Claims for Patent: 9,365,632

Summary for Patent: 9,365,632

Title:	Exendin-4 derivatives as dual GLP1/glucagon agonists
Abstract:	The present invention relates to exendin-4 derivatives and their medical use, for example in the treatment of disorders of the metabolic syndrome, including diabetes and obesity, as well as reduction of excess food intake.
Inventor(s):	Haack; Torsten (Frankfurt am Main, DE), Wagner; Michael (Frankfurt am Main, DE), Henkel; Bernd (Frankfurt am Main, DE), Stengelin; Siegfried (Frankfurt am Main, DE), Evers; Andreas (Frankfurt am Main, DE), Bossart; Martin (Frankfurt am Main, DE)
Assignee:	SANOFI (Paris, FR)
Application Number:	14/049,597
Patent Claims:	1. A peptidic compound having formula (I): R.sup.1--Z--R.sup.2 (I) or a salt, or solvate thereof, wherein Z is a peptide moiety having formula (II) His-X2-X3-Gly-Thr-Phe-Thr-Ser-Asp-Leu-Ser-Lys-Gln X14-X15-X16-X17-X18-Ala-X20-X21-Phe-Ile-Glu-Trp-Leu-Lys-X28-X29-Gly-Pro-S- er-Ser-Gly-X35-Pro-Pro-Pro-X39-X40 (II) wherein X2 is an amino acid residue selected from Ser, D-Ser, or Aib, X3 is an amino acid residue selected from Gln, His, and .alpha.-amino-functionalized Gln, wherein Gln is optionally functionalized in that an H of the .alpha.-amino group is substituted by (C.sub.1-C.sub.4)-alkyl, X14 is an amino acid residue having a side chain with a functionalized --NH.sub.2 group, wherein the functionalized --NH.sub.2 side chain group is functionalized by --C(O)--R.sup.5, --C(O)O--R.sup.5, --C(O)NH--R.sup.5, --S(O).sub.2--R.sup.5 or --R.sup.5, wherein R.sup.5 is a moiety up to 100 carbon atoms and optionally heteroatoms independently selected from halogen, N, O, S, P and combinations thereof, X15 is an amino acid residue selected from Glu and Asp, X16 is an amino acid residue selected from Ser, Glu, and Lys, X17 is an amino acid residue selected from Arg, Glu, Gln, Leu, Aib, and Lys, X18 is an amino acid residue selected from Arg, Ala, and Lys, X20 is an amino acid residue selected from Gln, Arg, Lys, His, Glu, and Aib, X21 is an amino acid residue selected from Asp, Leu, and Glu, X28 is an amino acid residue selected from Asn, Arg, Lys, Aib, Ser, Glu, Ala, and Asp, X29 is an amino acid residue selected from Gly, Ala, D-Ala, and Thr, X35 is an amino acid residue selected from Ala, Glu, Arg, and Lys, X39 is Ser or is absent, and X40 is absent or is an amino acid residue having a side chain with an --NH.sub.2 group, wherein the --NH.sub.2 side chain group is optionally functionalized by --C(O)--R.sup.5, --C(O)O--R.sup.5, --C(O)NH--R.sup.5, --S(O).sub.2--R.sup.5 or --R.sup.5, wherein R.sup.5 is a moiety comprising up to 100 carbon atoms and optionally heteroatoms independently selected from halogen, N, O, S, P and combinations thereof, R.sup.1 is the N-terminal group of the peptidic compound and is selected from --NH.sub.2 or mono- or bisfunctionalized NH.sub.2, wherein the mono- or bisfunctionalized NH.sub.2 is selected from the group consisting of --NH[(C.sub.1-C.sub.5)alkyl], --N[(C.sub.1-C.sub.5)alkyl].sub.2, --NH[(C.sub.0-C.sub.4)alkylene-(C.sub.3-C.sub.8)cycloalkyl], --NH--C(O)--H, --NH--C(O)--(C.sub.1-C.sub.5)-alkyl, and --NH--C(O)--(C.sub.0-C.sub.3)alkylene-(C.sub.3-C.sub.8)cycloalkyl, in which alkyl or cycloalkyl is unsubstituted or up to 5-fold substituted by --OH or halogen selected from F, CI, Br, and I, R.sup.2 is the C-terminal group of the peptidic compound and is selected from (i) --OH and functionalized --OH, wherein the functionalized --OH is selected from --O--(C.sub.1-C.sub.20)alkyl and --O(C.sub.0-C.sub.8)alkylene-(C.sub.3-C.sub.8)cycloalkyl, or (ii) --NH.sub.2 or mono- or bisfunctionalized NH.sub.2, wherein the mono- or bisfunctionalized NH.sub.2 is selected from the group consisting of --NH[(C.sub.1-C.sub.30)alkyl], --N[(C.sub.1-C.sub.30)alkyl].sub.2, --NH[(C.sub.0-C.sub.8)alkylene-(C.sub.3-C.sub.8)cycloalkyl], --N[C.sub.0-C.sub.8)alkylene-(C.sub.33-C.sub.8)cycloalkyl].sub.2, --NH[(CH.sub.2--CH.sub.2--O).sub.1-40--(C.sub.1-C.sub.4)alkyl], --NH--(C.sub.3-C.sub.8)heterocyclyl, and --NH--(C.sub.0-C.sub.8)alkylene-aryl, wherein aryl is selected from phenyl or naphthyl, the (C.sub.3-C.sub.8)-heterocyclyl contains 1 N-atom and optionally two additional heteroatoms selected from O, N, and S, and alkyl or cycloalkyl is unsubstituted or up to 5-fold substituted by --OH or a halogen selected from F, CI, Br, and I. 2. The compound, salt, or solvate according to claim 1, wherein X14 is an amino acid residue selected from Lys, Orn, Dab, and Dap, wherein the --NH.sub.2 side chain group is functionalized by --C(O)--R.sup.5, and X40 is an amino acid residue selected from Lys, Orn, Dab, and Dap, wherein the --NH.sub.2 side chain group is optionally functionalized by --C(O)--R.sup.5, where R.sup.5 is a lipophilic moiety selected from an acyclic (C.sub.4-C.sub.30) hydrocarbon group which is linear, branched, saturated, or unsaturated, or a cyclic hydrocarbon group which is saturated, unsaturated, or aromatic, wherein the lipophilic moiety is optionally attached to the --NH.sub.2 side chain group by a linker selected from the group consisting of (.beta.-Ala).sub.1-4, (.gamma.-Glu).sub.1-4, (.epsilon.-Ahx).sub.1-4, and (GABA).sub.1-4 in all stereoisomeric forms. 3. The compound, salt, or solvate according to claim 1, wherein X14 is an amino acid residue selected from Lys, Orn, Dab, and Dap, wherein the --NH.sub.2 side chain group is functionalized by --C(O)--R.sup.5, X40 is an amino acid residue selected from Lys, Orn, Dab, and Dap, wherein the --NH.sub.2 side chain group is optionally functionalized by --C(O)--R.sup.5, and --C(O)--R.sup.5 is selected from the group consisting of (S)-4-Carboxy-4-hexadecanoylamino-butyryl-, (S)-4-Carboxy-4-octadecanoylamino-butyryl-,4-Hexadecanoylamino-butyryl-, 4-{3-[(R)-2,5,7,8-tetramethyl-2-((4R,8R)-4,8, 12-trimethyl-tridecyl)-chroman-6-yloxycarbonyl]-propionylamino}-butyryl-, 4-octadecanoylamino-butyryl-, 4-((Z)-octadec-9-enoylamino)-butyryl-, 6-[(4,4-Diphenyl-cyclohexyloxy)-hydroxy-phosphoryloxy]-hexanoyl-, Hexadecanoyl-, (S)-4-Carboxy-4-(15-carboxy-pentadecanoylamino)-butyryl-, (S)-4-Carboxy-4-{3-[3-((2S,3R,4S,5R)-5-carboxy-2,3,4,5-tetrahydroxy-penta- noylamino)-propionylamino]-propionylamino}-butyryl, (S)-4-Carboxy-4-{3-[(R)-2,5,7,8-tetramethyl-2-((4R,8R)-4,8,12-trimethyl-t- ridecyl)-chroman-6-yloxycarbonyl]-propionylamino}-butyryl-, (S)-4-Carboxy-4-((9Z,12Z)-octadeca-9, 12-dienoylamino)-butyryl-, (S)-4-Carboxy-4-[6-((2S,3R,4S,5R)-5-carboxy-2,3,4, 5-tetrahydroxy-pentanoylamino)-hexanoylamino]-butyryl, (S)-4-Carboxy-4-((2S,3R,4S,5R)-5-carboxy-2,3,4,5-tetrahydroxy-pentanoylam- ino)-butyryl, (S)-4-Carboxy-4-tetradecanoylamino-butyryl-, (S)-4-(11-Benzyloxycarbonyl-undecanoylamino)-4-carboxy-butyryl, (S)-4-Carboxy-4-[11-((2S,3R,4R,5R)-2,3,4,5,6-pentahydroxy-hexylcarbamoyl)- -undecanoylamino]-butyryl-, (S)-4-Carboxy-4-((Z)-octadec-9-enoylamino)-butyryl-, (S)-4-Carboxy-4-(4-dodecyloxy-benzoylamino)-butyryl-, (S)-4-Carboxy-4-henicosanoylamino-butyryl-, (S)-4-Carboxy-4-docosanoylamino-butyryl-, (S)-4-Carboxy-4-((Z)-nonadec-10-enoylamino)-butyryl-, (S)-4-Carboxy-4-(4-decyloxy-benzoylamino)-butyryl-, (S)-4-Carboxy-4-[(4'-octyloxy-biphenyl-4-carbonyl)-amino]-butyryl-, (S)-4-Carboxy-4-(12-phenyl-dodecanoylamino)-butyryl-, (S)-4-Carboxy-4-icosanoylamino-butyryl-, (S)-4-Carboxy-4-((S)-4-carboxy-4-hexadecanoylamino-butyrylamino)-butyryl-- , (S)-4-Carboxy-4-((S)-4-carboxy-4-octadecanoylamino-butyrylamino)-butyryl- -, 3-(3-Octadecanoylamino-propionylamino)-propionyl-, 3-(3-Hexadecanoylamino-propionylamino)-propionyl-, 3-Hexadecanoylamino-propionyl-, (S)-4-Carboxy-4-[(R)-4-((3R,5S,7R,8R,9R,10S,12S,13R,14R,17R)-3,7,12-trihy- droxy-8,10,13-trimethyl-hexadecahydro-cyclopenta[a]phenanthren-17-yl)-pent- anoylamino]-butyryl-, (S)-4-Carboxy-4-[(R)-4-((3R,5R,8R,9S,10S,13R,14S,17R)-3-hydroxy-10,13-dim- ethyl-hexadecahydro-cyclopenta[a]phenanthren-17-yl)-pentanoylamino]-butyry- l-, (S)-4-Carboxy-4-((9S,10R)-9,10,16-trihydroxy-hexadecanoylamino)-butyry- l-, Tetradecanoyl-, 11-Carboxy-undecanoyl-, 11-Benzyloxycarbonyl-undecanoyl, (S)-4-Carboxy-4-((S)-4-carboxy-4-tetradecanoylamino-butyrylamino)-butyryl- -, 6-[Hydroxy-(naphthalen-2-yloxy)-phosphoryloxy]-hexanoyl-, 6-[Hydroxy-(5-phenyl-pentyloxy)-phosphoryloxy]-hexanoyl-, 4-(Naphthalene-2-sulfonylamino)-4-oxo-butyryl-, 4-(Biphenyl-4-sulfonylamino)-4-oxo-butyryl-, (S)-4-Carboxy-4-{(S)-4-carboxy-4-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-(17-c- arboxy-heptadecanoylamino)-butyrylamino]-ethoxy}-ethoxy)-acetylamino]-etho- xy }-ethoxy)-acetylamino]-butyrylamino}-butyryl-, (S)-4-Carboxy-4-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-(17-carboxy-heptadecan- oylamino)-butyrylamino]-ethoxy}-ethoxy)-acetylamino]-ethoxy}-ethoxy)-acety- lamino]-butyryl, (S)-4-Carboxy-2-{(S)-4-carboxy-2-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-(17-c- arboxy-heptadecanoylamino)-butyrylamino]-ethoxy }-ethoxy)-acetylamino]-ethoxy}-ethoxy)-acetylamino]-butyrylamino}-butyryl- , (S)-4-Carboxy-2-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-(17-carboxy-heptadeca- noylamino)-butyrylamino]-ethoxy }-ethoxy)-acetylamino]-ethoxy}-ethoxy)-acetylamino]-butyryl, (S)-4-Carboxy-4-{(S)-4-carboxy-4-[2-(2-{2-[(S)-4-carboxy-4-(17-carboxy-he- ptadecanoylamino)-butyrylamino]-ethoxy}-ethoxy)-acetylamino]-butyrylamino}- -butyryl, (S)-4-Carboxy-4-[2-(2-{2-[(S)-4-carboxy-4-(17-carboxy-heptadecan- oylamino)-butyrylamino]-ethoxy}-ethoxy)-acetylamino]-butyryl, (S)-4-Carboxy-2-{(S)-4-carboxy-2-[2-(2-{2-[(S)-4-carboxy-4-(17-carboxy-he- ptadecanoylamino)-butyrylamino]-ethoxy}-ethoxy)-acetylamino]-butyrylamino}- -butyryl, (S)-4-Carboxy-2-[2-(2-{2-[(S)-4-carboxy-4-(17-carboxy-heptadecan- oylamino)-butyrylamino]-ethoxy}-ethoxy)-acetylamino]-butyryl, 2-(2-{2-[2-(2-{2-[(S)-4-Carboxy-4-(17-carboxy-heptadecanoylamino)-butyryl- amino]-ethoxy}-ethoxy)-acetylamino]-ethoxy}-ethoxy)-acetyl-, 2-(2-{2-[(S)-4-Carboxy-4-(17-carboxy-heptadecanoylamino)-butyrylamino]-et- hoxy}-ethoxy)-acetyl, (S)-4-Carboxy-4-((S)-4-carboxy-4-{(S)-4-carboxy-4-[(S)-4-carboxy-4-(19-ca- rboxy-nonadecanoylamino)-butyrylamino]-butyrylamino}-butyrylamino)-butyryl- , 2-(2-{2-[2-(2-{2-[(S)-4-Carboxy-4-(16-1H-tetrazol-5-yl-hexadecanoylamino- )-butyrylamino]-ethoxy}-ethoxy)-acetylamino]-ethoxy}-ethoxy)-acetyl, 2-(2-{2-[2-(2-{2-[(S)-4-Carboxy-4-(16-carboxy-hexadecanoylamino)-butyryla- mino]-ethoxy }-ethoxy)-acetylamino]-ethoxy}-ethoxy)-acetyl, (S)-4-Carboxy-4-{(S)-4-carboxy-4-[(S)-4-carboxy-4-(17-carboxy-heptadecano- ylamino)-butyrylamino]-butyrylamino}-butyryl, (S)-4-Carboxy-4-((S)-4-carboxy-4-{2-[2-(2-{2-[2-(2-{(S)-4-carboxy-4-[10-(- 4-carboxy-phenoxy)-decanoylamino]-butyrylamino}-ethoxy)-ethoxy]-acetylamin- o}-ethoxy)-ethoxy]-acetylamino}-butyryl, (S)-4-Carboxy-4-{(S)-4-carboxy-4-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-(7-ca- rboxy-heptanoylamino)-butyrylamino]-ethoxy}-ethoxy)-acetylamino]-ethoxy}-e- thoxy)-acetylamino]-butyrylamino}-butyryl, (S)-4-Carboxy-4-{(S)-4-carboxy-4-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-(11-c- arboxy-undecanoylamino)-butyrylamino]-ethoxy}-ethoxy)-acetylamino]-ethoxy}- -ethoxy)-acetylamino]-butyrylamino}-butyryl, (S)-4-Carboxy-4-{(S)-4-carboxy-4-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-(13-c- arboxy-tridecanoylamino)-butyrylamino]-ethoxy}-ethoxy)-acetylamino]-ethoxy- }-ethoxy)-acetylamino]-butyrylamino}-butyryl, (S)-4-Carboxy-4-{(S)-4-carboxy-4-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-(15-c- arboxy-pentadecanoylamino)-butyrylamino]-ethoxy}-ethoxy)-acetylamino]-etho- xy}-ethoxy)-acetylamino]-butyrylamino}-butyryl, and (S)-4-Carboxy-4-{(S)-4-carboxy-4-[2-(2-{2-[2-(4-[2-{2-[(S)-4-carboxy-4-(1- 9-carboxy-nonadecanoylamino)-butyrylamino]-ethoxy}-ethoxy)-acetylamino]-et- hoxy}-ethoxy)-acetylamino]-butyrylamino}-butyryl. 4. The compound, salt or solvate according to claim 1, wherein R.sup.1 is --NH.sub.2, R.sup.2 is --NH.sub.2, or R.sup.1 and R.sup.2 are --NH.sub.2. 5. The compound, salt or solvate according to claim 1 wherein X14 is Lys, which is functionalized with a group --C(O)R.sup.5, wherein R.sup.5 is a moiety comprising up to 100 carbon atoms and optionally heteroatoms independently selected from halogen, N, O, S, P and combinations thereof. 6. The compound, salt or solvate according to claim 1, wherein X14 is Lys, which is functionalized with a group --C(O)R.sup.5, wherein R.sup.5 is an acyclic linear or branched (C.sub.12-C.sub.22) saturated hydrocarbon group attached directly to the --NH.sub.2 side chain group or attached to the --NH.sub.2 side chain group by a linker selected from the group consisting of .beta.-Ala, .gamma.-Glu, .beta.-Ala-.beta.-Ala, and .gamma.-Glu-.gamma.-Glu in all stereoisomeric forms. 7. The compound, salt or solvate according to claim 1, wherein X2 is an amino acid residue selected from Ser, D-Ser, and Aib, X3 is an amino acid residue selected from Gln, His, or .alpha.-amino-functionalized Gln, wherein Gln is optionally functionalized in that an H of the .alpha.-amino group is substituted by (C.sub.1-C.sub.4)-alkyl, X14 is an amino acid residue selected from Lys, Orn, Dab, and Dap, wherein the --NH.sub.2 side chain group is functionalized by --C(O)--R.sup.5, X15 is an amino acid residue selected from Glu and Asp, X16 is an amino acid residue selected from Ser, Lys, and Glu, X17 is an amino acid residue selected from Arg, Glu, Gln, Leu, and Lys, X18 is an amino acid residue selected from Arg and Ala, X20 is an amino acid residue selected from Gln, Arg, Lys, and Aib, X21 is an amino acid residue selected from Asp, Leu, and Glu, X28 is an amino acid residue selected from Asn, Arg, Lys, Aib, Ser, Glu, Asp, and Ala, X29 is an amino acid residue selected from Gly, Ala, D-Ala, and Thr, X35 is an amino acid residue selected from Ala and Glu, X39 is Ser or is absent, and X40 is either absent or is Lys, wherein the --NH.sub.2 side chain group is optionally functionalized by --C(O)--R.sup.5, wherein R.sup.5 is a lipophilic moiety selected from an acyclic (C.sub.4-C.sub.30) hydrocarbon group which is linear, branched, saturated, or unsaturated, or a cyclic hydrocarbon group, which is saturated, unsaturated, or aromatic, wherein the lipophilic moiety is optionally attached to the --NH.sub.2 side chain group by a linker selected from the group consisting of (.beta.-Ala).sub.1-4, (.gamma.-Glu).sub.1-4, (.epsilon.-Ahx).sub.1-4, and (GABA).sub.1-4 in all stereoisomeric forms. 8. The compound, salt or solvate according to claim 1, wherein X2 is an amino acid residue selected from D-Ser and Aib, X3 is Gln, X14 is an amino acid residue selected from Lys or Orn, wherein the --NH.sub.2 side chain group is functionalized by --C(O)--R.sup.5, X15 is an amino acid residue selected from Glu and Asp, X16 is an amino acid residue selected from Ser and Glu, X17 is an amino acid residue selected from Arg, Gln, and Lys, X18 is an amino acid residue selected from Arg and Ala, X20 is an amino acid residue selected from Gln, Arg, Lys, and Aib, X21 is an amino acid residue selected from Asp, Leu, and Glu, X28 is an amino acid residue selected from Asn, Arg, Lys, Aib, Ser, and Ala, X29 is an amino acid residue selected from Gly, Ala, and Thr, X35 is Ala, X39 is Ser or is absent, and X40 is either absent or is Lys, wherein the --NH.sub.2 side chain group is optionally functionalized by --C(O)--R.sup.5, wherein R.sup.5 is a lipophilic moiety selected from an acyclic (C.sub.4-C.sub.30) hydrocarbon group which is linear, branched, saturated, or unsaturated, or a cyclic hydrocarbon group which is saturated, unsaturated, or aromatic, wherein the lipophilic moiety is optionally attached to the --NH.sub.2 side chain group by a linker selected from the group consisting of (.beta.-Ala).sub.1-4, (.gamma.-Glu).sub.1-4, (.epsilon.-Ahx).sub.1-4, and (GABA).sub.1-4 in all stereoisomeric forms. 9. The compound, or salt or solvate thereof, according to claim 1, wherein X20 is an amino acid residue selected from Gln, Lys, and Aib. 10. The compound, salt or solvate according to claim 1, wherein X2 is an amino acid residue selected from D-Ser and Aib, X3 is Gln, X14 is Lys, wherein the --NH.sub.2 side chain group is functionalized by one of the functional groups selected from the group consisting of 3-(3-octadecanoylamino-propionyl-amino)-propionyl-, 4-hexadecanoylamino-butyryl-, 4-{3-[(R)-2,5,7,8-tetramethyl-2-((4R,8R)-4,8,12-trimethyl-tridecyl)-chrom- an-6-yloxycarbonyl]-propionylamino}-butyryl-, 4-octadecanoylamino-butyryl-, 4-((Z)-octadec-9-enoylamino)-butyryl-, hexadecanoyl-, (S)-4-carboxy-4-((Z)-octadec-9-enoylamino)-butyryl-, (S)-4-carboxy-4-(4-dodecyloxy-benzoylamino)-butyryl-, (S)-4-carboxy-4-henicosanoylamino-butyryl-, (S)-4-carboxy-4-docosanoylamino-butyryl-, (S)-4-carboxy-4-((Z)-nonadec-10-enoylamino)-butyryl-, (S)-4-carboxy-4-(4-decyloxy-benzoylamino)-butyryl-, (S)-4-carboxy-4-[(4'-octyloxy-biphenyl-4-carbonyl)-amino]-butyryl-, (S)-4-carboxy-4-(12-phenyl-dodecanoylamino)-butyryl-, (S)-4-carboxy-4-((S)-4-carboxy-4-hexadecanoylamino-butyrylamino)-butyryl-- , (S)-4-carboxy-4-((S)-4-carboxy-4-octadecanoylamino-butyrylamino)-butyryl- -, (S)-4-carboxy-4-{3-[(R)-2,5,7,8-tetramethyl-2-((4R,8R)-4,8,12-trimethyl- -tridecyl)-chroman-6-yloxycarbonyl]-propionylamino}-butyryl-, (S)-4-carboxy-4-((9Z,12Z)-octadeca-9,12-dienoylamino)-butyryl-, (S)-4-carboxy-4-octadecanoylamino-butyryl-, and (S)-4-carboxy-4-hexadecanoylamino-butyryl-, X15 is Glu, X16 is Ser, X17 is an amino acid residue selected from Arg, Gln, and Lys, X18 is Ala, X20 is Gln, X21 is Asp, X28 is Ala, X29 is Gly, X35 is Ala, X39 is Ser, and X40 is absent. 11. The compound, salt or solvate according to claim 1, wherein X2 is Aib, X3 is Gln, X14 is Lys, wherein the --NH.sub.2 side chain group is optionally functionalized by (S)-4-Carboxy-4-hexadecanoylamino-butyryl- or (S)-4-Carboxy-4-octadecanoylamino-butyryl-, X15 is an amino acid residue selected from Asp and Glu, X16 is an amino acid residue selected from Ser and Glu, X17 is an amino acid residue selected from Gln and Lys, X18 is Ala, X20 is an amino acid residue selected from Gln and Lys, X21 is an amino acid residue selected from Asp and Leu, X28 is Ala, X29 is an amino acid residue selected from Gly and D-Ala, X35 is Ala, X39 is Ser, and X40 is absent. 12. The compound, salt or solvate according to claim 1, wherein X2 is D-Ser, X3 is Gln, X14 is Lys, wherein the --NH.sub.2 side chain group is optionally functionalized by (S)-4-carboxy-4-hexadecanoylamino-butyryl- or hexadecanoyl-, X15 is an amino acid residue selected from Glu and Asp, X16 is an amino acid residue selected from Ser and Glu, X17 is an amino acid residue selected from Arg, Glu, Lys, and Aib, X18 is an amino acid residue selected from Arg, Lys, and Ala, X20 is an amino acid residue selected from Gln, Lys, and Aib, X21 is an amino acid residue selected from Asp and Leu, X28 is an amino acid residue selected from Ala and Asn, X29 is Gly, X35 is Ala, X39 is Ser, and X40 is absent. 13. The compound, salt or solvate according to claim 1, wherein X2 is an amino acid residue selected from Aib and D-Ser; X3 is an amino acid residue selected from Gln and His; X14 is Lys, wherein the --NH.sub.2 side chain group is functionalized by one of the functional groups selected from the group consisting of (S)-4-Carboxy-4-hexadecanoylamino-butyryl-, (S)-4-Carboxy-4-octadecanoylamino-butyryl-, (S)-4-Carboxy-4-((S)-4-carboxy-4-hexadecanoylamino-butyrylamino)-butyryl-- , (S)-4-Carboxy-4-((S)-4-carboxy-4-octadecanoylamino-butyrylamino)-butyryl- -, 3-(3-Octadecanoylamino-propionylamino)propionyl-, 3-(3-Hexadecanoylamino-propionylamino)-propionyl-, (S)-4-Carboxy-4-henicosanoylamino-butyryl-, 4-Hexadecanoylamino-butyryl-, and 4-octadecanoylamino-butyryl-, X15 is an amino acid residue selected from Asp and Glu; X16 is an amino acid residue selected from Ser and Glu; X17 is an amino acid residue selected from Arg, Gln, Lys, Aib, and Leu; X18 is an amino acid residue selected from Arg and Ala; X20 is an amino acid residue selected from Gln, Aib, and Lys; X21 is an amino acid residue selected from Asp, Glu, and Lys; X28 is an amino acid residue selected from Asn, Ser, Aib, Ala, and Arg; X29 is an amino acid residue selected from Gly, Thr, Ala, and D-Ala; X35 is Ala; X39 is Ser; and X40 is absent. 14. The compound, salt or solvate according to claim 1, wherein X14 is functionalized Lys which is functionalized at its .epsilon.-amino group with --C(O)--R.sup.5, wherein --C(O)--R.sup.5 is (S)-4-carboxy-4-hexadecanoyl-amino-butyryl, (S)-4-carboxy-4-octadecanoylamino-butyryl, hexadecanoyl, or octadecanoyl. 15. The compound, salt or solvate according to claim 14, wherein X2 is an amino acid residue selected from Aib and D-Ser; X3 is Gln; X14 is Lys, wherein the --NH.sub.2 side chain group is functionalized by one of the functional groups selected from the group consisting of (S)-4-carboxy-4-hexadecanoyl-amino-butyryl, (S)-4-carboxy-4-octadecanoylamino-butyryl, hexadecanoyl, and octadecanoyl; X15 is Glu; X16 is Ser; X17 is an amino acid residue selected from Arg, Gln, and Lys; X18 is Ala; X20 is Gln; X21 is Asp; X28 is Ala; X29 is Gly; X35 is Ala; X39 is Ser; and X40 is absent. 16. The compound, salt or solvate according to claim 1, wherein X2 is Aib, X3 is Gln, X14 is Lys, wherein the --NH.sub.2 side chain group is optionally functionalized by (S)-4-Carboxy-4-henicosanoylamino-butyryl- or (S)-4-Carboxy-4-octadecanoylamino-butyryl-, X15 is Asp, X16 is an amino acid residue selected from Lys and Glu, X17 is an amino acid residue selected from Arg and Glu, X18 is an amino acid residue selected from Ala and Arg, X20 is an amino acid residue selected from Gln and Lys, X21 is an amino acid residue selected from Asp and Leu, X28 is Ala, X29 is an amino acid residue selected from Gly and D-Ala, X35 is Ala, X39 is Ser, and X40 is absent. 17. The compound, salt or solvate according to claim 1, wherein the compound is any one of SEQ ID NO. 4-181, or a salt or solvate thereof. 18. The compound, salt or solvate according to claim 1, wherein the compound is any one of SEQ ID NO. 4-181, 196-223, 226-229, or a salt or solvate thereof. 19. The compound, salt or solvate according to claim 1, wherein the compound has a high solubility at at least one pH value selected from an acidic pH value or at physiological pH value, and wherein the solubility at said at least one pH value is at least 0.5 mg/ml. 20. A pharmaceutical composition comprising the compound, salt or solvate according to claim 1 as an active agent together and at least one pharmaceutically acceptable carrier. 21. The pharmaceutical composition according to claim 20 further comprising at least one additional therapeutically active agent, wherein said additional therapeutically active agent is selected from the group consisting of insulin and insulinic compounds; GLP-1, GLP-1 analogues, and GLP-1 receptor agonists selected from the group consisting of lixisenatide, AVE0010, ZP10, exenatide, exendin-4, ITCA 650, AC-2993, liraglutide, semaglutide, taspoglutide, albiglutide, dulaglutide, recombinant exendin-4, CJC-1134-PC, PB-1023, TTP-054, langlenatide, HM-11260C, CM-3, ORMD-0901, NN-9924, NN-9926, NN-9927, Nodexen, CVX-096, ZYOG-1, ZYD-1, GSK-2374697, DA-3091, MAR-701, MAR709, ZP-2929, ZP-3022, TT-401, BHM-034, MOD-6030, CAM-2036, DA-15864, ARI-2651, ARI-2255, xtenylated exenatide and xtenylated glucagon, and wherein the GLP-1 and GLP-1 analogues are optionally bound by a polymer; dual GLP1/GIP agonists; PYY3-36; pancreatic polypeptide; glucagon receptor agonists; GIP receptor agonists or antagonists; ghrelin antagonists or inverse agonists; xenin; DDP-IV inhibitors; SGLT2 inhibitors; dual SGLT2/SGLT1 inhibitors; biguanides; thiazolidinediones; dual PPAR agonists; sulfonylureas; meglitinides; alpha-glucosidase inhibitors; amylin and pramlintide; GPR119 agonists; GPR40 agonists; GPR120 agonists; GPR142 agonists; systemic or low-absorbable TGR5 agonists; bromocriptine mesylate; inhibitors of 11-beta-HSD; activators of glucokinase; inhibitors of DGAT; inhibitors of protein tyrosinephosphatase 1; inhibitors of glucose-6-phosphatase; inhibitors of fructose-1,6-bisphosphatase; inhibitors of glycogen phosphorylase; inhibitors of phosphoenol pyruvate carboxykinase; inhibitors of glycogen synthase kinase; inhibitors of pyruvate dehydrogenase kinase; alpha2-antagonists; CCR-2 antagonists; modulators of glucose transporter-4; somatostatin receptor 3 agonists; HMG-CoA-reductase inhibitors; fibrates; nicotinic acid and derivatives thereof; nicotinic acid receptor 1 agonists; PPAR-alpha, gamma, or alpha/gamma agonists or modulators; PPAR-delta agonists; ACAT inhibitors; cholesterol absorption inhibitors; bile acid-binding substances; IBAT inhibitors; MTP inhibitors; modulators of PCSK9; HDL-raising compounds; lipid metabolism modulators; PLA2 inhibitors; ApoA-I enhancers; thyroid hormone receptor agonists; cholesterol synthesis inhibitors; omega-3 fatty acids and derivatives thereof; substances for the treatment of obesity selected from the group consisting of sibutramine, tesofensine, tetrahydrolipstatin, CB-1receptor antagonists, MCH-1 antagonists, MC4 receptor agonists and partial agonists, NPY5 or NPY2 antagonists, NPY4 agonists, beta-3-agonists, leptin or leptin mimetics, agonists of the 5HT2c receptor, combinations of bupropione/naltrexone, combinations of bupropione/zonisamide, combinations of bupropione/phentermine, combinations of pramlintide/metreleptin, and combinations of phentermine/topiramate; lipase inhibitors; angiogenesis inhibitors; H3 antagonists; AgRP inhibitors; triple monoamine uptake inhibitors; MetAP2 inhibitors; nasal formulations of the calcium channel blocker diltiazem; inhibitors of fibroblast growth factor receptor 4; prohibitin targeting peptide-1; and drugs for influencing high blood pressure, chronic heart failure, or atherosclerosis selected from the group consisting of angiotensin II receptor antagonists, ACE inhibitors, ECE inhibitors, diuretics, beta-blockers, calcium antagonists, centrally acting hypertensives, antagonists of the alpha-2-adrenergic receptor, inhibitors of neutral endopeptidase, and thrombocyte aggregation inhibitors. 22. The pharmaceutical composition according to claim 20 further comprising at least one additional therapeutically active agent, wherein said at least one additional therapeutically active agent is selected from a GLP-1 compound, an insulinic compound, and a gastrointestinal peptide. 23. The pharmaceutical composition according to claim 20 further comprising at least one additional therapeutically active agent, wherein said additional therapeutically active agent is insulin or an insulinic compound. 24. The compound, salt or solvate according to claim 19, said compound having a high solubility at acidic pH values of pH 4.5 at 25.degree. C., and/or at physiological pH values of pH 7.4 at 25.degree. C. 25. The compound, salt or solvate according to claim 19, wherein the solubility at said acidic pH value and/or at said physiological pH value is at least 1.0 mg/ml. 26. The compound, salt or solvate according to claim 11, wherein X14 is Lys, wherein the --NH.sub.2 side chain group is functionalized by (S)-4-Carboxy-4-hexadecanoylamino-butyryl- or (S)-4-Carboxy-4-octadecanoylamino-butyryl-. 27. The compound, salt or solvate according to claim 12, wherein X14 is Lys, wherein the --NH.sub.2 side chain group is functionalized by (S)-4-carboxy-4-hexadecanoylamino-butyryl- or hexadecanoyl-. 28. The compound, salt or solvate according to claim 16, wherein X14 is LYS, wherein the --NH.sub.2 side chain group is functionalized by (S)-4-Carboxy-4-henicosanoylamino-butyryl- or (S)-4-Carboxy-4-octadecanoylamino-butyryl-. 29. The pharmaceutical composition according to claim 21, wherein the insulin or insulinic compound is selected from the group consisting of insulin glargine; insulin glulisin; insulin detemir; insulin lispro; insulin degludec; insulin aspart; a combination of insulin degludec and insulin aspart; basal insulin and analogues; pegylated insulin; human insulin (rDNA origin); polysialylated insulin; NN1045; insulin in combination with pramlintide; PE0139; fast-acting and short-acting insulins; insulin hydrogel; oral, inhalable, transdermal, and sublingual insulins; and insulinic compounds which are bonded to albumin or another protein by a bifunctional linker. 30. A compound, salt, or hydrate of claim 1. 31. A compound or salt of claim 1. 32. The compound, salt or solvate according to claim 1, wherein R.sup.5 is a moiety comprising up to 50 carbon atoms and optionally heteroatoms independently selected from halogen, N, O, S, P and combinations thereof. 33. The compound, salt or solvate according to claim 1, wherein the (C.sub.3-C.sub.8)-heterocyclyl is selected from azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, and homopiperidinyl. 34. The compound, salt, or solvate according to claim 1, wherein the compound is the amino acid sequence of SEQ ID NO:24, or a salt, or solvate thereof. 35. The compound, salt, or solvate according to claim 1, wherein the compound is the amino acid sequence of SEQ ID NO:35, or a salt, or solvate thereof. 36. The compound, salt, or solvate according to claim 1, wherein the compound is the amino acid sequence of SEQ ID NO:36, or a salt, or solvate thereof. 37. The compound, salt, or solvate according to claim 1, wherein the compound is the amino acid sequence of SEQ ID NO:44, or a salt, or solvate thereof. 38. The compound, salt, or solvate according to claim 1, wherein the compound is the amino acid sequence of SEQ ID NO:97, or a salt, or solvate thereof.

Details for Patent 9,365,632

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Eli Lilly And Company	HUMULIN R U-100	insulin human	Injection	018780	October 28, 1982		2032-10-09
Eli Lilly And Company	HUMULIN R U-500	insulin human	Injection	018780	December 29, 2015		2032-10-09
Eli Lilly And Company	HUMULIN R U-100	insulin human	Injection	018780	August 06, 1998		2032-10-09
Eli Lilly And Company	HUMULIN R U-500	insulin human	Injection	018780	March 31, 1994		2032-10-09