Claims for Patent: 10,519,211

Summary for Patent: 10,519,211

Title:	Compounds as peptidic GLP1/glucagon/GIP receptor agonists
Abstract:	The present invention relates to trigonal GLP-1/glucagon/GIP receptor agonists and their medical use, for example in the treatment of disorders of the metabolic syndrome, including diabetes and obesity, as well as for reduction of excess food intake.
Inventor(s):	Bossart; Martin (Frankfurt am Main, DE), Evers; Andreas (Frankfurt am Main, DE), Haack; Torsten (Frankfurt am Main, DE), Lorenz; Katrin (Frankfurt am Main, DE), Kadereit; Dieter (Frankfurt am Main, DE), Wagner; Michael (Frankfurt am Main, DE), Pfeiffer-Marek; Stefania (Frankfurt am Main, DE), Lorenz; Martin (Frankfurt am Main, DE)
Assignee:	SANOFI (Paris, FR)
Application Number:	15/829,698
Patent Claims:	1. A compound of the formula I: TABLE-US-00020 I H.sub.2N-His-Aib-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Leu-Ser- Lys-Leu-X14-Glu-X16-Gln-Arg-Gln-Aib-Glu-Phe-Ile- Glu-Trp-Leu-Lys-Ala-X29-Gly-X31-Pro-Ser-Aib-Lys- Pro-Pro-Pro-Lys-R.sup.1 wherein: X14 is an amino acid residue with a functionalized --NH.sub.2 side chain group, selected from the group consisting of Lys, Orn, Dab, and Dap, wherein the --NH.sub.2 side chain group is functionalized by --Z--C(O)--R.sup.5, wherein Z is a linker having a length of 1-5 amino acid linker groups, wherein the amino acid linker groups are selected from the group consisting of gamma-Glutamate (gGlu), gAAA (gamma-amino adipic acid) and AEEAc ((2-(2-aminoethoxy)ethoxy)acetyl) and combinations thereof in all stereoisomeric forms; and R.sup.5 is a moiety comprising up to 50 carbon atoms and heteroatoms selected from N and O; X16 is an amino acid residue selected from Glu and Lys; X29 is an amino acid residue selected from D-Ala and Gly; X31 is an amino acid residue selected from His and Pro; and R.sup.1 is NH.sub.2 or OH; or a salt or solvate thereof. 2. The compound of claim 1, wherein R.sup.1 is NH.sub.2, or a salt or solvate thereof. 3. The compound of claim 1, or a salt or solvate thereof, which has a relative activity of at least 1% compared to that of natural glucagon at the glucagon receptor. 4. The compound of claim 1, or a salt or solvate thereof, which exhibits a relative activity of at least 10% compared to that of GLP-1(7-36)-amide at the GLP-1 receptor. 5. The compound of claim 1, or a salt or solvate thereof, which exhibits a relative activity of at least 2% compared to that of GIP at the GIP receptor. 6. The compound of claim 1, wherein X14 is Lys, wherein the --NH.sub.2 side chain group is functionalized with a group --Z--C(O)R.sup.5, wherein: Z is a group selected from gGlu, gGlu-gGlu, gGlu-AEEAc-gAAA-, gGlu-gGlu-AEEAc, AEEAc-AEEAc-gGlu and AEEAc-AEEAc-AEEAc; and R.sup.5 is a group selected from pentadecanyl and heptadecanyl; or a salt or solvate thereof. 7. The compound of claim 6, wherein X14 is Lys, wherein the --NH.sub.2 side chain group is functionalized with a group --Z--C(O)R.sup.5, wherein: Z is a group selected from gGlu, gGlu-gGlu, gGlu-AEEAc-gAAA- and gGlu-gGlu-AEEAc; and R.sup.5 is a group selected from pentadecanyl and heptadecanyl; or a salt or solvate thereof. 8. The compound of claim 1, wherein: X14 is Lys, wherein the --NH.sub.2 side chain group is functionalized by a group selected from (S)-4-Carboxy-4-hexadecanoylamino-butyryl-, (S)-4-Carboxy-4-octadecanoylamino-butyryl-, (S)-4-Carboxy-4-((S)-4-carboxy-4-hexadecanoylamino-butyrylamino)-butyryl-- , (2-{2-[2-(2-{2-[(4 S)-4-Carboxy-4-hexadecanoylamino-butyrylamino]-ethoxy}-ethoxy)-acetylamin- o]-ethoxy}-ethoxy)-acetyl, (2-{2-[2-(2-{2-[(4S)-4-Carboxy-4-octadecanoylamino-butyrylamino]-ethoxy}-- ethoxy)-acetylamino]-ethoxy}-ethoxy)-acetyl, and [2-(2-{2-[2-(2-{2-[2-(2-Octadecanoylamino-ethoxy)-ethoxy]-acetylamino}-et- hoxy)-ethoxy]-acetylamino}-ethoxy)-ethoxy]-acetyl-; and R.sup.1 is NH.sub.2; or a salt or solvate thereof. 9. The compound of claim 8, wherein: X14 is Lys, wherein the --NH.sub.2 side chain group is functionalized by a group selected from (S)-4-Carboxy-4-hexadecanoylamino-butyryl-, (S)-4-Carboxy-4-octadecanoylamino-butyryl-, (S)-4-Carboxy-4-((S)-4-carboxy-4-hexadecanoylamino-butyrylamino)-butyryl-- , (2-{2-[2-(2-{2-[(4S)-4-Carboxy-4-hexadecanoylamino-butyrylamino]-ethoxy}- -ethoxy)-acetylamino]-ethoxy}-ethoxy)-acetyl, and (2-{2-[2-(2-{2-[(4S)-4-Carboxy-4-octadecanoylamino-butyrylamino]-ethoxy}-- ethoxy)-acetylamino]-ethoxy}-ethoxy)-acetyl; and R.sup.1 is NH.sub.2; or a salt or solvate thereof. 10. The compound of claim 1, wherein: X14 is Lys, wherein the --NH.sub.2 side chain group is functionalized by (S)-4-Carboxy-4-((S)-4-carboxy-4-hexadecanoylamino-butyrylamino)-butyryl-- ; X16 is an amino acid residue selected from Glu and Lys; X29 is an amino acid residue selected from D-Ala and Gly; X31 is an amino acid residue selected from His and Pro; and R.sup.1 is NH.sub.2; or a salt or solvate thereof. 11. The compound of claim 1, wherein: X14 is Lys, wherein the --NH.sub.2 side chain group is functionalized by a group selected from (S)-4-Carboxy-4-((S)-4-carboxy-4-hexadecanoylamino-butyrylamino)-butyryl- and (S)-4-Carboxy-4-octadecanoylamino-butyryl-; X16 is an amino acid residue selected from Glu and Lys; X29 is Gly; X31 is an amino acid residue selected from His and Pro; and R.sup.1 is NH.sub.2; or a salt or solvate thereof. 12. The compound of claim 1, wherein: X14 is Lys, wherein the --NH.sub.2 side chain group is functionalized by a group selected from (S)-4-Carboxy-4-((S)-4-carboxy-4-hexadecanoylamino-butyrylamino)-butyryl- and (S)-4-Carboxy-4-octadecanoylamino-butyryl-; X16 is Lys; X29 is an amino acid residue selected from D-Ala and Gly; X31 is an amino acid residue selected from His and Pro; and R.sup.1 is NH.sub.2; or a salt or solvate thereof. 13. The compound of claim 1, wherein: X14 is Lys, wherein the --NH.sub.2 side chain group is functionalized by a group selected from (S)-4-Carboxy-4-((S)-4-carboxy-4-hexadecanoylamino-butyrylamino)-butyryl- and (S)-4-Carboxy-4-octadecanoylamino-butyryl-; X16 is an amino acid residue selected from Glu and Lys; X29 is an amino acid residue selected from D-Ala and Gly; X31 is Pro; and R.sup.1 is NH.sub.2; or a salt or solvate thereof. 14. The compound of claim 1, selected from the compounds of SEQ ID NOs: 6-23, or salts or solvates thereof. 15. The compound of claim 1, wherein the compound is the compound of SEQ ID NO: 6, or a salt or solvate thereof. 16. The compound of claim 1, wherein the compound is the compound of SEQ ID NO: 9, or a salt or solvate thereof. 17. The compound of claim 1, wherein the compound is the compound of SEQ ID NO: 11, or a salt or solvate thereof. 18. A pharmaceutical composition comprising the compound of claim 1, or a salt or solvate thereof. 19. A pharmaceutical composition comprising the compound of claim 1, or a pharmaceutically acceptable salt or solvate thereof, which is present as an active agent together with at least one pharmaceutically acceptable carrier. 20. The pharmaceutical composition of claim 18, further comprising at least one additional therapeutically active agent. 21. The pharmaceutical composition of claim 20, wherein the at least one additional therapeutically active agent is selected from the group consisting of: insulin and insulin derivatives; glucagon-like peptide 1 (GLP-1), GLP-1 analogues and GLP-1 receptor agonists; dipeptidyl peptidase 4 (DPP-4) inhibitors; sodium-glucose cotransporter-2 (SGLT2) inhibitors; dual SGLT2/sodium-glucose cotransporter-1(SGLT1) inhibitors; biguanides; thiazolidinediones; dual peroxisome proliferator-activated receptors (PPAR) agonists; sulfonylureas; meglitinides; alpha-glucosidase inhibitors; amylin and amylin analogues; G protein-coupled receptor 119 (GPR119) agonists; G protein-coupled receptor 40 (GPR40) agonists; G protein-coupled receptor 120 (GPR120) agonists; G protein-coupled receptor 142 (GPR142) agonists; G protein-coupled bile acid receptor 1 (TGR5) agonists; bromocriptine mesylate; inhibitors of 11.beta.-hydroxysteroid dehydrogenase (11-beta-HSD); activators of glucokinase; inhibitors of diglyceride acyltransferase (DGAT); inhibitors of protein tyrosine-phosphatase 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 dehydrokinase; alpha 2-antagonists; C--C chemokine receptor type 2 (CCR-2) antagonists; SGLT-1 inhibitors; modulators of glucose transporter-4; somatostatin receptor 3 agonists; lipid lowering agents; an active substance for the treatment of obesity selected from the group consisting of sibutramine, tesofensine, orlistat, antagonists of the cannabinoid-1 receptor, melanine-concentrating hormone (MCH-1) receptor antagonists, melanocortin (MC4) receptor agonists, neuropeptide Y receptor type Y5 (NPY5) or neuropeptide Y receptor type Y2 (NPY2) antagonists, beta-3-agonists, leptin or leptin mimetics, agonists of the 5HT.sub.2C receptor, combinations of bupropione/naltrexone, combinations of bupropione/zonisamide, combinations of bupropione/phentermine, and combinations of pramlintide/metreleptin; a gastrointestinal peptide selected from the group consisting of peptide YY 3-36 (PYY3-36), pancreatic polypeptide (PP), and combinations thereof; lipase inhibitors; angiogenesis inhibitors; H3 antagonists; agouti-related protein (AgRP) inhibitors; triple monoamine uptake inhibitors; methionine aminopeptidase (2MetAP2) inhibitors; nasal formulation of the calcium channel blocker diltiazem; prohibitin targeting peptide-1; and one or more drugs for influencing high blood pressure, chronic heart failure or atherosclerosis selected from the group consisting of angiotensin II receptor antagonists, telmisartan, candesartan, valsartan, losartan, eprosartan, irbesartan, olmesartan, tasosartan, azilsartan, angiotensin-converting-enzyme (ACE) inhibitors, endothelin converting enzyem (ECE) inhibitors, diuretics, beta-blockers, calcium antagonists, centrally acting hypertensives, antagonists of the alpha-2-adrenergic receptor, inhibitors of neutral endopeptidase, thrombocyte aggregation inhibitors, and combinations thereof. 22. A method for the treatment of glucose intolerance, insulin resistance, pre-diabetes, increased fasting glucose, hyperglycemia, diabetes, obesity, or any combination of these individual diseases in a patient, the method comprising administering to the patient in need thereof a compound of claim 1, or a salt or solvate thereof. 23. A method for the treatment of non-alcoholic liver-disease (NAFLD) or non-alcoholic steatohepatitis (NASH) in a patient, the method comprising administering to the patient in need thereof a compound of claim 1, or a salt or solvate thereof. 24. The method of claim 22 for the simultaneous treatment of diabetes and obesity. 25. The method of claim 22 for the treatment of type 2 diabetes. 26. The method of claim 22 wherein the treatment of obesity is reducing body weight of a patient. 27. A method for reducing blood glucose levels and/or reducing HbA1c levels of a patient, the method comprising administering to the patient in need thereof a compound of claim 1, or a salt or solvate thereof. 28. A method for treating hyperglycemia, type 2 diabetes or obesity in a patient, the method comprising administering to the patient in need thereof an effective amount of a compound of claim 1, or a salt or solvate thereof; and an effective amount of at least one other compound useful for treating diabetes, obesity, dyslipidemia, or high blood pressure. 29. The method of claim 28, wherein the effective amount of a compound of claim 1, or a salt or solvate thereof, and the at least one other compound are administered to the patient simultaneously. 30. The method of claim 28, wherein the effective amount of a compound of claim 1, or a salt or solvate thereof, and the at least one other compound are administered to the patient sequentially.

Details for Patent 10,519,211

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Amryt Pharmaceuticals Dac	MYALEPT	metreleptin	For Injection	125390	02/24/2014		2036-12-02