# US 9,751,926 B2 · Dual GLP-1/GIP receptor agonists

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- Number: US 9,751,926 B2
- Document ID: US9751926B2
- Status: Granted
- Kind: B2
- Application number: 14/569,260
- Filed: 2014-12-12
- Published: 2015-06-18
- Granted: 2017-09-05
- Earliest claimed: 2013-12-13
- Assignees: Sanofi
- Applicants: Sanofi
- Inventors: Dieter Kadereit; Katrin Lorenz; Andreas Evers; Torsten Haack; Michael Wagner; Bernd Henkel; Martin Lorenz; Siegfried Stengelin
- Web page: https://patentgrep.com/patent/US9751926B2

## CPC

- C07K 14/605: Glucagons
- A61K 38/26: Glucagons
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 3/04: Anorexiants; Antiobesity agents
- A61P 3/10: for hyperglycaemia, e.g. antidiabetics
- C07K 14/57563: {Vasoactive intestinal peptide [VIP]; Related peptides}
- C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00)
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## 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.

## Claims

### Claim 1

A peptidic compound of formula (I):
R1—Z—R2 (I),
or a salt or solvate thereof,
wherein Z is a peptide moiety of formula (II):
Tyr-Aib-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Leu-Ser-Ile-Gln-X14-Glu-X16-Glu-Ala-Val-X20-Leu-Phe-Ile-Glu-Trp-Leu-Lys-Ala-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-X40 (II),
wherein:
X14 is an amino acid residue selected from Met, Leu, Nle, Met(O), and Met(O2),
X16 is an amino acid residue selected from Lys and Glu,
X20 is an amino acid residue selected from Arg, Aib, (S)Me-Lys, (R)Me-Lys, and (S)Me-Orn,
X40 is absent or is Lys,
R1 is NH2, and
R2 is OH or NH2.

### Claim 2 (depends on 1)

The compound, salt, or solvate of claim 1, which is a glucagon-like peptide (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) receptor agonist.

### Claim 3 (depends on 1)

The compound, salt or solvate of claim 1, wherein R2 is NH2.

### Claim 4 (depends on 1)

The compound, salt or solvate of claim 1, wherein the peptidic compound has a relative activity of at least 0.04% compared to that of natural GIP at the GIP receptor.

### Claim 5 (depends on 1)

The compound, salt or solvate of claim 1, wherein the peptidic compound exhibits a relative activity of at least 0.07% compared to that of GLP-1(7-36) at the GLP-1 receptor.

### Claim 6 (depends on 1)

The compound, salt or solvate of claim 1, wherein
X14 is an amino acid residue selected from Met, Leu, Nle, Met(O), and Met(O2),
X16 is an amino acid residue selected from Lys and Glu,
X20 is an amino acid residue selected from Arg, Aib, (S)Me-Lys, (R)Me-Lys, and (S)Me-Orn, and
X40 is absent.

### Claim 7 (depends on 1)

The compound, salt or solvate of claim 1, wherein
X14 is Leu,
X16 is Lys,
X20 is an amino acid residue selected from Aib, (S)Me-Lys, (R)Me-Lys, and (S)Me-Orn, and
X40 is absent.

### Claim 8 (depends on 1)

The compound, salt or solvate of claim 1, wherein
X14 is an amino acid residue selected from Met, Leu, Nle, Met(O), and Met(O2),
X16 is an amino acid residue selected from Lys and Glu,
X20 is Arg, and
X40 is absent or is Lys.

### Claim 9 (depends on 1)

The compound, salt or solvate of claim 1, wherein
X14 is an amino acid residue selected from Met, Leu, Nle, Met(O), and Met(O2),
X16 is Lys,
X20 is Arg, and
X40 is absent or is Lys.

### Claim 10 (depends on 1)

The compound, salt or solvate of claim 1, wherein
X14 is an amino acid residue selected from Met and Leu,
X16 is Glu,
X20 is an amino acid residue selected from Arg, Aib, (S)Me-Lys, (R)Me-Lys, and (S)Me-Orn, and
X40 is absent or is Lys.

### Claim 11 (depends on 1)

The compound, salt or solvate of claim 1, wherein
X14 is an amino acid residue selected from Leu and Nle,
X16 is an amino acid residue selected from Lys and Glu,
X20 is an amino acid residue selected from Arg, Aib, (S)Me-Lys, (R)Me-Lys, and (S)Me-Orn, and
X40 is absent.

### Claim 12 (depends on 1)

The compound, salt or solvate of claim 1, wherein
X14 is an amino acid residue selected from Met, Met(O), and Met(O2),
X16 is an amino acid residue selected from Lys and Glu,
X20 is Arg, and
X40 is absent.

### Claim 13 (depends on 1)

The compound, salt or solvate of claim 1, wherein the compound comprises any one of SEQ ID NOs: 8-20 or a salt or solvate thereof.

### Claim 14 (depends on 1)

The compound, salt or solvate of claim 1, wherein the compound is any one of SEQ ID NOs: 10-14 and 16-20 or a salt or solvate thereof.

### Claim 15 (depends on 1)

A pharmaceutical composition comprising the compound of claim 1, or a salt or solvate thereof.

### Claim 16 (depends on 15)

The pharmaceutical composition of claim 15, together with at least one pharmaceutically acceptable carrier.

### Claim 17 (depends on 15)

The pharmaceutical composition of claim 15, further comprising at least one additional therapeutically active agent, wherein the additional therapeutically active agent is selected from the group consisting of:
insulin and insulin derivatives selected from the group consisting of insulin glargine, insulin glusiline, insulin detemir, insulin lispro, insulin degludec, insulin aspart, basal insulin and analogues thereof, pegylated insulin, recombinant human insulin, polysialated insulins, long-acting insulin, NN1045, insulin in combination with pramlintide, PE0139, fast-acting and short-acting insulins, insulin hydrogel, oral insulin, inhalable insulin, transdermal insulin and sublingual insulin, and insulin derivatives which are bonded to albumin or another protein by a bifunctional linker;
GLP-1; GLP-1 analogues; GLP-1 receptor agonists selected from the group consisting of lixisenatide, exenatide, ITCA 650, AC-2993, liraglutide, semaglutide, taspoglutide, albiglutide, dulaglutide, rExendin-4, CJC-1134-PC, PB-1023, TTP-054, Langlenatide, HM-11260C, CM-3, ORMD-0901, NN-9924, NN-9926, NN-9927, 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, xtenylated glucagon, and polymer bound derivatives thereof;
dual GLP-1/GIP receptor agonists; dual GLP-1/glucagon receptor agonists; protein YY3-36 (PYY3-36); pancreatic polypeptide; glucagon receptor agonists; GIP receptor agonists or antagonists; ghrelin antagonists or inverse agonists; xenin; dipeptidyl peptidase IV (DPP-IV) inhibitors; sodium glucose cotransporter 2 (SGLT2) inhibitors; dual SGLT2/SGLT1 inhibitors; biguanides; thiazolidinediones; dual peroxisome proliferator-activated receptor (PPAR) agonists; sulfonylureas; meglitinides; alpha-glucosidase inhibitors; amylin and pramlintide; G protein-coupled receptor 119 (GPR119) agonists; GPR40 agonists; GPR120 agonists; GPR142 agonists; systemic or low-absorbable transmembrane G protein-coupled receptor 5 (TGR5) agonists; bromocriptine mesylate; inhibitors of 11-beta-hydroxysteroid dehydrogenase (HSD); activators of glucokinase; inhibitors of diacylglycerol acyltransferase (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; C—C motif receptor (CCR-2) antagonists; modulators of glucose transporter-4; somatostatin receptor 3 agonists; 3-hydroxy-3-methyl-glutaryl-coenzyme A (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; acyl-CoA cholesterol acyltransferase (ACAT) inhibitors; cholesterol absorption inhibitors; bile acid-binding substances; ileal bile acid transporter (IBAT) inhibitors; microsomal triglyceride transfer protein (MTP) inhibitors; modulators of proprotein convertase subtilisin/kinexin type 9 (PCSK9); low-density lipoprotein (LDL) receptor up-regulators by liver selective thyroid hormone receptor β agonists; high-density lipoprotein (HDL)-raising compounds; lipid metabolism modulators; phospholipase A2 (PLA2) inhibitors; apolipoprotein A1 (ApoA-1) 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, cannabinoid-1 (CB-1) receptor antagonists, melanin-concentrating hormone-1 (MCH-1) antagonists, melanocortin 4 (MC4) receptor agonists and partial agonists, neuropeptide Y5 (NPY5) or NPY2 antagonists, NPY4 agonists, beta-3-agonists, leptin or leptin mimetics, agonists of the 5-hydroxy tryptophan 2c (5HT2c) receptor, combinations of bupropione/naltrexone, combinations of bupropione/zonisamide, combinations of bupropione/phentermine, combinations of pramlintide/metreleptin, and combinations of phentermine/topiramate; and
lipase inhibitors; angiogenesis inhibitors; H3 antagonists; Agouti-related protein (AgRP) inhibitors; triple monoamine uptake inhibitors; methionine aminopeptidase type 2 (MetAP2) inhibitors; nasal formulation of the calcium channel blocker diltiazem; antisense molecules against production 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, angiotensin-converting-enzyme (ACE) inhibitors, endothelin-converting-enzyme (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.

### Claim 18 (depends on 15)

The pharmaceutical composition of claim 15, together with at least one additional therapeutically active agent, wherein the at least one additional therapeutically active agent is selected from the group consisting of a GLP-1 agonist, an insulin, an insulin analogue, and a gastrointestinal peptide.

### Claim 19 (depends on 1)

A solvate of a compound of claim 1.

### Claim 20 (depends on 1)

A hydrate of a compound of claim 1.

### Claim 21 (depends on 15)

A method of treating a disease or disorder comprising administering to a patient in need thereof the pharmaceutical composition of claim 15, wherein the disease or disorder is selected from the group consisting of hyperglycemia, type 2 diabetes, type 1 diabetes, and obesity.

### Claim 22 (depends on 21)

The method of claim 21, wherein the disease or disorder is selected from the group consisting of hyperglycemia, type 2 diabetes, and obesity.

### Claim 23 (depends on 21)

The method of claim 21, wherein the method delays the progression of impaired glucose tolerance (IGT) to type 2 diabetes or the progression of type 2 diabetes to insulin-requiring diabetes.

### Claim 24 (depends on 21)

The method of claim 21, wherein the method regulates appetite or induces satiety.

### Claim 25 (depends on 1)

A method of treating hyperglycemia, type 2 diabetes, or obesity in a patient, the method comprising administering to the patient an effective amount of at least one compound of formula I, or a salt or solvate thereof, according to claim 1 and an effective amount of at least one additional compound for treating hyperglycemia, type 2 diabetes, or obesity.

### Claim 26 (depends on 25)

The method of claim 25, wherein the effective amounts of the at least one compound of formula I, or a salt or solvate thereof, and of the at least one additional compound are administered to the patient simultaneously.

### Claim 27 (depends on 25)

The method of claim 25, wherein the effective amounts of the at least one compound of formula I, or a salt or solvate thereof, and of the at least one additional compound are administered to the patient sequentially.