods as described below. Analytical data after preparative HPLC purification are shown in Table 1.

[0609] 1.2 Analytical Methods

[0610] Analytical Method A:

[0611] Analytical HPLC retention times (RT, in minutes) were determined using an Ascentis Express C18 column (502.1 mm, 2.7 m) with the following solvents A (H.sub.2O+0.1% TFA) and B (CH.sub.3CN+0.085% TFA) and the gradient: 0-0.05 min: 97% A, 3% B; 3.3 min: 15% A, 85% B; 3.32 min: 3% A, 97% B; 3.32-3.55 min: 3% A, 97% B; 3.57-3.7 min: 97% A, 3% B. Flow rate=1.6 ml/min at 55 C.

[0612] Analytical Method B:

[0613] Analytical HPLC retention times (RT, in minutes) were determined using an Ascentis Express C18 column (503 mm, 2.7 m) with the following solvents A (H.sub.2O+0.1% TFA) and B (CH.sub.3CN+0.085% TFA) and the gradient: 0-0.05 min: 97% A, 3% B; 4.95 min: 3% A, 97% B; 4.95-5.35 min: 3% A, 97% B; 5.37-5.4 min: 97% A, 3% B. Flow rate=1.3 ml/min at 55 C. Analytical Method C:

[0614] Analytical HPLC retention times (RT, in minutes) were determined using an Ascentis Express C8 column (1003 mm, 2.7 m) with the following solvents A (H.sub.2O+0.1% TFA) and B (CH.sub.3CN+0.085% TFA) and the gradient: 0-0.1 min: 95% A, 5% B; 7.0 min: 15% A, 85% B; 7.02 min: 3% A, 97% B; 7.02-7.5 min: 3% A, 97% B; 7.52-7.8 min: 95% A, 5% B. Flow rate=1.4 ml/min at 55 C.

[0615] Analytical Method D:

[0616] Analytical HPLC retention times (RT, in minutes) were determined using an Ascentis Express C8 column (1003 mm, 2.7 m) with the following solvents A (H.sub.2O+0.1% TFA) and B (CH.sub.3CN+0.085% TFA) and the gradient: 0-0.1 min: 95% A, 5% B; 11.0 min: 15% A, 85% B; 11.02 min: 3% A, 97% B; 11.02-12.5 min: 3% A, 97% B; 12.55-13.5 min: 95% A, 5% B. Flow rate=0.750 ml/min at 55 C.

[0617] 1.3 Synthesis of Peptide Sequences

Examples 1 to 42 and 44 to 54 Shown in Table 1

[0618] The peptides were synthesized according the general method starting with the amino acid L-Ala which was grafted to the resin (Fmoc-Ala-2-chlorotrityl resin). The linear peptides were synthesized on the solid support according to the procedure described above in the following sequence: Resin-Ala-P.sup.4-P.sup.3-P.sup.2-P.sup.1-T.sup.2-T.sup.1-P.sup.8-P.sup.7-P.sup.6. The products were cleaved from the resin, cyclized, deprotected and purified by preparative reverse phase LC-MS as described above.

[0619] After lyophilisation the products were obtained as white to off-white powders and characterised by HPLC-MS, analytical method A, B, or C as described above. For analytical data, see Ex. 1. to 42 and 44 to 54 in Table 1.

Example 43 is Shown in Table 1.

[0620] The peptide was synthesized according to the general method starting with the amino acid L-Leu which was grafted to the resin (Fmoc-Leu-2-chlorotrityl resin). The linear peptide was synthesized on the solid support according to the procedure described above in the following sequence: Resin-Leu-P.sup.3-P.sup.2-P.sup.1-T.sup.2-T.sup.1-P.sup.8-P.sup.7-P.sup.6-P.sup.5. The product was cleaved from the resin, cyclized, deprotected and purified by preparative reverse phase LC-MS as described above.

[0621] After lyophilisation the product was obtained as white to off-white powder and characterised by HPLC-MS, analytical method B as described above. For analytical data, see Ex. 43 in Table 1.

[0622] 1.4 Sequence Data

TABLE-US-00002 TABLE 1 Examples (Ex.) Analyt. RT Purity Ex. P.sup.1.sup.a) P.sup.2.sup.a) P.sup.3.sup.a) P.sup.4.sup.a) P.sup.5.sup.a) P.sup.6.sup.a) P.sup.7.sup.a) P.sup.8.sup.a) T.sup.1.sup.a) T.sup.2.sup.a) Meth. MS.sup.b) [min] [%] 1 Phe Phe Gln Tyr Ala Trp Glu Tyr .sup.DPro Chx A 1357.7 1.80 94 2 Phe 3Pal Gln Tyr Ala Trp Glu Tyr .sup.DPro Chx A 680.0 1.49 95 3 Phe Phe(4NH.sub.2) Gln Tyr Ala Trp Glu Tyr .sup.DPro Chx A 687.0 1.51 95 4 Phe His(Bn) Gln Tyr Ala Trp Glu Tyr .sup.DPro Chx A 719.5 1.68 95 5 Phe Tyr(Bn) Gln Tyr Ala Trp Glu Tyr .sup.DPro Chx A 732.5 2.08 92 6 Phe Tyr(Ph) Gln Tyr Ala Trp Glu Arg .sup.DPro Chx A 722.0 1.82 95 7 Phe Tyr(Ph) Gln Tyr Ala Trp Glu Tyr .sup.DPro Chx A 1449.5 2.06 87 8 Phe Trp Gln Tyr(Me) Ala Trp Glu Tyr .sup.DPro Chx A 1410.7 1.93 85 9 Phe Trp Gln Tyr Ala Trp Glu Tyr(Me) .sup.DPro Chx A 1410.7 2.03 92 10 Phe Phe Gln Tyr Ala Trp Glu Arg .sup.DPro Chx A 676.0 1.55 95 11 Phe Tyr(Ph) Gln Tyr Ala Trp Glu Arg .sup.DPro Aib A 702.0 1.68 95 12 Phe Trp Leu Tyr Ala Trp Glu Tyr .sup.DPro Chx A 1381.6 2.15 86 13 Phe Glu Leu Tyr Ala Trp Glu Tyr .sup.DPro Ind C 1358.3 4.31 93 14 Phe Tyr Gln Tyr Ala Trp Glu Tyr .sup.DPro Chx A 687.5 1.64 95 15 Phe Trp Gln Tyr Ala Trp Glu His(Bn) .sup.DPro Chx C 731.0 3.85 89 16 Phe Glu Leu Tyr Ala Trp Glu Trp .sup.DPro Chx A 1347.6 2.15 90 17 Phe Trp Gln Tyr Ala Trp Glu Trp .sup.DPro Chx A 1419.7 1.99 89 18 Phe Trp Gln Tyr Ala Trp Glu Trp(5OH) .sup.DPro Chx C 718.4 3.84 88 19 Phe 3Pal Gln Tyr Ala Trp Glu Arg .sup.DPro Chx A 676.5 1.22 95 20 Phe His Leu Tyr Ala Trp Glu Tyr .sup.DPro Chx A 667.0 1.81 95 21 Phe Phe(4NH.sub.2) Gln Tyr Ala Trp Glu Arg .sup.DPro Chx A 683.5 1.26 95 22 Phe Trp Gln Tyr Ala Trp Glu Tyr(Bn) .sup.DPro Chx A 1486.6 2.32 95 23 Phe Trp Gln Tyr(Me) Ala Trp Glu Arg .sup.DPro Chx A 702.7 1.69 95 24 Phe Trp Gln Tyr Ala Trp Glu Phe .sup.DPro Chx A 1380.7 2.06 95 25 Phe Glu Leu Tyr Ala Trp Glu Trp(5OH) .sup.DPro Chx A 682.5 1.92 95 26 Phe Glu Leu Leu Ala Trp Glu Phe .sup.DPro Dpg C 1274.5 5.99 95 27 Phe Trp Gln Phe Ala Trp Glu Tyr .sup.DPro Chx A 1380.6 1.93 95 28 Phe Glu Leu Tyr Ala Trp Trp(5OH) Tyr .sup.DPro Chx A 1397.6 2.08 95 29 Phe Glu Leu Tyr(Me) Ala Trp Glu Tyr .sup.DPro Chx A 670.1 2.23 95 30 Phe Trp Gln Tyr Ala Trp Glu Phe(4NH.sub.2) .sup.DPro Chx A 698.5 1.55 95 31 Phe Glu Leu Tyr Ala Trp Glu Phe .sup.DPro Chx A 1308.4 2.23 95 32 Phe Tyr(Me) Gln Tyr Ala Trp Glu Tyr .sup.DPro Chx A 1387.5 1.80 95 33 Phe 4Pal Gln Tyr Ala Trp Glu Tyr .sup.DPro Chx A 680.0 1.47 95 34 Phe Glu Leu Tyr(Me) Ala Trp Glu Tyr(Me) .sup.DPro Chx C 1352.3 5.35 95 35 Phe Trp(5OH) Gln Tyr Ala Trp Glu Tyr .sup.DPro Chx A 1412.5 1.69 90 36 Phe Glu Leu Tyr Ala Trp Glu His(Bn) .sup.DPro Chx A 695.0 1.84 95 37 Phe Glu Leu Phe(4CN) Ala Trp Glu Tyr .sup.DPro Chx C 1333.3 4.70 95 38 Phe Glu Leu Tyr Ala Trp Cit Tyr .sup.DPro Chx A 677.0 1.92 95 39 Phe Glu Leu Tyr Ala Trp Glu His .sup.DPro Chx A 650.0 1.64 95 40 Phe Gln Leu Tyr Ala Trp Glu Tyr .sup.DPro Chx A 1323.7 1.94 95 41 Phe Glu Leu Tyr Ala Trp Glu 3Pal .sup.DPro Chx D 655.3 6.07 95 42 Phe Glu Leu Tyr Ala Trp Glu Arg .sup.DPro Chx D 659.4 6.04 95 43 Phe Glu Leu Leu Ala Trp Glu Phe .sup.DPro Chx B 1258.7 3.64 95 44 Phe Glu Leu Leu Ala Trp Glu Phe .sup.DPro Cyp B 622.9 3.58 95 45 Phe Glu Leu Leu Ala Trp Glu Phe .sup.DPro Aib A 1218.6 2.37 95 46 Phe Trp Gln Leu Ala Trp Glu Phe .sup.DPro Cyp B 658.9 3.08 86 47 Phe Glu Leu Leu Ala Trp Glu Phe .sup.DPro Deg B 1246.6 3.65 95 48 Phe Glu Leu Tyr Ala Trp Glu Phe .sup.DPro Cyp B 648.0 3.12 95 49 Phe Gln Leu Tyr Ala Trp Hgl Tyr .sup.DPro Chx B 1337.7 2.82 89 50 Phe Glu Leu Tyr Ala Trp Glu Phg .sup.DPro Chx B 1294.7 3.08 95 51 Phe His Leu Tyr Ala Trp Gln Tyr .sup.DPro Aib A 646.4 1.73 95 52 Phe Glu Leu Leu Ala Trp Glu Phe .sup.DPro Ind B 1292.7 3.61 89 53 Phe Glu Leu Leu Ala Trp Glu Phe .sup.DPro Ac7c B 1272.6 3.77 95 54 Phe Glu Leu Leu Ala Trp Glu Phe .sup.DPro Ac8c B 1286.6 3.87 95 .sup.a)Abbreviations of amino acid see listing above. .sup.b)MS: m/z for either [M + 1H].sup.1+ or [M + 2H].sup.2+.

[0623] 2. Biological Methods

[0624] 2.1 Preparation of the Peptide Samples

[0625] Lyophilized peptides were weighed on a Microbalance (Mettler MX5) and dissolved in aqueous 90% DMSO to a final concentration of 10 mM unless otherwise stated. Stock solutions were kept at +4 C, and protected from light.

[0626] 2.2 Human GLP-1 Receptor Cell-Based Assay

[0627] CHO chAMPion cells (Axxam SpA; S. Corazza, Assay Drug Dev. Technol. 2009, 7, 304-307) stably co-expressing the human glucagon-like peptide-1 receptor (GLP-1R), the Ca.sup.2+-sensitive photoprotein Photina (S. Bovolenta et al., J. Biomol. Screen. 2007, 12, 694-704) and a mutated cAMP-activated calcium ion channel (WO2004/083803 A2) were used to monitor GLP-1R signaling after stimulation with an agonist. Activation of the Gas-coupled GPCR GLP-1R was monitored by measuring the flash luminescence of the Ca.sup.2+-sensitive photoprotein as reporter system with FLIPR.sup.TETRA screening instrumentation (Molecular Devices) upgraded with an ICCD Camera (MDC). For data quality check and data analysis the Genedata Screener software was used.

[0628] The reference agonist GLP-1 (glucagon-like peptide-1 amide fragment 7-36) and forskolin were purchased from Sigma (cat. G8147 and F6886, respectively) and prepared according to each ligand's specifications. All handling of ligands were done to ensure proper control throughout the experiments. The steps of the implemented workflow and data analysis are mainly as follows:

[0629] Assay Plate Seeding:

[0630] Stably transfected chAMPion cells are seeded 10000 c/w in 384 MTP in Dulbecco's MEM/nutrient mix F12 (BioWhittaker cat. BE04-687F/U1; 500 mL) supplemented with sodium pyruvate (BioWhittaker cat. BE13-115E; 5 mL of 100 mM solution), HEPES (BioWhittaker cat. BE17-737E; 6.5 mL of 1M solution), sodium bicarbonate (BioWhittaker cat. BE17-613E; 25 mL of 7.5% solution), fetal bovine serum (Euroclone cat. ECS 0180L; 50 mL), penicillin-streptomycin (BioWhittaker cat. DE17-602E; 5 mL of 100solution), 1 mg/mL G418 (selection antibiotic for GLP-1R) and 200 g/mL hygromycin in 25 L/well for 24 hours. On the day of the experiment, plates are removed from the incubator, freed from the growth medium, equilibrated at room temperature for 1 h, loaded with 30 l/well of Ca.sup.2+ free Tyrode's buffer containing 20 M coelentrazine and 500 M IBMX, and incubated for 4 hours at room temperature.

[0631] Assay:

[0632] All compounds were tested at 8 concentrations, starting from 50 M in quadruplicate, intra-plate (dilution step 1:2.15) to determine EC.sub.50 values. After incubation, the volume in all the wells is flattened to 20 L by aspiration with a CyBio-Vario pipettor. First Injection (10 L of test compounds in Ca.sup.2+ free Tyrode's buffer, DMSO 0.5% v/v and BSA 0.01%; or 10 L of reference compounds GLP-1 or forskolin in Ca.sup.2+ free Tyrode's buffer, DMSO 0.5% v/v and BSA 0.01%) is performed by the FLIPR.sup.TETRA and the kinetic response is optionally monitored over a period of 60 seconds. Incubation for 30 minutes at room temperature is followed by the Second Injection (Tyrode's buffer+10 mM CaCl.sub.2) and the kinetic response is monitored over a period of 60 seconds.

[0633] Data Analysis and Results:

[0634] The kinetic response is divided into two distinct phases: monitoring the kinetic response after the First Injection, termed Compound Addition (CA), and monitoring the kinetic response after the Second Injection of 10 mM CaCl.sub.2, termed Target Activation (TA). Agonist activity of compounds is evaluated in the Target Activation (TA) phase and it is based on normalization to TA activation by forskolin at 10 M or GLP-1 at 3.16 nM (EC.sub.100)

[0635] A good correlation was observed between EC.sub.50, data normalized by forskolin and by GLP-1. The results of the GLP-1R assays based on normalization by forskolin are summarized in Table 2.

[0636] 2.3 Results

TABLE-US-00003 TABLE 2 Glucagon-like peptide-1 (GLP-1) receptor assay EC.sub.50 (M) Target Activation Ex. (TA) 1 0.09 0.05 2 0.28 0.26 3 0.18 0.18 4 0.09 0.02 5 0.15 0.05 6 0.19 0.12 7 0.57 0.58 8 0.35 0.30 9 0.80 0.69 10 0.39 0.23 11 0.54 0.43 12 0.48 0.24 13 0.66 0.25 14 0.72 0.43 15 0.70 0.42 16.sup.a) 0.41 17 0.60 0.29 18 0.82 0.55 19 0.72 0.38 20 0.59 0.35 21 0.67 0.28 22 0.72 0.40 23 0.67 0.22 24 0.89 0.51 25 0.94 0.68 26 1.0 0.5 27.sup.a) 0.58 28 1.2 0.9 29.sup.a) 0.62 30.sup.a) 0.63 31.sup.a) 0.68 32 0.92 0.31 33 0.99 0.37 34.sup.a) 0.73 35 1.1 0.5 36.sup.a) 0.85 37.sup.a) 0.88 38.sup.a) 0.93 39 1.0 0.1 40 1.2 0.6 41 0.83 0.60 42 2.2 1.0 43 4.5 2.6 44 2.9 0.7 45.sup.a) 1.8 46 5.1 1.4 47.sup.a) 2.0 48 0.90 0.18 49.sup.a) 3.1 50.sup.a) 2.4 51.sup.a) 3.3 52 0.82 0.25 53.sup.a) 2.1 54.sup.a) 1.1 .sup.a)Values obtained from single experiment