Compounds

Abstract

The present invention provides novel compounds which are peptide hormone analogs and which are useful in the treatment of conditions such as diabetes and obesity. The compounds of the general sequences set forth in this specification have tailored profiles of potency properties against the GIP receptor. With respect to in vivo properties, it has been demonstrated that administration of example peptides of the invention in animal models results in increased weight loss. Preferred compounds achieve this without a significant reduction in food intake.

Description

Technical Field

[0001] This disclosure relates to compounds that are peptide hormone analogs and that can be used to treat conditions such as diabetes and obesity. Background Technology

[0002] According to the National Health and Nutrition Examination Survey (NHANES, 2009-2010), among adults aged 20 and older in the United States, 33.0% were overweight, 35.7% were obese, and 6.3% were extremely obese. Furthermore, a large proportion of children in the United States are overweight or obese.

[0003] Obesity has complex and multifactorial causes. Growing evidence suggests that obesity is not a simple matter of self-control, but a complex condition involving appetite regulation and energy metabolism. Furthermore, obesity is associated with a number of diseases that contribute to increased morbidity and mortality in populations. Although the exact causes of obesity remain unclear, genetic, metabolic, biochemical, cultural, and socio-psychological factors are considered contributing factors. Generally, obesity is described as a condition in which excess body fat exposes an individual to health risks.

[0004] There is strong evidence that obesity is associated with increased morbidity and mortality. Disease risks, such as cardiovascular disease and type 2 diabetes, increase independently with increasing body mass index (BMI). In fact, this risk has been quantified; for every point increase in BMI above 24.9, the risk of heart disease increases by 5% in women and 7% in men (see Kenchaiah et al.). N. Engl. J. Med. 347:305, 2002; Massie, N. Engl. J. Med. 347:358, 2002).

[0005] Diabetes mellitus is a chronic syndrome caused by insufficient insulin secretion or insulin resistance in target tissues, leading to impaired carbohydrate, protein, and fat metabolism. There are two main forms of diabetes: insulin-dependent diabetes mellitus (Type 1) and non-insulin-dependent diabetes mellitus (Type 2). Type 1 diabetes, or insulin-dependent diabetes mellitus (IDDM), is caused by insufficient endogenous insulin levels due to the destruction of beta cells. Type 2 diabetes, or non-insulin-dependent diabetes mellitus, is caused by a defect in the body's sensitivity to insulin and a relative insufficiency in insulin production. According to the National Diabetes Statistics report, approximately 28.9 million adults aged 20 and older in the United States had diabetes in 2014 (estimates from the 2009-2012 National Health and Nutrition Examination Survey, applied to 2012 U.S. Census data). In adults, 90% to 95% of diabetes cases are type 2 diabetes.

[0006] There is substantial evidence that weight loss in obese individuals can reduce important disease risk factors. Even small amounts of weight loss, such as 10% of initial body weight in overweight and obese adults, have been shown to be associated with reductions in risk factors such as hypertension, hyperlipidemia, and hyperglycemia. Studies have shown that significant weight loss can effectively cure type 2 diabetes (Lim et al., Diabetologia, June 2011).

[0007] While diet and exercise offer simple ways to reduce weight gain, overweight and obese individuals often cannot adequately manage these factors to achieve effective weight loss. Drug therapies are available; the U.S. Food and Drug Administration has approved several weight-loss drugs that can be used as part of a comprehensive weight-loss program. However, many of these drugs have serious adverse side effects. Bariatric surgery is one of the options for clinically selected severely obese patients when low-invasive methods fail and the patient is at high risk of obesity-related morbidity or death. However, these treatments are high-risk and only suitable for a limited number of patients. It's not just obese subjects who desire weight loss. People whose weight is within the recommended range (e.g., at the upper end of the recommended range) may also desire to reduce their weight to get closer to their ideal weight. Therefore, there remains a need for medications that can be used to achieve weight loss in both overweight and obese subjects, as well as those with normal weight.

[0008] Many approaches to developing drugs for weight loss involve gastrointestinal peptide hormones and their analogues. Glucose-dependent insulinotropic peptide (GIP), also known as gastric inhibitory peptide or gastric inhibitory peptide, is a gastrointestinal hormone belonging to a class of molecules called incretins. GIP is produced in the body by K cells in the upper small intestine in response to food. The primary function of GIP is to induce the release of insulin from β cells in the pancreas after eating. Increased insulin secretion leads to a decrease in circulating glucose concentration.

[0009] In addition to its role as an incretin, GIP can also inhibit pancreatic β-cell apoptosis and promote their proliferation. GIP is also known to stimulate glucagon secretion and fat accumulation. GIP receptors are present in other organs of the body, such as in the central nervous system, where GIP affects hippocampal memory formation and the regulation of appetite and satiety. GIP is also thought to play a role in bone remodeling by increasing bone formation while reducing bone breakdown.

[0010] Tirzepatide is a first-in-class drug, a GIP analog that activates GLP-1 and GIP receptors, and was approved in the United States in May 2022 for medical use to treat type 2 diabetes.

[0011] However, despite significant progress, the process of identifying substances that can be used as drugs remains a complex and, in many cases, unpredictable field. For use as a therapeutic agent, a compound must possess an appropriate range of properties. In addition to good efficacy against the biological target of interest, a compound must also exhibit favorable in vivo pharmacokinetic properties, low toxicity, and an acceptable profile of side effects. For example, even with commercially available agents such as liraglutide, side effects can include nausea and vomiting, and there are also concerns about thyroid cancer and pancreatitis.

[0012] Therefore, there remains a need for other compounds that can be used to treat conditions and diseases such as diabetes and obesity. For example, it is desirable to identify peptides with beneficial properties (e.g., improved activity profile) and / or fewer side effects. For instance, it is desirable to identify peptides that increase energy expenditure in subjects without significantly reducing food intake. If a compound reduces food intake to a lesser extent, fewer side effects (e.g., nausea) are expected. Alternatively, it is also desirable to identify peptides that exhibit these and other biological effects over a sustained period. Compounds with longer periods of activity can be administered at lower frequencies and doses, which helps improve subject convenience, reduce side effects, and lower costs. Summary of the Invention

[0013] In a first aspect of the invention, a compound of the following formula is provided: Xaa1 – Xaa2 – Xaa3 – Gly4 – Thr5 – Phe6 – al23–Xaa24–Xaa25–Leu26–Xaa27–Xaa28–Xaa29–Xaa30–Xaa31–Xaa32–Xaa 33–Xaa34–Xaa35–Xaa36–Xaa37–Xaa38–Xaa39–Xaa40–Thr41–Gln42–Xaa43 [SEQ ID NO: 1] in: Xaa1 is DTyr, His, Phe, or Tyr, or does not exist; Xaa2 is either AIB or Ala, or it does not exist; Xaa3 can be Asp, Gln, Glu, or His; Xaa7 is Ile, Thr, or Ser; Xaa10 is either Tyr or His; Xaa12 is Lys; Xaa13 is AIB, Ala, Gln, Glu, Gly, His, Pro, Ser, Thr, Tyr, Val, Asp, or Asn; Xaa14 is Leu, Met, or NLeu; Xaa17 is either Gln or Ile; Xaa18 can be Ala, Arg, or His; Xaa19 is either Ala or Gln; Xaa20 is AIB, Gln, His, or Lys; Xaa21 is Ala, Asp, or Glu; Xaa24 is either Asn, Gln, or Glu; Xaa25 is Arg, His, Trp, or Tyr; Xaa27 is either Ile or Leu; Xaa28 is either Ala or Asn; Xaa29 is Gln, Gly, or Thr; Xaa30 is Gly, Lys, or Lys Or it may not exist; Xaa31 is Arg, Gly, or Pro, or it does not exist; Xaa32 is Asn, Lys, or Lys Or it may not exist; Xaa33 represents Lys or Lys Or it may not exist; Xaa34 represents Asn or Lys Or it may not exist; Xaa35 is either an Asp or does not exist; Xaa36 is either Trp or Lys Or it may not exist; Xaa37 is Lys or Lys Or it may not exist; Xaa38 is His or does not exist; Xaa39 is either Asn or Lys Or it may not exist; Xaa40 is for Ile, Leu, or Lys Or it may not exist; Xaa43 is Lys Or it may not exist; Lys Lys with the ε-amino group substituted by the following group: Z–Xaa44–Xaa45–Xaa46–Xaa47– in: Xaa44 is Gly, Ser, Thr or does not exist; Xaa45 is Gly, Ser, or does not exist; Xaa46 is Asn, Gln, Gly, Ser, Thr or does not exist; Xaa47 is Asn, Gln, Glu, Gly, His, Lys, Pro, Ser, Thr or does not exist; And Z is a group of the following formula: (i): Or (ii): , Where R is C8-C 28 An alkylene or alkenylene chain and R1 is -CO2H; And the compound said compound contains a Lys residues; Or a derivative of the compound; or a salt or solvation of the compound or its derivative.

[0014] This document also provides a composition comprising the compounds, derivatives, salts or solvates of the present invention, and a pharmaceutically acceptable carrier, and optionally another therapeutic agent.

[0015] This document also provides compounds, derivatives, salts, or solvates of the present invention, or compositions comprising such compounds, derivatives, salts, or solvates and pharmaceutically acceptable carriers, for use as medicines, such as for the prevention or treatment of diabetes, obesity, heart disease, stroke, or non-alcoholic fatty liver disease, for improving insulin release in subjects, for improving carbohydrate metabolism in subjects, for improving lipid profile in subjects, for reducing appetite, for reducing food intake, for reducing calorie intake, for improving glucose tolerance in subjects, and / or for use as cytoprotective agents, such as for the prevention or treatment of Parkinson's disease, Alzheimer's disease, and other types of neurodegeneration.

[0016] This article also provides a method for treating or preventing a disease or condition or other undesirable physiological state in a subject, the method comprising administering a therapeutically effective amount of a compound, derivative, salt or solvate of the present invention, or a composition comprising such a compound, derivative, salt or solvate and a pharmaceutically acceptable carrier, for example in: treating or preventing diabetes, obesity, heart disease, stroke or non-alcoholic fatty liver disease in a subject, improving insulin release in a subject, improving carbohydrate metabolism in a subject, improving lipid profile in a subject, improving glucose tolerance in a subject, reducing appetite, reducing food intake, reducing calorie intake, and / or providing cellular protection in a subject.

[0017] This document also provides the use of the compounds, derivatives, salts, or solvates of the present invention in the manufacture of medicaments for the prevention or treatment of diabetes, obesity, heart disease, stroke, or non-alcoholic fatty liver disease, to improve insulin release in subjects, to improve carbohydrate metabolism in subjects, to improve lipid profile in subjects, to improve glucose tolerance in subjects, to reduce appetite, to reduce food intake, to reduce calorie intake, and / or as cytoprotective agents, such as for the prevention or treatment of Parkinson's disease, Alzheimer's disease, and other types of neurodegeneration.

[0018] This article also provides a method for reducing weight or preventing weight gain in subjects for cosmetic purposes, the method comprising administering an effective amount of the compound, derivative, salt or solvate of the present invention. Attached Figure Description

[0019] Figure 1 The amino acid sequences of the compounds from the embodiments of the present invention are shown. The N-terminal residues of the compounds are presented on the left side of the table (indicated by a column titled "1"). The results of the feeding experiments are shown in... Figure 1 In the rightmost column.

[0020] Figure 2 The amino acid sequences of the compound examples and comparative compound of the present invention are shown. The N-terminal residues of the compounds are presented on the left side of the table (indicated by a column titled "1"). Results of the feeding experiments are shown in... Figure 2 In the rightmost column.

[0021] sequence The amino acid sequences in this paper are shown with the N-terminus on the left and, when the sequence spans multiple lines, the N-terminus is positioned at the top left. Unless otherwise stated, the amino acid residues in the sequence are L-amino acids.

[0022] The amino acid sequences listed in this application are shown using the standard letter abbreviations for amino acids. The non-natural amino acid 2-aminoisobutyric acid is usually abbreviated as "AIB". Leucine is given the abbreviation "NLeu".

[0023] The specific sequences given in this article relate to specific embodiments of the present invention. Detailed Implementation

[0024] definition To facilitate access to the various embodiments of this disclosure, the following explanations of specific terms are provided: Animal: A living multicellular vertebrate organism, including, for example, mammals and birds. The term mammal includes both human and non-human mammals. Similarly, the term subject includes both human and veterinary subjects. In a preferred embodiment of the invention, the subject is a human subject.

[0025] Appetite: The natural desire or craving for food. In one implementation, appetite is measured by a survey used to assess the desire for food. Increased appetite typically leads to increased eating behavior.

[0026] Appetite suppressants: Compounds that reduce the desire for food. Commercially available appetite suppressants include, but are not limited to, amfepramone (diethylpropion), phentermine, mazindol, phenylpropanolamine, fenfluramine, dexfenfluramine, and fluoxetine.

[0027] Body Mass Index (BMI): A mathematical formula used to measure body mass, sometimes also called the Quetelet's Index. BMI is calculated by dividing weight (in kilograms) by height. 2 (rice 2Currently, the standard for what is considered "normal" for both men and women is a BMI of 20-24.9 kg / m². 2 In one implementation scheme, greater than 25 kg / m 2 BMI can be used to identify obese subjects. Grade I obesity (sometimes referred to as "overweight" rather than obesity) corresponds to a BMI of 25-29.9 kg / m². 2 Grade II obesity corresponds to a BMI of 30-40 kg / m². 2 Furthermore, grade III obesity corresponds to a BMI greater than 40 kg / m². 2 (Jequier, Am. J Clin. Nutr. (45:1035-47, 1987). Ideal body weight varies depending on the species and individual's height, body type, skeletal structure, and sex.

[0028] Cardiac protection refers to protecting heart cells (especially cardiomyocytes) from apoptosis, necrosis, or degeneration (loss of function). Cardiac protection is most commonly needed after myocardial infarction, but it can also be used in subjects with ischemic heart disease (such as angina).

[0029] Cell protection refers to protecting cells from apoptosis, necrosis, cell death, or degeneration (loss of function).

[0030] Diabetes mellitus: A chronic syndrome caused by insufficient insulin secretion or insulin resistance in target tissues, resulting in impaired carbohydrate, protein, and fat metabolism. It has two main forms: insulin-dependent diabetes mellitus (IDDM, type I) and non-insulin-dependent diabetes mellitus (NIDDM, type II), which differ in etiology, pathology, genetics, age of onset, and treatment.

[0031] Both main forms of diabetes are characterized by the inability to deliver insulin in the amount and at the precise time required to control glucose homeostasis. Type 1 diabetes, or insulin-dependent diabetes mellitus (IDDM), is caused by insufficient endogenous insulin levels due to the destruction of beta cells. Type 2 diabetes, or non-insulin-dependent diabetes mellitus, is caused by a defect in the body's sensitivity to insulin and a relative insufficiency in insulin production.

[0032] Energy metabolism: The body needs to consume a certain amount of energy to maintain normal metabolism. For modern people, this is typically set at about 2,800 calories per day. If food intake cannot provide this, weight loss will occur. However, energy metabolism is also regulated. For example, the administration of glucagon is thought to increase the metabolic rate, thus requiring more food intake to achieve energy balance and maintain weight. Therefore, if food intake remains at a normal level, but energy metabolism increases, weight loss will result.

[0033] Food intake: The amount of food consumed by an individual. Food intake can be measured by volume or by weight. For example, food intake can be the total amount of food consumed by an individual. In feeding experiments, 'food intake' is the standardized weight of food consumed by an animal over a 24-hour period. Alternatively, food intake can be the amount of protein, fat, carbohydrates, cholesterol, vitamins, minerals, or any other food component consumed by an individual. "Protein intake" refers to the amount of protein consumed by an individual. Similarly, "fat intake," "carbohydrate intake," "cholesterol intake," "vitamin intake," and "mineral intake" refer to the amount of protein, fat, carbohydrates, cholesterol, vitamins, or minerals consumed by an individual.

[0034] GIP: Glucose-dependent insulinotropic polypeptide (GIP), also known as gastric inhibitory polypeptide or gastric inhibitory peptide, is a 42-amino acid peptide released by K cells in the duodenum and jejunum in response to food intake. GIP and GLP-1 are both members of the incretin class of hormone peptides.

[0035] The sequence of human GIP is: Tyr-Ala-Glu-Gly-Thr-Phe-Ile-Ser-Asp-Tyr-Ser-Ile-Ala-Met-Asp-Lys-Ile-His-Gln-Gln-Asp-Phe-Val-Asn-Trp-Leu-Leu-Ala-Gln-Lys-Gly-Lys-Lys-Asn-Asp-Trp-Lys-His-Asn-Ile-Thr-Gln [SEQ ID NO: 2].

[0036] GLP-1: Glucagon-like peptide-1 (GLP-1) is a transcription product derived from the proglucagon gene. The biologically active form of GLP-1 is a truncated form, called GLP-1(GLP-1). 7-37 ) and GLP-1 ( 7-36 -NH2 (the name -NH2 indicates an amino acid sequence in which the C-terminal amino acid has a -C(O)NH2 group instead of a carboxylic acid group).

[0037] Human GLP-1 ( 7-37The sequence is His-Ala-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-Tyr-Leu-Glu-Gly-Gln-Ala-Ala-Lys-Glu-Phe-Ile-Ala-Trp-Leu-Val-Lys-Gly-Arg-Gly [SEQ ID NO: 3].

[0038] Human GLP-1 ( 7-36 The sequence of )-NH2 is His-Ala-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-Tyr-Leu-Glu-Gly-Gln-Ala-Ala-Lys-Glu-Phe-Ile-Ala-Trp-Leu-Val-Lys-Gly-Arg-–CONH2 [SEQ ID NO: 4].

[0039] Glucagon: Glucagon is a peptide derived from the proglucagon gene. It is a 29-amino acid polypeptide in humans and has the following sequence: His-Ser-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Lys-Tyr-Leu-Asp-Ser-Arg-Arg-Ala-Gln-Asp-Phe-Val-Gln-Trp-Leu-Met-Asn-Thr [SEQ ID NO: 5].

[0040] Neuroprotection refers to the protection of neurons within the nervous system (preferably the central nervous system) from apoptosis, necrotic cell death, or degeneration (loss of function). Neuroprotective treatment may be necessary after brain injury, including treatments relevant to various aspects of this invention (e.g., treatment following physical trauma or non-traumatic injuries such as stroke, brain tumors, infections, poisoning, hypoxia, ischemia, encephalopathy, or drug abuse). Neuroprotective treatments, including those relevant to various aspects of this invention, may also be applicable to subjects with chronic neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Gehrig's disease, or Huntington's disease.

[0041] Normal daily diet: The average food intake of an individual of a specific species. A normal daily diet can be expressed in terms of calorie intake, protein intake, carbohydrate intake, and / or fat intake. A normal daily diet for humans typically consists of approximately 2,000, 2,400, or 2,800 calories to significantly more. In addition, a normal daily diet for humans typically includes approximately 12g to approximately 45g of protein, approximately 120g to approximately 610g of carbohydrates, and approximately 11g to approximately 90g of fat. Low-calorie diets do not exceed approximately 85% of a human individual's normal calorie intake, and preferably not more than approximately 70%.

[0042] Animal calorie and nutritional requirements vary depending on the species and size of the animal. For example, for cats, the total calorie intake per pound and the percentage distribution of protein, carbohydrates, and fat vary with the cat's age and reproductive status. However, a general guideline for cats is 40 calories / pound / day (18.2 calories / kg / day). Approximately 30% to 40% should come from protein, approximately 7% to 10% from carbohydrates, and approximately 50% to 62.5% from fat intake. Those skilled in the art can readily determine the normal daily diet of an individual of any species.

[0043] Obesity: Excess body fat can lead to various health risks (see Barlow and Dietz). Pediatrics 102:E29, 1998; National Institutes of Health, National Heart, Lung, and Blood Institute (NHLBI), Obes. Res 6 (Supplement 2):51S-209S, 1998). Excessive body fat is a result of an imbalance between energy intake and energy expenditure. For example, body mass index (BMI) can be used to assess obesity. In a common practice, a BMI of 25.0 kg / m² is defined as... 2 Up to 29.9 kg / m 2 He is overweight, with a BMI of 30 kg / m². 2 Or more likely, it's obesity.

[0044] In another practice, waist circumference is used to assess obesity. In this practice, a waist circumference of 102 cm or greater is considered obese for men, and 89 cm or greater for women. There is strong evidence that obesity affects morbidity and mortality. For example, obese individuals have an increased risk of heart disease, non-insulin-dependent (type 2) diabetes, hypertension, stroke, cancers (e.g., endometrial cancer, breast cancer, prostate cancer, and colon cancer), dyslipidemia, gallbladder disease, sleep apnea, decreased fertility, and osteoarthritis (see Lyznicki et al.). Am. Fam. Phys.63:2185, 2001).

[0045] Overweight: An individual whose weight exceeds their ideal weight. An overweight individual may be obese, but not necessarily obese. For example, an overweight individual is anyone who wants to lose weight. In a common definition, an overweight individual is someone with a BMI of 25.0 kg / m². 2 Up to 29.9 kg / m 2 Individuals.

[0046] Gastrin (OXM): Gastrin is a 37-amino acid peptide member of the glucagon superfamily, containing the complete 29-amino acid sequence of glucagon, with an eight-amino acid carboxyl-terminal extension. It is produced by tissue-specific processing of the proglucagon precursor in the brain and gut. The human OXM sequence is as follows: His-Ser-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Lys-Tyr-Leu-Asp-Ser-Arg-Arg-Ala-Gln-Asp-Phe-Val-Gln-Trp-Leu-Met-Asn-Thr-Lys-Arg-Asn-Arg-Asn-Asn-Ile-Ala [SEQ ID NO: 6].

[0047] Polyethylene glycolation and polyethylene glycol-modified: Polyethylene glycolation refers to the process of reacting a polyalkylene glycol, preferably an activated polyalkylene glycol, to form a covalent bond. Additives, such as amino acids, like lysine, may be used. Although “polyethylene glycolation” is generally performed using polyethylene glycol or its derivatives (e.g., methoxy polyethylene glycol), the term is not limited herein to the use of methoxy polyethylene glycol, but also includes the use of any other useful polyalkylene glycol, such as polypropylene glycol. The term polyethylene glycol-modified refers to compounds containing such polyalkylene glycol groups.

[0048] pI: pI is an abbreviation for isoelectric point. Sometimes another abbreviation, IEP, is used. It is the pH at which a particular molecule carries no net charge. At pH values ​​below its pI, proteins or peptides carry a net positive charge. At pH values ​​above its pI, proteins or peptides carry a net negative charge. Proteins and peptides can be separated based on their isoelectric points using a technique called isoelectric focusing, an electrophoretic method that utilizes the pH gradient contained within a polyacrylamide gel.

[0049] Peripheral application: Application outside the central nervous system. Peripheral application does not include direct application to the brain. Peripheral application includes, but is not limited to, intravascular, intramuscular, subcutaneous, inhalation, oral, rectal, transdermal, or intranasal application.

[0050] Polypeptide: A polymer in which monomers are amino acid residues linked together by amide bonds. Unless the context otherwise requires, the terms “polypeptide,” “peptide,” or “protein” as used herein cover any amino acid sequence and include modified sequences such as glycoproteins. The term “polypeptide” covers naturally occurring proteins as well as recombinant or synthetically produced proteins. The term “polypeptide fragment” refers to a portion of a polypeptide, such as a fragment exhibiting at least one sequence useful in binding to a receptor. The term “functional fragment of a polypeptide” refers to all fragments of a polypeptide that retain its polypeptide activity. Biologically functional peptides may also include fusion proteins, where the target peptide has been fused with another peptide that does not diminish its desired activity.

[0051] Subcutaneous administration: Subcutaneous administration involves applying a substance to the subcutaneous fat layer between the dermis and the underlying tissue of the skin. Subcutaneous administration can be performed using a subcutaneous injection needle fitted to a syringe or "pen"-type injection device. Other administration methods, such as microneedling, can also be used. Injections using a subcutaneous injection needle typically cause some degree of pain to the recipient. This pain can be masked by using local anesthetics or analgesics. However, a common method for reducing injection pain is to distract the subject simply before and during the injection. Pain can be minimized by using relatively small-gauge subcutaneous injection needles, injecting relatively small volumes of substance, and avoiding excessively acidic or alkaline compositions that may cause a "tingling" sensation at the injection site. Compositions with a pH between pH 4 and pH 10 are generally considered comfortable.

[0052] Therapeutic effective amount: a dose sufficient to prevent disease progression, or to resolve disease, or to alleviate signs or symptoms of disease, or to achieve the desired outcome. In some embodiments, the therapeutically effective amount of the compound of the present invention is an amount sufficient to inhibit or stop weight gain, or an amount sufficient to reduce appetite.

[0053] The compounds of the present invention The inventors of this invention have discovered that the compounds of the embodiments of this invention have properties including inducing weight loss in vivo. The compounds also have a fairly long half-life in the blood, meaning they can be readily administered at a lower frequency.

[0054] Compared to GIP and previous GIP derivatives, the compounds of the present invention have a substituent at one of the lysine residues at one of the multiple positions in the peptide sequence, the substituted lysine being functionalized at its ε-amino group, and the substituent comprising a peptide sequence of up to 4 residues with terminal groups R-R1, wherein R1 is CO2H.

[0055] The inventors further discovered that when the amino acid residue at position Xaa12 is lysine, the resulting compound, in a mouse feeding study, was particularly effective in reducing weight gain or achieving weight loss compared to the corresponding compound where Xaa12 is not lysine.

[0056] These are previously unexplored functionalization methods, and the beneficial properties discovered by the inventors of this invention are also unprecedented.

[0057] As described above, the compounds of the present invention have the formula: Xaa1 – Xaa2 – Xaa3 – Gly4 – Thr5 – Phe6 – al23–Xaa24–Xaa25–Leu26–Xaa27–Xaa28–Xaa29–Xaa30–Xaa31–Xaa32–Xaa 33–Xaa34–Xaa35–Xaa36–Xaa37–Xaa38–Xaa39–Xaa40–Thr41–Gln42–Xaa43 [SEQ ID NO:1] in: Xaa1 is DTyr, His, Phe, or Tyr, or does not exist; Xaa2 is either AIB or Ala, or it does not exist; Xaa3 can be Asp, Gln, Glu, or His; Xaa7 is Ile, Thr, or Ser; Xaa10 is either Tyr or His; Xaa12 is Lys; Xaa13 is AIB, Ala, Gln, Glu, Gly, His, Pro, Ser, Thr, Tyr, Val, Asp, or Asn; Xaa14 is Leu, Met, or NLeu; Xaa17 is either Gln or Ile; Xaa18 can be Ala, Arg, or His; Xaa19 is either Ala or Gln; Xaa20 is AIB, Gln, His, or Lys; Xaa21 is Ala, Asp, or Glu; Xaa24 is either Asn, Gln, or Glu; Xaa25 is Arg, His, Trp, or Tyr; Xaa27 is either Ile or Leu; Xaa28 is either Ala or Asn; Xaa29 is Gln, Gly, or Thr; Xaa30 is Gly, Lys, or Lys Or it may not exist; Xaa31 is Arg, Gly, or Pro, or it does not exist; Xaa32 is Asn, Lys, or Lys Or it may not exist; Xaa33 represents Lys or Lys Or it may not exist; Xaa34 represents Asn or Lys Or it may not exist; Xaa35 is either an Asp or does not exist; Xaa36 is either Trp or Lys Or it may not exist; Xaa37 is Lys or Lys Or it may not exist; Xaa38 is His or does not exist; Xaa39 is either Asn or Lys Or it may not exist; Xaa40 is for Ile, Leu, or Lys Or it may not exist; Xaa43 is Lys Or it may not exist; Lys Lys with the ε-amino group substituted by the following group: Z–Xaa44–Xaa45–Xaa46–Xaa47– in: Xaa44 is Gly, Ser, Thr or does not exist; Xaa45 is Gly, Ser, or does not exist; Xaa46 is Asn, Gln, Gly, Ser, Thr or does not exist; Xaa47 is Asn, Gln, Glu, Gly, His, Lys, Pro, Ser, Thr or does not exist; And Z is a group of the following formula: (i): Or (ii): , Where R is C8-C 28 An alkylene or alkenylene chain and R1 is –CO2H; And the compound said compound contains a Lys Residues.

[0058] Consider the residues in sequence. Xaa1 is selected from DTyr, His, Phe, or Tyr, or Xaa1 may not exist. Preferably, Xaa1 is selected from His, Phe, and Tyr. For example, Xaa1 is selected from His and Tyr, or Xaa1 is selected from Phe and Tyr. For example, Xaa1 is Tyr. In a particularly preferred embodiment, Xaa1 is Tyr.

[0059] Xaa2 is selected from AIB or Ala, or may not exist. Preferably, Xaa2 is AIB.

[0060] Xaa3 is selected from Asp, Gln, Glu, or His. Preferably, Xaa3 is selected from Glu and Gln. For example, Xaa3 is Glu. Alternatively, Xaa3 is Gln. In a particularly preferred embodiment, Xaa3 is Glu.

[0061] Xaa7 is selected from Ile, Thr, or Ser. In one embodiment, Xaa7 is selected from Ile or Thr. In another embodiment, Xaa7 is selected from Ile or Ser. Preferably, Xaa7 is Ile.

[0062] Xaa10 is selected from Tyr or His. Preferably, Xaa10 is Tyr.

[0063] Xaa13 is selected from AIB, Ala, Gln, Glu, Gly, His, Pro, Ser, Thr, Tyr, Val, Asp, or Asn. In one embodiment, Xaa13 is selected from AIB, Ala, Gln, Glu, Gly, His, Pro, Ser, Thr, Tyr, or Val. Preferably, Xaa13 is selected from Ala, Gln, Thr, and Val. For example, Xaa3 is selected from Ala, Gln, and Val. For example, Xaa13 is selected from Ala and Gln, or Xaa13 is selected from Ala and Val. In a particularly preferred embodiment, Xaa13 is Ala.

[0064] In another embodiment, Xaa13 is selected from Ala, Asp, Asn, and Ser. In a particularly preferred embodiment, Xaa13 is Ala.

[0065] Xaa14 is selected from Leu, Met, or NLeu. Preferably, Xaa14 is Leu.

[0066] Xaa17 is selected from Gln or Ile. Preferably, Xaa17 is Ile.

[0067] Xaa18 is selected from Ala, Arg, or His. Preferably, Xaa18 is selected from Ala and His. For example, Xaa18 is His. Alternatively, Xaa18 is Ala. In a particularly preferred embodiment, Xaa18 is His.

[0068] Xaa19 is selected from Ala or Gln. Preferably, Xaa19 is Gln.

[0069] Xaa20 is selected from AIB, Gln, His, or Lys. Preferably, Xaa20 is selected from AIB, Gln, and His. For example, Xaa20 is selected from AIB and Gln, or Xaa20 is selected from Gln and His. In a particularly preferred embodiment, Xaa20 is Gln.

[0070] Xaa21 is selected from Ala, Asp, or Glu. Preferably, Xaa21 is selected from Asp and Glu. For example, Xaa21 is Asp. Alternatively, Xaa21 is Glu. In a particularly preferred embodiment, Xaa21 is Asp.

[0071] Xaa24 is selected from Asn, Gln, or Glu. Preferably, Xaa24 is selected from Asn and Gln. For example, Xaa24 is Asn. Alternatively, Xaa24 is Gln. In a particularly preferred embodiment, Xaa24 is Asn.

[0072] Xaa25 is selected from Arg, His, Trp, or Tyr. Preferably, Xaa25 is Trp.

[0073] Xaa27 is selected from Ile or Leu. Preferably, Xaa27 is Leu.

[0074] Xaa28 is selected from Ala or Asn. Preferably, Xaa28 is Ala.

[0075] Xaa29 is selected from Gln, Gly, or Thr. Preferably, Xaa29 is selected from Gln and Gly. For example, Xaa29 is Gln. Alternatively, Xaa29 is Gly. In a particularly preferred embodiment, Xaa29 is Gln.

[0076] Xaa30 is selected from Gly, Lys, or Lys. Alternatively, Xaa30 may not be present. Preferably, Xaa30 is selected from Lys and Gly. For example, Xaa30 is Lys. Or, Xaa30 is Gly. In a particularly preferred embodiment, Xaa30 is Lys.

[0077] Xaa31 is selected from Arg, Gly, or Pro, or Xaa31 may not exist. Preferably, Xaa31 is selected from Gly and Pro. For example, Xaa31 is Gly. Alternatively, Xaa31 is Pro. In a particularly preferred embodiment, Xaa31 is Gly.

[0078] Xaa32 is selected from Asn, Lys, or Lys Alternatively, Xaa32 may not exist. Preferably, Xaa32 is selected from Asn, Lys, and Lys. For example, Xaa32 is selected from Lys and Lys Alternatively, Xaa32 is selected from Asn and Lys. In a particularly preferred embodiment, Xaa32 is Lys .

[0079] Xaa33 represents Lys or Lys Or Xaa33 is not present. Preferably, Xaa33 is selected from Lys and Lys Alternatively, Xaa33 may be Lys or may not exist. In a particularly preferred embodiment, Xaa33 may be Lys.

[0080] Xaa34 represents Asn or Lys Or Xaa34 is not present. Preferably, Xaa34 is selected from Asn and Lys. Or Xaa34 does not exist. For example, Xaa34 is selected from Asn and Lys. Alternatively, Xaa34 may be Asn or not exist. In a particularly preferred embodiment, Xaa34 is Asn.

[0081] Xaa35 is Asp; or Xaa35 does not exist. For example, Xaa35 is Asp. Or, Xaa35 does not exist. In a preferred embodiment, Xaa35 is Asp.

[0082] Xaa36 is either Trp or Lys Or Xaa36 does not exist. Preferably, Xaa36 is Trp or does not exist. For example, Xaa36 is Trp. Or, Xaa36 does not exist. In a particularly preferred embodiment, Xaa35 is Trp.

[0083] Xaa37 is Lys or Lys Or Xaa37 is absent. Preferably, Xaa37 is Lys or is absent. For example, Xaa37 is Lys. Or, Xaa37 is absent. In a particularly preferred embodiment, Xaa37 is Lys.

[0084] Xaa38 is His or Xaa38 does not exist. For example, Xaa38 is His. Or, Xaa38 does not exist. In a particularly preferred embodiment, Xaa38 is His.

[0085] Xaa39 is either Asn or Lys Or Xaa39 does not exist. Preferably, Xaa39 is Asn or does not exist. For example, Xaa39 is Asn. Or, Xaa39 does not exist. In a particularly preferred embodiment, Xaa39 is Asn.

[0086] Xaa40 is for Ile, Leu, or Lys Or Xaa40 is absent. Preferably, Xaa40 is 1e or is absent. For example, Xaa40 is 1e. Or, Xaa40 is absent. In a particularly preferred embodiment, Xaa40 is 1e.

[0087] Xaa41 is Thr, or Xaa41 does not exist. Preferably, Xaa41 is Thr.

[0088] Xaa42 is Gln, or Xaa42 does not exist. Preferably, Xaa42 is Gln.

[0089] Xaa43 is Lys Alternatively, Xaa43 may not exist. Preferably, Xaa43 may not exist.

[0090] Lys Linkage of substituents In the compounds of this invention, Lys The ε-amino group on the molecule is attached to the α-acid group of the Xaa47 residue, making the bond an amide bond. If Xaa47 is absent, then Lys The ε-amino group is attached to the α-acid group of the next present residue, or to the α-acid group of the Z group if no residue is present.

[0091] In lysine residues, the ε-amino group is an amino group attached to a 6-carbon. According to standard IUPAC nomenclature, the atoms in lysine are numbered as follows (indicating carbon atom numbers and α to ε positions):

[0092] Lys mentioned in this article The ε-amino group is the amino group on the C-6 carbon atom as indicated.

[0093] According to the present invention, substituents can be linked to the peptide sequence labeled Lys in formula (I). The substituent can be attached to a Lys residue at any position. That is, the substituent can be attached to a Lys residue at one of positions Xaa30, Xaa32, Xaa33, Xaa34, Xaa36, Xaa37, Xaa39, Xaa40, or Xaa43. The preferred positions are selected from Xaa30, Xaa32, Xaa33, Xaa34, and Xaa43, for example, Xaa32, Xaa33, and Xaa43. In a particularly preferred embodiment, the substituent is attached to a Lys residue at position Xaa32.

[0094] The substituents in the compounds of this invention have the following formula: Z–Xaa44–Xaa45–Xaa46–Xaa47– Consider each residue sequentially: Xaa44 is selected from Gly, Ser, and Thr; or Xaa44 is not present. Preferably, Xaa44 is Thr, or Xaa44 is not present. For example, Xaa44 is Thr, or Xaa44 is not present. In a particularly preferred embodiment, Xaa44 is not present.

[0095] Xaa45 is selected from Gly and Ser; or Xaa45 is not present. For example, Xaa45 is Gly or is not present. Alternatively, Xaa45 is Ser or is not present. Preferably, Xaa45 is Gly or is not present. In a particularly preferred embodiment, Xaa45 is not present.

[0096] Xaa46 is selected from Asn, Gln, Gly, Ser, and Thr; or Xaa46 is not present. Preferably, Xaa46 is selected from Asn, Gly, Ser, and Thr; or Xaa46 is not present. More preferably, Xaa46 is selected from Asn, Gly, and Ser; or Xaa46 is not present. For example, Xaa46 is selected from Asn and Ser; or Xaa46 is not present. Alternatively, Xaa46 is selected from Gly and Ser; or Xaa46 is not present. In a more preferred embodiment, Xaa46 is Ser or is not present. In a particularly preferred embodiment, Xaa46 is not present.

[0097] Xaa47 is selected from Asn, Gln, Glu, Gly, His, Lys, Pro, Ser, and Thr; or Xaa47 is absent. Preferably, Xaa47 is selected from Gly, Gln, His, and Lys; or Xaa47 is absent. More preferably, Xaa47 is selected from Gly and Lys; or Xaa47 is absent. In a preferred embodiment, Xaa47 is Lys or is absent. In a particularly preferred embodiment, Xaa47 is Lys.

[0098] Group Z The Z part of the compound is a group of the following formula: (i): Or (ii): , Where R is C8-C 28 An alkylene or alkenylene chain and R1 is –CO2H.

[0099] In the Z part of the molecule, group R is an alkylene or alkenylene chain, one end of which is connected to residue Xaa44 via an amide bond through a Glu residue (or, if Xaa44 is absent, then Xaa45; or, if neither Xaa44 nor Xaa45 is present, then Xaa46, etc.; if none of Xaa44 to Xaa47 are present, then one end of R is connected to Lys). At its other end, the R alkylene or alkenylene chain is attached to the R1 acid group (CO2H).

[0100] Option (i) above indicates that the Glu residue in the Z group is linked to Lys via the γ-carboxylic acid group of Glu. Regarding the residue configuration, option (ii) above indicates that the Glu residue in the Z group is linked to Lys via the α-carboxylic acid group of Glu. Regarding the residue situation. In a preferred embodiment of the invention, the Z part of the compound is of formula (i), that is, the Glu residue in the Z group is linked to Lys via the γ-carboxylic acid group of Glu. Residues.

[0101] Typically, R has an even number of carbon atoms. For example, R can be an alkylene or alkenylene chain found in naturally occurring fatty acids. The chain length of a fatty acid is the number of carbon atoms in the alkylene or alkenylene chain of R plus two.

[0102] In a preferred embodiment, R is C 16 -C 18 Alkylene or alkenylene chain. For example, R is a straight-chain alkylene or alkenylene chain. For example, R is C 16 Or C 18 Straight-chain alkylene groups. For example, when R is C 16 When R is a group, it can be provided by the octadecanoic acid moiety. For example, when R is C 18 When the group is present, it can be provided by the eicosidine moiety.

[0103] In a more preferred embodiment, R is C 18 Alkylene.

[0104] In another embodiment of the invention, it is preferred that: Xaa1 is His, Phe, or Tyr; Xaa2 is AIB; Xaa3 can be Glu, Gln, or His; Xaa7 is either Ile or Ser; Xaa10 is either Tyr or His; Xaa12 is Lys; Xaa13 is Ala, Asp, Asn, Gln, Ser, Thr, or Val; Xaa14 is either Leu or Met; Xaa17 is either Gln or Ile; Xaa18 is either Ala or His; Xaa19 is either Ala or Gln; Xaa20 is AIB, Gln, His, or Lys; Xaa21 is either Asp or Glu; Xaa24 is either Asn, Gln, or Glu; Xaa25 is a Trp; Xaa27 is Leu; Xaa28 is either Ala or Asn; Xaa29 is Gln, Gly, or Thr; Xaa30 is Gly, Lys, or Lys ; Xaa31 is either Arg, Gly, or Pro; Xaa32 is Asn, Lys, or Lys ; Xaa33 represents Lys or Lys Or Xaa33 does not exist; Xaa34 represents Asn or Lys Or Xaa34 does not exist; Xaa35 is an Asp; or Xaa35 does not exist; Xaa36 is a Trp; or Xaa36 does not exist; Xaa37 is Lys; or Xaa37 does not exist; Xaa38 is His; or Xaa38 does not exist; Xaa39 is an Asn; or Xaa39 does not exist; Xaa40 is Ile; or Xaa40 does not exist; Xaa41 is Thr; or Xaa41 does not exist; Xaa42 is Gln, or Xaa42 does not exist; Xaa43 is Lys Or Xaa43 does not exist; Z is (i):

[0105] Where R is C 16 Or C 18 Alkylene chain and R1 is –CO2H; Xaa44 is Thr, or Xaa44 does not exist; Xaa45 is Gly, or Xaa45 does not exist; Xaa46 is Asn, Gly, or Ser, or Xaa46 does not exist; and Xaa47 is either Gly or Lys, or Xaa47 does not exist.

[0106] For example, in this implementation scheme: Xaa1 is Tyr; Xaa2 is AlB; Xaa3 is Glu; Xaa7 is either Ile or Ser; Xaa10 is either Tyr or His; Xaa12 is Lys; Xaa13 is Asp, Asn, Ala, or Ser; Xaa14 is Leu; Xaa17 is Ile; Xaa18 is His; Xaa19 is Gln; Xaa20 is Gln; Xaa21 is an Asp; Xaa24 is an Asn; Xaa25 is a Trp; Xaa27 is Leu; Xaa28 is Ala; Xaa29 is Gln; Xaa30 is Lys; Xaa31 is Gly; Xaa32 is Lys; Xaa33 is Lys Or it may not exist; Xaa34 is Lys Or it may not exist; Xaa35 does not exist; Xaa36 does not exist; Xaa37 does not exist; Xaa38 does not exist; Xaa39 does not exist; Xaa40 does not exist; Xaa41 does not exist; Xaa42 does not exist; Xaa43 does not exist; Z is (i): Where R is C 18 Alkylene chain and R1 is –CO2H; Xaa44 does not exist; Xaa45 does not exist; Xaa46 is either Asn or does not exist; and Xaa47 is either Lys or His, or it does not exist. For example, Xaa47 is either Lys or His.

[0107] As another example: Xaa7 is Ile; Xaa10 is Tyr; Xaa12 is Lys; Xaa13 is either Ala or Asp; Xaa33 is Lys ; Xaa34 does not exist; Xaa46 does not exist; and Xaa47 is either Lys or does not exist. For example, Xaa47 is Lys.

[0108] In one embodiment of the first aspect of the invention, a compound of formula (II) is provided:

[0109] in W represents the amino acid sequence: Xaa1–Xaa2–Xaa3–Gly4–Thr5–Phe6–Xaa7–Ser8–Asp9–Xaa10–Ser11–Xaa12–Xaa13–Xaa14–Asp15–L ys16–Xaa17–Xaa18–Xaa19–Xaa20–Xaa21–Phe22–Val23–Xaa24–Xaa25–Leu26–Xaa27–Xaa28–Xaa29– [SEQ ID NO: 7] in: Xaa1 is DTyr, His, Phe, or Tyr, or does not exist; Xaa2 is either AIB or Ala, or it does not exist; Xaa3 can be Asp, Gln, Glu, or His; Xaa7 is Ile, Thr, or Ser; Xaa10 is either Tyr or His; Xaa12 is Lys; Xaa13 is AIB, Ala, Gln, Glu, Gly, His, Pro, Ser, Thr, Tyr, Val, Asp, or Asn; Xaa14 is Leu, Met, or NLeu; Xaa17 is either Gln or Ile; Xaa18 can be Ala, Arg, or His; Xaa19 is either Ala or Gln; Xaa20 is AIB, Gln, His, or Lys; Xaa21 is Ala, Asp, or Glu; Xaa24 is either Asn, Gln, or Glu; Xaa25 is Arg, His, Trp, or Tyr; Xaa27 is either Ile or Leu; Xaa28 is either Ala or Asn; and Xaa29 is Gln, Gly, or Thr; Y represents the amino acid sequence: –Xaa30–Xaa31–Xaa32–Xaa33–Xaa34 in: Xaa30 is either Gly or Lys, or it does not exist; Xaa31 is Arg, Gly, or Pro, or it does not exist; Xaa32 is either Asn or Lys, or it does not exist; Xaa33 represents Lys, Lys Or it may not exist; Xaa34 is Lys Or it may not exist; Lys Lys with the ε-amino group substituted by the following group: Z–Xaa44–Xaa45–Xaa46–Xaa47– in: Xaa44 is Gly, Ser, or Thr, or does not exist; Xaa45 is either Gly or Ser, or it does not exist; Xaa46 is Asn, Gln, Gly, Ser, or Thr, or does not exist; Xaa47 is Asn, Gln, Glu, Gly, His, Lys, Pro, Ser, or Thr, or does not exist; And Z is a group of the following formula: (i): Or (ii): , Where R is C8-C 28 An alkylene or alkenylene chain and R1 is –CO2H; Furthermore, the compound of formula (I) or formula (II) contains a Lys residues; Or a derivative of the compound; or a salt or solvation of the compound or its derivative.

[0110] In another embodiment, when the compound of the present invention is a compound of formula (II), Xaa1 is Tyr; Xaa2 is AlB; Xaa3 is Glu; Xaa7 is Ile, Ser, or Thr; Xaa10 is either Tyr or His; Xaa12 is Lys; Xaa13 is AIB, Ala, Asn, Asp, Ser, or Tyr; Xaa14 is Leu; Xaa17 is either Gln or Ile; Xaa18 is either Ala or His; Xaa19 is either Ala or Gln; Xaa20 is AIB, Gln, or Lys; Xaa21 is Ala, Asp, or Glu; Xaa24 is either Asn, Gln, or Glu; Xaa25 is Arg, His, Trp, or Tyr; Xaa27 is either Ile or Leu; Xaa28 is either Ala or Asn; Xaa29 is Gln, Gly, or Thr; Xaa30 is either Gly or Lys, or it does not exist; Xaa31 is Arg, Gly, or Pro, or it does not exist; Xaa32 is either Asn or Lys, or it does not exist; Xaa33 is Lys, or does not exist; and Xaa34 is Lys .

[0111] In a preferred embodiment, when the compound of the present invention is a compound of formula (II), Xaa30 is either Lys or Gly; Xaa31 is either Gly or Pro; Xaa32 is either Lys or does not exist; Xaa33 does not exist; and Xaa34 is Lys .

[0112] In a preferred embodiment, when the compound of the present invention is a compound of formula (II), Xaa1 is Tyr; Xaa2 is AIB; Xaa3 is Glu; Xaa7 is either Ile or Ser; Xaa10 is either Tyr or His; Xaa12 is Lys; Xaa13 is Asp, Asn, Ala, or Ser; Xaa14 is Leu; Xaa17 is Ile; Xaa18 is His; Xaa19 is Gln; Xaa20 is Gln; Xaa21 is an Asp; Xaa24 is an Asn; Xaa25 is a Trp; Xaa27 is Leu; Xaa28 is Ala; Xaa29 is Gln; Xaa30 is Lys; Xaa31 is Gly; Xaa32 is Lys; Xaa33 is either Lys or does not exist; and Xaa34 is Lys ; Lys Lys with the ε-amino group substituted by the following group: Z–Xaa44–Xaa45–Xaa46–Xaa47–; in: Xaa44 does not exist; Xaa45 does not exist; Xaa46 is either Asn or does not exist; and Xaa47 is either Lys or His; Z is (i):

[0113] Where R is C 18 It has an alkylene chain and R1 is –CO2H.

[0114] For example, Xaa10 is Tyr; Xaa12 is Lys; Xaa13 is either Ala or Asp; Xaa33 does not exist; Xaa34 is Lys ; Xaa46 does not exist; and Xaa47 is Lys.

[0115] In a particularly preferred embodiment, the compound is Figure 1 One of the compounds of the present invention is shown in the table.

[0116] Derivatives and salts The present invention provides compounds of formula (I), derivatives of such compounds, and salts or solvates of such compounds and derivatives.

[0117] The compounds, derivatives, and salts can be prepared by recombination methods well known in the art, or they can be prepared by synthetic methods well known in the art.

[0118] derivative Although in some embodiments the invention relates to compounds of formula (I) rather than derivatives, in other embodiments the invention relates to derivatives of compounds of formula (I). The derivatives may, for example, comprise one or more derivatizations selected from amidation, glycosylation, carbamylation, acylation, sulfation, phosphorylation, cyclization, lipidization, PEGylation, and fusion with another peptide or protein to form a fusion protein. The structure may be modified at random positions within the molecule or at predetermined positions within the molecule, and may include one, two, three, or more linked chemical moieties.

[0119] In some embodiments, it is preferred that the C-terminus of the major peptide chain of the compounds of the present invention be amidated. This modification is very common in nature, and approximately half of naturally occurring peptides (including certain gastrointestinal peptide hormones) readily undergo amidation at their C-terminus. The present invention covers all general and specific sequences disclosed herein, including amidated and non-amidated forms in the sequence listing and figures, wherein amidation is particularly preferred to be present at the C-terminus of the major peptide sequence.

[0120] The derivative may be, for example, a fusion protein, in which the structure of formula (I) is fused to another protein or polypeptide (fusion chaperone) using recombinant methods known in the art. Alternatively, such a fusion protein may be synthesized synthetically by any known method. This fusion protein comprises the structure of formula (I). Any suitable peptide or protein may be used as a fusion chaperone (e.g., serum albumin, carbonic anhydrase, glutathione S-transferase, or thioreductase, etc.). This fusion protein may be prepared by attaching the carboxyl terminus of the fusion chaperone to the amino terminus of the structure of formula (I), or vice versa. Optionally, a cleavable linker may be used to attach the structure of formula (I) to the fusion chaperone. The resulting cleavable fusion protein may be cleaved in vivo to release the active form of the compound of the invention. Examples of such cleavable adapters include, but are not limited to, the adapters Asp-Asp-Asp-Asp-Tyr [SEQ ID NO: 10], Gly-Pro-Arg, Ala-Gly-Gly, and His-Pro-Phe-His-Leu [SEQ ID NO: 11], which can be cleaved by enterokinase, thrombin, ubiquitin lyase, and renin, respectively. For details, see, for example, U.S. Patent No. 6,410,707, the contents of which are incorporated herein by reference.

[0121] The derivatives of this invention may be, for example, physiologically functional derivatives of the structure of formula (I). The term "physiologically functional derivative" is used herein to refer to a chemical derivative of a compound of formula (I) having the same physiological function as the corresponding unmodified compound. For example, the physiologically functional derivative can be converted in vivo into a compound of formula (I). According to the invention, examples of physiologically functional derivatives include esters, amides, and carbamates; preferably esters and amides.

[0122] Besides Lys Derivatization at the site of the compound can further occur at additional sites. For example, pharmaceutically acceptable esters and amides of the compounds of the present invention may contain C 1-20 Alkyl-, C 2-20 alkenyl-, C 5-10 Aryl-, C 5-10 Aryl-C 1-20 Alkyl or amino acid-ester group or amide group attached to a suitable site, formed, for example, by reacting an alkyl, alkenylaryl, aralkyl, or aminoalkyl group containing an alcohol or amino moiety with an acid moiety present in a compound of formula (I), or by reacting an alkyl, alkenylaryl, aralkyl, or aminoalkyl group containing an activated acyl group with an alcohol or amino group present in a compound of formula (I). Examples of suitable moieties are hydrophobic substituents having 4 to 26 carbon atoms, preferably 5 to 19 carbon atoms. Suitable lipid groups include fatty acids (e.g., lauroyl (C 12 H23 Palmityl (C) 15 H 31 ), oil-based (C 15 H 29 ) or stearoyl (C 17 H 35 )) and bile acids (such as bile salts or deoxycholates).

[0123] Methods for lipidating thiol-containing compounds using fatty acid derivatives are disclosed in U.S. Patent Nos. 5,936,092, 6,093,692, and 6,225,445, the contents of which are incorporated herein by reference. Fatty acid derivatives of the compounds of the present invention, comprising compounds of the present invention linked to fatty acids via disulfide bonds, can be used to deliver the compounds of the present invention to nerve cells and tissues. Lipidification significantly increases the absorption rate of the compounds relative to the absorption rate of the corresponding unlipidated compounds and prolongs the retention of the compounds in blood and tissues. Furthermore, the disulfide bonds in the lipidized derivatives are relatively unstable in cells, thus facilitating the release of the molecules from the fatty acid moiety within cells. Suitable lipid moieties are hydrophobic substituents having 4 to 26 carbon atoms, preferably 5 to 19 carbon atoms. Suitable lipid groups include fatty acids (e.g., lauroyl (C 12 H 23 Palmityl (C) 15 H 31 ), oil-based (C 15 H 29 ) or stearoyl (C 17 H 35 And bile acids (e.g., bile salts or deoxycholates). Although the lipid-functionalized compounds of the present invention may be advantageous in certain situations, it is anticipated that in most cases, in the simplest and most preferably, the compounds of the present invention will not be further derivatized so that no additional lipid groups are present.

[0124] Cyclization methods include cyclization by forming disulfide bridges and head-and-tail cyclization using cyclizing resins. Due to their conformational constraints, cyclized peptides can exhibit enhanced stability, including increased resistance to enzymatic degradation. Cyclization may be particularly advantageous when the uncyclized peptide includes an N-terminal cysteine ​​group. Suitable cyclized peptides include monomeric and dimer head-and-tail cyclization structures. Cyclized peptides may include one or more additional residues, particularly additional cysteine ​​residues incorporated to form disulfide bonds, or side chains incorporated for resin-based cyclization.

[0125] The derivatives may be, for example, polyethylene glycol-modified structures of formula (I). Derivatives of the polyethylene glycol-modified compounds of the present invention may provide additional advantages, such as increased solubility, stability and cycling time of peptides, or reduced immunogenicity (see U.S. Patent No. 4,179,337, the contents of which are incorporated herein by reference).

[0126] The derivatized chemical portion of the compounds of the present invention may also be selected from water-soluble polymers, such as polyethylene glycol, ethylene glycol / propylene glycol copolymers, carboxymethyl cellulose, dextran, polyvinyl alcohol, etc. The polymer portion used for the derivatization of the compounds of the present invention may have any molecular weight and may be branched or unbranched. For ease of handling and manufacture, the preferred molecular weight of the polyethylene glycol used for the derivatization of the compounds of the present invention is from about 1 kDa to about 100 kDa, the term "about" indicating that in the polyethylene glycol formulation, some molecules will have a molecular weight larger than the specified molecular weight, and some molecules will have a molecular weight smaller than the specified molecular weight. Polymers having other molecular weights may be used, depending on the desired therapeutic profile, such as the desired duration of sustained release, the effect on biological activity (if present), ease of handling, the degree or absence of antigenicity, and other known effects of polyethylene glycol on therapeutic proteins or analogues. For example, polyethylene glycol can have values ​​of approximately 200, 500, 1000, 1500, 2000, 2500, 3000, 3500, 4000, 4500, 5000, 5500, 6000, 6500, 7000, 7500, 8000, 8500, 9000, 9500, 10,000, 10,500, 11,000, 11,500, 12,000, 12,500, 13,000, 13,500, 14,000, 14,500, and 15,000. Average molecular weight of 0, 15,500, 16,000, 16,500, 17,000, 17,500, 18,000, 18,500, 19,000, 19,500, 20,000, 25,000, 30,000, 35,000, 40,000, 45,000, 50,000, 55,000, 60,000, 65,000, 70,000, 75,000, 80,000, 85,000, 90,000, 95,000, or 100,000 kDa.

[0127] Salt Salts of compounds of formula (I) and salts of derivatives of such compounds are also part of this invention. In some embodiments, the salt is a salt of a compound of formula (I). In other embodiments, the salt is a salt of a derivative of a compound of formula (I).

[0128] The salts of the compounds of this invention include those that are pharmaceutically acceptable, i.e., suitable for pharmaceutical preparations. However, salts having non-pharmaceuticalally acceptable counterions are also within the scope of this invention, for example, as intermediates in the preparation of the compounds.

[0129] Suitable salts according to the invention include those formed with organic or inorganic acids or bases. Pharmaceutically acceptable acid addition salts include those formed with hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, citric acid, tartaric acid, acetic acid, phosphoric acid, lactic acid, pyruvic acid, acetic acid, trifluoroacetic acid, succinic acid, perchloric acid, fumaric acid, maleic acid, glycolic acid, salicylic acid, oxalic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, formic acid, benzoic acid, malonic acid, naphthalene-2-sulfonic acid, benzenesulfonic acid, and 2-hydroxyethanesulfonic acid. Other acids such as oxalic acid may be used as intermediates to obtain the compounds of the invention in their final form.

[0130] Pharmaceutically acceptable salts that form with bases include ammonium salts, alkali metal salts (e.g., potassium and sodium salts), alkaline earth metal salts (e.g., calcium and magnesium salts), and salts that form with organic bases (e.g., dicyclohexylamine and N-methyl-D-glucosamine).

[0131] solvates Those skilled in the art of organic and / or medicinal chemistry will understand that many organic compounds can form complexes with solvents that can react with them or from which they precipitate or crystallize. Such complexes are called "solvents." For example, a complex with water is called a "hydrate." This invention also covers solvates of compounds of formula (I), solvates of derivatives of said compounds, and solvates of salts of said derivatives.

[0132] Those skilled in the art of organic and / or medicinal chemistry will also understand that many organic compounds can exist in different forms, including as amorphous materials and / or in one or more crystalline forms. Different physical forms of organic compounds are referred to as polymorphs. This invention also covers all such different physical forms of compounds of formula (I), as well as different physical forms of their derivatives and salts.

[0133] Bioactivity The compounds of the present invention are active against the human GIP receptor and can be considered GIP receptor agonists. This can be evaluated, for example, by in vitro or cell binding assays or reporter gene assays. For example, when tested according to the assays described in the Examples section below, the preferred compounds of the present invention exhibit at least 1 / 50 of the activity against the human GIP receptor, and more preferably at least 1 / 30, 1 / 20, 1 / 10, 1 / 5, 1 / 3, or 1 / 2 of the activity against the human GIP receptor.

[0134] Methods for assessing GIP receptor activity are well-known. For example, homogeneous time-resolved fluorescence (RJ Samms et al., GIPR agonism mediates weight-independent insulin sensitization by tirzepatide in obese mice, J. Clin. Invest. (2021, 131(12):e146353) The study detected changes in cAMP accumulation in response to activation of Gs-coupled G protein-coupled receptor (GPCR). The specific method is described below.

[0135] The preferred compounds of this invention effectively promote insulin release / secretion. This can be assessed, for example, by in vitro or in vivo assays. Methods for assessing insulin release are well known.

[0136] The compounds of the present invention meet some or more preferably all of the following criteria: 1) Sustained biological activity against human GIP receptors leads to appetite suppression; 2) Activity that promotes insulin release; 3) Its high solubility in aqueous solutions at pH 3.0–8.0 allows for the administration of effective doses in small volumes (thus reducing injection pain). Solubility can be easily assessed through simple in vitro tests. 4) Long-term in vivo activity (as evaluated in human or animal models) to allow for injections no more than once a day, and preferably no more than twice a day, or more preferably no more than once a week, while still producing acceptable therapeutic or cosmetic benefits; 5) Good weight loss (as assessed in human subjects or animal models, where assessment can be accomplished using co-administration of GLP1r agonists).

[0137] According to certain embodiments of the present invention, particularly those related to weight loss, obesity, carbohydrate metabolism, and diabetes, the compounds, derivatives, and salts of the present invention have one, several, or all of the following characteristics: A. Sufficient solubility between pH 3.0 and pH 8.0 to allow for the administration of an effective dose in volumes of less than 1 mL, less than 0.5 mL, or less than 0.3 mL; B. Activation of cAMP signaling in cells overexpressing the human GIP receptor; C. One, several, or all of the 1 to 5 further features listed above.

[0138] Pharmacokinetics, duration of action and solubility The compounds of this invention exhibit an effective and prolonged duration of action in vivo after subcutaneous administration. To achieve this, the compounds must possess both good activity against the biological target and excellent pharmacokinetic properties.

[0139] The compounds of the present invention have a therapeutically usable duration of action and demonstrate the beneficial effects observed over several days in the experiments described below. In addition to exhibiting a long in vivo half-life, the compounds of the present invention also possess good storage stability, with no significant degradation observed after storage in solution at 4°C for 4 weeks.

[0140] Poor water solubility is a known problem with lipid-containing molecules. In contrast, the compounds of this invention exhibit very good water solubility.

[0141] condition The present invention also provides compounds, derivatives or salts of the invention for use as medicaments, or compositions comprising said compounds, derivatives or salts with a pharmaceutically acceptable carrier and optionally another therapeutic agent.

[0142] The present invention also provides a method for treating or preventing a disease or condition or other undesirable physiological state in a subject, the method comprising administering a therapeutically effective amount of a compound, derivative, or salt of the present invention, or a composition comprising said compound, derivative, or salt with a pharmaceutically acceptable carrier and optionally another therapeutic agent. Preferably, said compound, derivative, salt, or composition is administered subcutaneously.

[0143] According to certain implementations, the disease or condition or other undesirable physiological state is diabetes or obesity, especially diabetes (e.g., type 2 diabetes).

[0144] According to certain implementations, the disease or condition or other undesirable physiological condition may be an overweight physiological condition.

[0145] Subjects administering the compound may be overweight, such as obese. Or, additionally, subjects may be diabetic, such as having insulin resistance or glucose intolerance, or both. Subjects may have diabetes, for example, type 2 diabetes. Subjects may be overweight (e.g., obese) and have diabetes, such as type 2 diabetes.

[0146] Alternatively, participants may have or be at risk of having conditions that are risk factors for obesity or being overweight. These conditions include, but are not limited to, heart disease, cardiovascular disease (e.g., hypertension, atherosclerosis, congestive heart failure, and dyslipidemia); stroke; gallbladder disease; osteoarthritis; sleep apnea; reproductive disorders (e.g., polycystic ovary syndrome); cancers (e.g., breast cancer, prostate cancer, colon cancer, endometrial cancer, kidney cancer, and esophageal cancer); varicose veins; acanthosis nigricans; eczema; exercise intolerance; insulin resistance; hypertension and hypercholesterolemia; gallstones; osteoarthritis; orthopedic injuries; insulin resistance (e.g., type 2 diabetes and syndrome X); and thromboembolic diseases (see Kopelman, ...). Nature 404:635-43, 2000; Rissanen et al. British Med. J 301, 835, 1990).

[0147] Other obesity-related conditions include depression, anxiety disorders, panic disorders, migraines, PMS, chronic pain states, fibromyalgia, insomnia, impulsivity, obsessive-compulsive disorder, and muscle spasms. Certain neurological disorders and some neurodegenerative diseases are also associated with obesity. Furthermore, obesity is a recognized risk factor for increased complications from general anesthesia (see, for example, Kopelman). Nature (404:635-43, 2000). Generally speaking, obesity shortens lifespan and carries a serious risk of complications (such as those listed above).

[0148] Other diseases or conditions related to obesity include congenital defects and neural tube defects. Increased incidence of defects associated with maternal obesity, carpal tunnel syndrome (CTS); chronic venous insufficiency (CVI); daytime sleepiness; deep vein thrombosis (DVT); end-stage renal disease (ESRD); gout; fever; impaired immune response; impaired respiratory function; infertility; liver disease; lower back pain; obstetric and gynecological complications; pancreatitis; and abdominal hernia; acanthosis nigricans; endocrine disorders; chronic hypoxia and hypercapnia; dermatological effects; elephantiasis; gastroesophageal reflux; calcaneal spurs; lower extremity edema; breast enlargement (which causes a number of problems, such as bra strap pain, skin lesions, neck pain, persistent odor and infection in the skin folds under the breast, etc.); large anterior abdominal wall masses (such as panniculitis with frequent peritonitis), obstructing walking, leading to frequent infections, odor, difficulty dressing, lower back pain; musculoskeletal disorders; pseudotumor cerebri (or benign intracranial hypertension) and sliding diaphragmatic hernia.

[0149] In some implementation schemes, the disease or condition may be non-alcoholic fatty liver disease.

[0150] According to certain embodiments, the disease or condition or other undesirable physiological state may be having an undesirable weight despite not being obese or overweight. Subjects may have a normal weight (this includes, but is not limited to, subjects who were previously overweight or obese and wish to prevent returning to an unhealthy weight). Subjects may be subjects who wish to lose weight, such as female and / or male subjects who wish to change their appearance. In some cases where the subject's weight is normal, aspects of the invention may relate to cosmetic rather than therapeutic treatments.

[0151] The present invention also provides a method for reducing appetite, reducing food intake, reducing calorie intake, improving insulin release, improving carbohydrate metabolism, and / or improving glucose tolerance in a subject, said method comprising administering a therapeutically effective amount of a compound, derivative, salt, or composition of the present invention. Such methods may relate to treating subjects with a prediabetic state (e.g., poor insulin sensitivity) or prediabetes.

[0152] The present invention also provides a method for improving lipid profile in a subject, the method comprising administering a therapeutically effective amount of a compound, derivative, salt, or composition of the present invention. The present invention further provides a method for alleviating a disease or symptom that can be alleviated by reducing nutrient utilization, the method comprising administering a therapeutically effective amount of a compound, derivative, salt, or composition of the present invention.

[0153] The compounds, derivatives, salts, or compositions of the present invention can be used for weight control and treatment, such as reducing or preventing obesity, particularly any or more of the following: preventing and reducing weight gain; inducing and promoting weight loss; and reducing the degree of obesity (as measured by body mass index). The compounds, derivatives, salts, or compositions of the present invention can be used to maintain any or more of a desired weight, a desired body mass index, a desired appearance, and good health.

[0154] This invention can also be used to treat, prevent, improve, or alleviate diseases or conditions caused, complicated by, or aggravated by relatively high nutrient utilization. The term "disease or condition that can be alleviated by reducing caloric (or nutrient) utilization" is used herein to refer to any disease or condition in a subject that is caused, complicated by, or aggravated by relatively high nutrient utilization, or that can be alleviated by reducing nutrient utilization, for example, by reducing food intake. Subjects with insulin resistance or glucose intolerance, or suffering from any form of diabetes, such as type 1, type 2, or gestational diabetes, may also benefit from the method according to the invention.

[0155] Disorders or conditions associated with increased calorie intake include, but are not limited to, insulin resistance, glucose intolerance, obesity, diabetes (including type 2 diabetes), eating disorders, insulin resistance syndrome, and Alzheimer's disease.

[0156] J. Cereb. Blood Flow Metab. On April 13, 2011, Teramoto S et al. discussed the use of GLP-1 and exendin-4 to provide cardioprotection after myocardial infarction and demonstrated that exendin-4 could provide neuroprotection against cerebral ischemia-reperfusion injury. The study showed that mice receiving intravenous exendin-4 experienced a significant reduction in infarct volume and improvement in functional deficits after 60 minutes of localized cerebral ischemia, as well as suppression of oxidative stress, inflammatory responses, and cell death after reperfusion. The evidence provided by this study suggests that the protective effect of exendin-4 is mediated by increased intracellular cAMP levels and indicates that exendin-4 may be helpful in the treatment of acute ischemic stroke.

[0157] Accordingly, the present invention also provides a method for providing cellular protection in a subject, such as providing cardiac protection, providing neuroprotection, and / or treating or preventing neurodegeneration, comprising administering a therapeutically effective amount of a compound, derivative, salt, or composition of the present invention.

[0158] In some embodiments, the compounds, derivatives, salts, or compositions of the present invention can be used to treat or prevent diseases or conditions or other undesirable physiological states such as neurodegeneration. Such neurodegeneration can be caused by apoptosis, necrosis, or loss of function of nerve cells (preferably in the CNS). The neurodegeneration being treated or prevented can be post-traumatic neurodegeneration (e.g., after physical trauma or non-traumatic injury such as stroke, tumor, hypoxia, poisoning, infection, ischemia, encephalopathy, or drug abuse). Alternatively, neurodegeneration can be prevented or treated in subjects with neurodegenerative diseases (or diagnosed with a predisposition to neurodegenerative diseases), such as Alzheimer's disease, Parkinson's disease, Glick's disease (amyotrophic lateral sclerosis), Huntington's disease, multiple sclerosis, other demyelinating disorders, Alzheimer's disease, subcortical dementia, arteriosclerotic dementia, AIDS-related dementia, other dementias, cerebellar vasculitis, epilepsy, Tourette's syndrome, Guillain-Barré syndrome, Wilson's disease, Pick's disease, neuroinflammatory diseases, encephalitis, encephalomyelitis, meningitis, other central nervous system infections, prion diseases, cerebellar ataxia, cerebellar degeneration, spinocerebellar degeneration syndrome, and Friedrich's ataxia. Neurodegenerative diseases include ataxia, ataxic telangiectasia, spinal muscular dystrophy, progressive supranuclear palsy, dystonia, muscle spasms, tremor, retinitis pigmentosa, striatonigral degeneration, mitochondrial encephalomyopathies, and neuronal ceroid lipofuscinosis. Preferably, the neurodegenerative disease is selected from the group consisting of Alzheimer's disease, Parkinson's disease, Glickman's disease (amyotrophic lateral sclerosis), and Huntington's disease. In such cases, the treatment will be considered neuroprotective. According to certain preferred embodiments, the treatment is a neuroprotective treatment after cerebral ischemia, or a neuroprotective treatment in subjects with neurodegenerative diseases or diagnosed as having a predisposition to neurodegenerative diseases.

[0159] According to other embodiments, the disease or condition or other undesirable physiological state is cardiac degeneration (particularly myocardial degeneration caused by cardiomyocyte apoptosis, necrosis, or loss of function), in which case the compounds, derivatives, salts, or compositions according to the invention provide cardiac protection. According to certain preferred embodiments, the treatment is to protect myocardial function after myocardial infarction.

[0160] The present invention also provides compounds, derivatives, salts or compositions thereof for the treatment of obesity or diabetes.

[0161] This invention also provides compounds, derivatives, salts, or compositions of this invention for increasing energy expenditure in subjects, improving insulin release in subjects, improving glucose tolerance in subjects, and / or improving carbohydrate metabolism in subjects. Such use may relate to treating subjects with a prediabetic state (e.g., poor insulin sensitivity) or prediabetes.

[0162] The present invention also provides compounds, derivatives, salts, or compositions thereof for use in reducing appetite in subjects, reducing food intake in subjects, reducing calorie intake in subjects, improving insulin release in subjects, and / or improving glucose tolerance in subjects. Such use may relate to treating subjects with a prediabetic state (e.g., poor insulin sensitivity) or prediabetes.

[0163] The present invention also provides compounds, derivatives, salts, or compositions of the invention for use as cytoprotective agents (e.g., for treating or preventing neurodegeneration, providing neuroprotection, and / or providing cardioprotection). For example, said compounds, derivatives, salts, or compositions can be used for cardioprotection in subjects following myocardial infarction, or for neuroprotection in subjects following cerebral ischemia or stroke, or for neuroprotection in subjects with chronic neurodegenerative diseases. Various features of the neuroprotective or cardioprotective uses of said compounds, derivatives, salts, or compositions can be summarized above regarding the methods of the present invention.

[0164] In cases of neuroprotection, the subject may have previously experienced brain injury, stroke, or other events leading to cerebral ischemia. Alternatively, the subject may have a chronic neurodegenerative disease or be diagnosed with a predisposition to chronic neurodegenerative disease. In cases of cardioprotection, the subject may have previously experienced events causing myocardial ischemia, such as myocardial infarction and angina. According to some embodiments, the compounds, derivatives, salts, or compositions of the present invention may be administered as soon as possible after a subject has experienced a suspected myocardial infarction. According to some embodiments, the compounds, derivatives, salts, or compositions of the present invention may be administered as soon as possible after a subject has experienced a suspected stroke.

[0165] The present invention also provides the use of the compounds, derivatives, salts or compositions of the present invention for the manufacture of a medicament for treating obesity or diabetes in a subject, the subject of which may be as described above with respect to other aspects of the invention.

[0166] The present invention also provides the use of the compounds, derivatives, or salts of the invention in the manufacture of medicaments for improving insulin release, improving glucose tolerance, and / or improving carbohydrate metabolism in subjects. Such use may relate to treating subjects with a prediabetic state (e.g., poor insulin sensitivity) or prediabetes.

[0167] The present invention also provides the use of the compounds, derivatives or salts of the present invention for manufacturing drugs for reducing appetite in subjects, reducing food intake in subjects, reducing calorie intake in subjects, improving insulin release in subjects and / or improving glucose tolerance in subjects.

[0168] The present invention also provides the use of the compounds, derivatives or salts of the invention for the manufacture of medicaments for providing cellular protection to a subject (e.g., prevention or treatment of neurodegeneration, providing neuroprotection and / or providing cardioprotection), the subject being as described above with respect to other aspects of the invention.

[0169] According to some embodiments, the compounds, derivatives, salts, or compositions of the present invention are administered parenterally. According to other embodiments, the compounds, derivatives, salts, or compositions of the present invention are administered subcutaneously, intravenously, intramuscularly, intranasally, transdermally, or sublingually. According to other embodiments, the compounds, derivatives, salts, or compositions of the present invention are administered orally. In a preferred embodiment, the compounds, derivatives, salts, or compositions of the present invention are administered subcutaneously.

[0170] The compounds, derivatives, salts, or compositions of the present invention are preferably used to treat human subjects. However, although the compounds, derivatives, salts, or compositions of the present invention are generally used to treat human subjects, they may also be used to treat similar or identical diseases in other vertebrates, such as other primates; farm animals, such as pigs, cattle, and poultry; locomotion animals, such as horses; or companion animals, such as dogs and cats.

[0171] Composition Preferably, the pharmaceutical formulation or composition contains a compound of formula (I) or a derivative thereof and / or a salt thereof. Accordingly, the present invention provides compositions comprising the compounds, derivatives or salts of the present invention with pharmaceutically acceptable excipients and optionally another therapeutic ingredient. Compositions comprising said compounds, derivatives or salts are suitable for pharmaceutical use. According to certain preferred embodiments, the composition is present in a syringe or other administration device for subcutaneous administration to humans. According to certain preferred embodiments, the pH of the composition is 3.0-8.0. The compositions of the present invention can be in the form of pharmaceutical formulations as described below.

[0172] Pharmaceutical formulations according to the invention include those suitable for oral, parenteral (including subcutaneous, intradermal, intramuscular, intravenous, and intra-articular), inhalation (including particulate powders or mists that can be produced by means of various types of metered-dose pressurized aerosols, nebulizers, or blowers), rectal, and topical (including dermal, transdermal, transmucosal, oral, sublingual, and intraocular) administration, but the most suitable route may depend, for example, on the recipient's disease and condition.

[0173] Formulations can be conveniently present in unit dosage forms and can be prepared by any method well known in the pharmaceutical field. All methods involve the step of combining the active ingredient with a carrier constituting one or more auxiliary ingredients. Generally, formulations are prepared by uniformly and closely mixing the active ingredient with a liquid carrier or a finely powdered solid carrier, or both, and then, if necessary, shaping the product into the desired formulation.

[0174] Formulations of the present invention suitable for oral administration may be presented in the following forms: discrete units, such as capsules, caches, or tablets, each containing a predetermined amount of the active ingredient; powders or granules; solutions or suspensions in aqueous or non-aqueous liquids; or oil-in-water or water-in-oil liquid emulsions. The active ingredient may also be present in the form of bolus, electuary, or paste. Various pharmaceutically acceptable carriers and their formulations are described in standard formulation monographs, for example, Remington's Pharmaceutical Sciences EW Martin. See also Wang, YJ, and Hanson, MA. Journal of Parenteral Science and Technology Technical Report, Vol. 10, Supplement 42:2S, 1988. The contents of the cited document are incorporated herein by reference.

[0175] Tablets can be prepared by compression or molding, optionally with one or more excipients. Compressed tablets can be prepared by pressurizing an active ingredient (e.g., powder or granules) in free-flowing form in a suitable machine, optionally mixed with a binder, lubricant, inert diluent, surfactant, or dispersant. Molded tablets can be prepared by molding a mixture of powdered compounds wetted with an inert liquid diluent using a die in a suitable machine. Tablets can optionally be coated or scored and can be formulated to allow for slow or controlled release of the active ingredient. The compounds of the present invention can be administered, for example, in a form suitable for immediate or prolonged release. Immediate or prolonged release can be achieved by using a suitable pharmaceutical composition comprising the compounds of the present invention, or, particularly in the case of prolonged release, by using a device such as a subcutaneous implant or an osmotic pump. The compounds of the present invention can also be administered via liposomes.

[0176] Preferably, the compositions according to the invention are suitable for subcutaneous administration, for example by injection. According to some embodiments, the compositions may contain metal ions, such as copper, iron, aluminum, zinc, nickel, or cobalt ions. The presence of such ions may limit solubility, thereby delaying the time it takes for the contents to be absorbed from the subcutaneous application site into the circulatory system.

[0177] Exemplary compositions for oral administration include suspensions that may contain, for example, microcrystalline cellulose for volume impartation, alginate or sodium alginate as a suspending agent, methylcellulose as a viscosity enhancer, and sweeteners or flavoring agents (e.g., those known in the art); and immediately released tablets that may contain, for example, microcrystalline cellulose, dicalcium phosphate, starch, magnesium stearate and / or lactose and / or other excipients, binders, expanders, disintegrants, diluents, and lubricants (e.g., those known in the art). Such compositions may also contain penetration enhancers. The compounds of the present invention may also be delivered orally via sublingual and / or buccal administration. Molded tablets, compressed tablets, or lyophilized tablets are exemplary forms that may be used. Exemplary compositions include those formulated using rapidly dissolving diluents such as mannitol, lactose, sucrose, and / or cyclodextrin. Such formulations may also contain high molecular weight excipients such as cellulose (avicel) or polyethylene glycol (PEG). Such formulations may also contain excipients that promote mucosal adhesion, such as hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), sodium carboxymethyl cellulose (SCMC), maleic anhydride copolymers (e.g., Gantrez), and release-controlled agents such as polyacrylic acid copolymers (e.g., Carbopol 934). Lubricants, flow aids, flavoring agents, colorants, and stabilizers may also be added for ease of manufacture and use.

[0178] Formulations for parenteral administration include aqueous and non-aqueous sterile injectable solutions that may contain antioxidants, buffers, antibacterial agents, and solutes that make the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions that may contain suspending agents and thickeners. Formulations may be presented in single-dose or multi-dose containers, such as sealed ampoules and vials, and may be stored under lyophilized (freeze-dried) conditions, requiring only the addition of a sterile liquid carrier, such as saline or water for injection, just before use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules, and tablets of the aforementioned types. Exemplary compositions for parenteral administration include injectable solutions or suspensions that may contain, for example, suitable non-toxic, parenteral-acceptable diluents or solvents, such as mannitol, 1,3-butanediol, water, Ringer's solution, isotonic sodium chloride solution, or other suitable dispersants or wetting agents and suspending agents, containing synthetic monoglycerides or diglycerides, and fatty acids, including oleic acid, or cremaphores. The aqueous carrier may be, for example, an isotonic buffer solution with a pH of about 3.0 to about 8.0, preferably a pH of about 3.5 to about 7.4, for example 3.5 to 6.0, or for example 3.5 to about 5.0. Useful buffers include sodium citrate-citric acid and sodium phosphate-phosphate, as well as sodium acetate / acetic acid buffers. The composition preferably does not contain any compounds known to be harmful to peptide compounds.

[0179] It may contain excipients, such as other proteins, such as human serum albumin or plasma preparations. Where necessary, the pharmaceutical composition may also contain small amounts of non-toxic excipients, such as wetting agents or emulsifiers, preservatives, and pH buffers, such as sodium acetate or sorbitol monolaurate.

[0180] Exemplary compositions for nasal aerosol or inhalation administration comprise an aqueous saline solution, which may contain, for example, benzyl alcohol or other suitable preservatives, absorption enhancers to improve bioavailability, and / or other solubilizers or dispersants, such as those known in the art. In compositions for nasal aerosol or inhalation administration, the compounds of the present invention are conveniently delivered from a pressurized container or nebulizer in the form of an aerosol spray using a suitable propellant, such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide, or other suitable gases. In the case of pressurized aerosols, the dosage unit can be determined by providing a valve to deliver a metered amount. Capsules and cartridges for inhalers or blowpipes, such as gelatin, may be formulated as powder mixtures containing the compound and a suitable powder matrix (e.g., lactose or starch). In a specific, non-limiting embodiment, the compounds of the present invention are administered from a metering valve in aerosol form via an aerosol adapter (also referred to as an actuator). Optionally, it also includes a stabilizer and / or porous particles for deep lung delivery (see, for example, U.S. Patent No. 6,447,743).

[0181] Formulations intended for rectal administration may be provided in the form of enemas or suppositories containing common carriers such as cocoa butter, synthetic glycerides, or polyethylene glycol. These carriers are typically solid at room temperature but liquefy and / or dissolve in the rectal lumen to release the drug.

[0182] Formulations for topical application in the oral cavity (e.g., via the buccal or sublingual route) include tablets containing an active ingredient in a flavoring base (e.g., sucrose and gum arabic or tragacanth); and pellets containing an active ingredient in a base (e.g., gelatin and glycerin or sucrose and gum arabic). Exemplary compositions for topical application include a local carrier, such as a resin matrix (mineral oil gelled with polyethylene).

[0183] Preferred unit-dose formulations are those containing the active ingredient at the effective dose or a suitable portion thereof as described above.

[0184] It should be understood that, in addition to the ingredients specifically mentioned above, the formulations of the present invention may include other agents conventional in the art, taking into account the types of formulations discussed, such as flavoring agents, in formulations suitable for oral administration.

[0185] The compounds, derivatives, and salts of the present invention can also be suitably administered as sustained-release systems. Suitable examples of sustained-release systems of the present invention include suitable polymeric materials, such as semi-permeable polymer matrices in the form of molded articles, such as films or microcapsules; suitable hydrophobic materials, such as emulsions in acceptable oils; or ion exchange resins; and slightly soluble derivatives of the compounds of the present invention, such as slightly soluble salts. Sustained-release systems can be administered orally, rectally, parenterally, intracerebrospinally, intravaginally, topically (e.g., as powders, ointments, gels, drops, or transdermal patches), buccally, or as oral or nasal sprays.

[0186] Formulations for administration can be suitably formulated to provide controlled release of the compounds, derivatives, and salts of the present invention. For example, pharmaceutical compositions may be in particulate form and may comprise one or more of a biodegradable polymer, a polysaccharide gel and / or a bioadhesive polymer, an amphiphilic polymer, or an agent capable of altering the interfacial properties of the particles of the compounds of the present invention. These compositions exhibit specific biocompatibility characteristics that allow for controlled release of the active substance, see U.S. Patent No. 5,700,486, the contents of which are incorporated herein by reference.

[0187] The controlled-release composition is preferably used for indications such as treating obesity and / or diabetes, where the time between injections needs to be maximized. However, for indications such as providing neuroprotection or cardioprotection (e.g., after suspected myocardial infarction or stroke), where therapeutic plasma concentrations of the active agent need to be achieved within the shortest possible time, an immediate-release formulation would be preferred. In such cases, a dosing regimen comprising an immediate-release formulation administered with one dose of the active agent (i.e., as soon as possible after suspected myocardial infarction or stroke) followed by a controlled-release formulation administered with one dose of the active agent may be preferred.

[0188] The compounds, derivatives, or salts of this invention can be delivered by a pump (see Langer, ibid.; Sefton, ...). CRC Crit. Ref. Biomed. Eng 14:201, 1987; Buchwald et al., Surgery 88:507, 1980; Saudek et al., N. Engl. J. Med. 321:574, 1989) or by continuous subcutaneous infusion, for example using a microinfusion pump. Intravenous bag solutions may also be used. The key factor in selecting an appropriate dose is the outcome obtained, measured by a decrease in total body weight or fat-to-lean mass ratio, or by other criteria used to measure control or prevention of obesity or obesity-related disorders, as deemed appropriate by a professional. Langer's review ( ScienceOther controlled release systems are discussed in U.S. Patent Nos. 249:1527-1533 (1990), which are incorporated herein by reference. In another aspect of this disclosure, the compounds of the invention are delivered via implantation pumps, as described, for example, in U.S. Patent Nos. 6,436,091, 5,939,380, and 5,993,414, the contents of which are incorporated herein by reference.

[0189] Implantable drug infusion devices are used to provide patients with a stable and long-term dose or infusion of a drug or any other therapeutic agent. Essentially, such devices can be classified as active or passive. The compounds, derivatives, or salts of the present invention can be formulated as reservoir-type formulations. Such long-acting reservoir-type formulations can be administered via implantation, such as subcutaneously or intramuscularly; or by intramuscular injection. Thus, for example, the active ingredient can be formulated with suitable polymeric or hydrophobic materials, such as as an emulsion in an acceptable oil; or as an ion exchange resin; or as a slightly soluble derivative, such as a slightly soluble salt.

[0190] A therapeutically effective amount of the active agent of the present invention can be administered as a single pulse dose, as a bolus dose, or as a pulse dose administered over time. Thus, in a pulse dose, a bolus administration of the active agent is provided, followed by a period without administration of the active agent to the subject, and then a second bolus administration. In specific, non-limiting embodiments, the pulse dose is administered over a day, over a week, or over a month.

[0191] Combination therapy In some embodiments, a therapeutically effective amount of the compound, derivative, salt, or composition of the present invention is administered together with a therapeutically effective amount of another or more pharmaceutical agents. The compound, derivative, or salt may be administered, for example, simultaneously with one or more other therapeutic agents, or it may be administered sequentially or alone. Accordingly, the present invention provides compounds, derivatives, or salts of the present invention for use as pharmaceuticals, wherein the compound, derivative, or salt is used together with a therapeutically effective amount of another or more therapeutic agents (e.g., for simultaneous, sequential, or alone administration). In some embodiments, the active agent of the present invention is formulated together with another or more therapeutic agents and administered as a single dose.

[0192] In some implementations, the additional therapeutic agent or multiple therapeutic agents are additional antidiabetic agents, appetite suppressants, food intake reduction agents, plasma glucose lowering agents, or plasma lipid modifiers. Specific, non-limiting examples of additional appetite suppressants include amphetamine (diethylamine benzophenone), phentermine, masindole and phenylpropanolamine, fluamphenicol, dexfenfluramine, phendimetrazine, benzphenamine, sibutramine, rimonabant, topiramate, fluoxetine, amphetamine, zonisamide, naltrexone, orlistat, and cetirizine. Specific, non-limiting examples of additional antidiabetic agents include metformin, phenformin, rosiglitazone, pioglitazone, troglitazone, repaglinide, nateglinide, tolbutamide, acesulfame potassium, tolazoline, chlorpropamide, glipizide, glibenclamide, glimepiride, gliclazide, fibroblast growth factor 21, miglitol, acarbose, exenatide, pramlintide, vildagliptin, and sitagliptin.

[0193] In one preferred embodiment, the other therapeutic agent or agents are GLP-1 receptor agonists. In another preferred embodiment, the other therapeutic agent or agents are amylin receptor agonists. In yet another preferred embodiment, the other therapeutic agent or agents are glucagon receptor agonists.

[0194] In one alternative embodiment, the additional therapeutic agent is a GLP-1 receptor agonist and an amylin receptor agonist. In another alternative embodiment, the additional therapeutic agent is a GLP-1 receptor agonist and a glucagon receptor agonist. In yet another alternative embodiment, the additional therapeutic agent is an amylin receptor agonist and a glucagon receptor agonist.

[0195] In another alternative implementation, the additional therapeutic agents are GLP-1 receptor agonists, amylin receptor agonists, and glucagon receptor agonists.

[0196] In an alternative implementation, another therapeutic agent or multiple therapeutic agents are additional cardioprotective or neuroprotective agents. Specific, non-limiting examples of additional cardioprotective agents include aspirin, N-acetylcysteine, phenethylamine, coenzyme Q10, vitamin E, vitamin C, L-carnitine, carvedilol, and dexrazoxane. Specific, non-limiting examples of neuroprotective agents include statins (e.g., simvastatin), steroids (e.g., progesterone), minocycline, resveratrol, and vitamin E. Examples of agents used to treat Parkinson's disease include anticholinergics, pramipexole, bromocriptine, levodopa, carbidopa, rasagiline, amantadine, and ropinirole.

[0197] dose The compounds, derivatives, salts, or compositions of the present invention may be applied whenever an effect such as appetite suppression, reduction of food intake, or reduction of calorie intake is required, or may be applied slightly earlier than when said effect is required, for example, but not limited to about 10 minutes, about 15 minutes, about 30 minutes, about 60 minutes, about 90 minutes, or about 120 minutes before the time when said effect is required.

[0198] The therapeutically effective amount of the active agent of the present invention will depend on the molecule used, the subject being treated, the severity and type of the ailment, and the manner and route of administration. For example, the therapeutically effective amount of the compound of the present invention may vary from about 0.01 μg per kilogram of body weight to about 1 g per kilogram of body weight, for example, from about 0.1 μg to about 20 mg per kilogram of body weight, for example, from about 1 μg to about 5 mg per kilogram of body weight, or from about 5 μg to about 1 mg per kilogram of body weight.

[0199] In one embodiment of the invention, the compound, derivative, or salt of the invention may be administered to the subject at a dose of 0.5 to 1,333 nmol per kilogram of body weight, for example, 1 to 1,333 nmol / kg body weight, for example, 2 to 1,000 nmol per kilogram of body weight, for example, 4 to 1,333 nmol per kilogram of body weight, for example, 5 to 1,000 nmol per kilogram of body weight, for example, 10 to 750 nmol per kilogram of body weight, for example, 20 to 500 nmol per kilogram of body weight, and particularly 30 to 240 nmol per kilogram of body weight. In a preferred embodiment, the highly active compound of the invention is administered to the subject at a dose of 0.2 to 10 nmol per kilogram of body weight, for example, 0.5 to 5.0 nmol / kg body weight, for example, 1.0 to 2.0 nmol per kilogram of body weight, for example, 1.5 nmol per kilogram of body weight. For a 75 kg subject, such a dose corresponds to 37.5 nmol to 100 μmol, for example 75 nmol to 100 μmol, for example 150 nmol to 100 μmol, for example 300 nmol to 100 μmol, for example 375 nmol to 75 μmol, for example 750 nmol to 56.25 μmol, for example 1.5 to 37.5 μmol, and particularly 2.25 to 18 μmol. In a preferred embodiment of the highly active compound of the invention, for a 75 kg subject, such a dose corresponds to 15 to 750 nmol, for example 37.5 to 375.0 nmol, for example 75 to 150 nmol, for example 112.5 nmol. The invention also covers the dose range defined by any particular dose mentioned herein.

[0200] Those skilled in the art can easily determine the exact dosage based on the potency of the specific compound used, the route of delivery of the compound, and the age, weight, sex, and physiological condition of the subject.

[0201] For compounds with a long blood half-life, the above-mentioned doses may be administered, for example, once or twice a month, or once, twice, three or four times a week. For preferred compounds, the frequency of administration may not exceed once a week. Alternatively, for compounds with a short blood half-life, the above-mentioned doses may be administered, for example, once, twice, three or four times a day, or once or twice a week. In some embodiments, the dose may be administered every 2, 3 or 4 days. According to some embodiments, it may be administered once shortly before each meal.

[0202] Example The invention is further described with reference to the following non-limiting embodiments.

[0203] Materials and methods peptide synthesis Peptide synthesis was performed on a tricyclic amide linker resin. Amino acids were linked using the Fmoc strategy. For moieties Xaa1 through Xaa34, each amino acid was added sequentially from the C-terminus to the N-terminus. Peptide coupling was mediated using a reagent such as HBTU. Trifluoroacetic acid was used to cleave the peptide from the resin in the presence of a scavenger. In the second stage, the lysine residue to be substituted was functionalized at its ε-amino group after deprotection of the ε-amino group. The chain on the substituted lysine residue was then sequentially constructed using the same amino acid linker chemistry.

[0204] Peptides were purified by reversed-phase HPLC. All purified peptides underwent quality control and were detected by HPLC in two buffer systems; in most cases, the purity of the peptides exceeded 90%. MALDI-MS revealed the expected molecular ions.

[0205] Example Synthesis Compound 2 (GIP B) of Example was prepared using standard Fmoc chemistry as follows: 1. Resin Preparation: Fmoc-Lys(Dde)-OH (35 mmol, 1.00 eq.) and DIEA (140 mmol, 4.00 eq.) in DCM (500 mL) were added to 70 g of 1-chloro-2-[chloro(diphenyl)methyl]benzene (substitute: 0.50 mmol / g). The mixture was stirred at 20 °C in the presence of N2 for 2 hours, then MeOH (70.0 mL) was added and stirred again in the presence of N2 for 30 minutes. The resin was washed with DMF (800.0 mL x 5).

[0206] 2. Deprotection: Add 20% piperidine to DMF (800.0 mL) and stir the resin at 25°C in the presence of N2 for 25 minutes. Wash the resin with DMF (800.0 mL x 5) and filter the mixture to obtain the resin.

[0207] 3. Coupling: A solution of HATU (2.85 eq.) and Fmoc-Lys(Boc)-OH (3.00 eq.) in DMF (600.0 mL) was added to the resin, followed by DIEA (6.00 eq). The mixture was stirred at 25 °C in the presence of N2 for 30 minutes. The resin was washed with DMF (800.0 mL x 5).

[0208] 4. Repeat steps 2 and 3 using the reagents in Table 1 to couple the following amino acids (3-33): Table 1:

[0209] 5. Add 3% N2H4 H2O / DMF (800.0 mL) was added to the resin and allowed to react for 30 minutes. The reaction was repeated, and the mixture was drained and washed 5 times with DMF (800.0 mL).

[0210] 6. Repeat steps 2 and 3 using the reagents in Table 2 to couple the remaining amino acids (34-36): Table 2:

[0211] Group 33 in Table 1 is Figure 1 and residue Xaa34 in the structural definition of the claims. Groups 34-36 are Figure 1 And residues Xaa47 and Z in the structural definition of the claims.

[0212] Because the C-1 acid group of the protected glutamic acid reagent 35 is protected by tBu, its C-5 acid reacts with lysine 34. When Z is (i): , The Fmoc-Glu-OtBu reagent provides the glutamic acid residue moiety in the Z portion of the compound.

[0213] Peptide cleavage and purification: 7. Wash the resin with MeOH (800.0 mL x 3) and dry under vacuum. Then add the lysis solution (2.6 L, 91% TFA / 3% TIS / 3% H2O / 3% 3-mercaptopropionic acid) to the flask containing the resin at room temperature and stir the mixture for 2 hours.

[0214] 8. Precipitate the peptide with cold isopropyl ether (13.0 L), filter and collect as a filter cake. Wash the filter cake with isopropyl ether (3 L x 2). Dry the crude peptide under vacuum for 4 hours to obtain crude peptide (80 g), and confirm the identity of the crude peptide by LCMS (LCMS monitoring -1, Rt = 1.700 min).

[0215] 9. The crude peptide was purified by preparative HPLC (TFA conditions: A: 0.075% TFA in H2O, B: ACN) and preparative HPLC (HOAc conditions: A: 0.5% HOAc in H2O, B: ACN) to obtain the title compound (10.58 g, 2.36 mmol, yield 6.75%, purity 95.64%, HOAc) as a white solid. The identity of the title compound was confirmed by LCMS (MH00500-2-P1-P1C, Rt = 1.115 min) and HPLC (MH00500-2-P1-P1B, Rt = 10.803 min, purity 95.64%).

[0216] All other peptides described herein are treated using an equivalent method. The sequences and other structural features of exemplary peptides are as follows: Figure 1 and Figure 2 As shown in the attached figure. Lys The ε-amino group of the residue is replaced by the group Z–Xaa44–Xaa45–Xaa46–Xaa47– (blanks in the columns discussed indicate the absence of the residue), and Z is a group having the following structure: (i): , Where R is C8-C 28 alkylene or alkenylene chains; and R1 is CO2H.

[0217] The number of carbon atoms (n, n=8-28) of the alkylene or alkenylene group of R is shown in Figure 1 The column is titled "n (R = Cn)". In the illustrated embodiment, n is 18.

[0218] In vivo efficacy study: Single-dose feeding study in male rats Male mice (Charles River Ltd, Margate, UK) were used for animal testing. Mice housed individually in IVC cages were randomly assigned to treatment groups and stratified by body weight. Mice were fasted overnight prior to injection. All peptide solutions were freshly prepared just before administration. Control animals were administered 5% v / v water and 95% NaCl (0.9% w / v). Treatment groups received a single subcutaneous injection of 10–45 nmol / kg body weight of a GIP analogue and 1–1.5 nmol / kg body weight of the GLP-1r agonist G7097, prepared in water for injection. Body weight was measured in grams (g) at the time of injection (early light; 0900–1000) and each mouse was refeeded with a known amount of food. Remaining food and body weight were then measured 72 hours after administration. Animals had free access to water during the study period.

[0219] The results of compounds 1 to 3 in Examples and compounds 1 to 3 in Comparative Examples are as follows: Figure 1 and Figure 2 As shown. Mice were fasted overnight and administered the drug early in the light exposure period, followed by a known amount of food. Mice were given a single subcutaneous injection of a combination of a subtherapeutic dose of the GLP-1r agonist G7097 (0.5–1 nmol / kg) and the compound of the example (4.5–30 nmol / kg). Figure 1 and Figure 2 In the table, column "n" indicates the number of tests conducted on the compound in question. Each test typically involved administering the compound to a group of five animals. The compound was assessed for its tendency to suppress food intake and its ability to induce changes in body weight. Figure 1 and Figure 2 In this study, the sum of its effects is reported as a single numerical value, called "x," representing efficacy. To score "efficacy," the difference in average food intake (in grams) (compared to the carrier control) is measured at at least two time points: 24, 48, and 72 hours after administration, and the difference in average body weight (in grams) (compared to the carrier control) is measured at at least two time points: 24, 48, and 72 hours after administration. The two values ​​are then multiplied. The higher the number, the more effective the analogue.

[0220] result Figure 1 and Figure 2 This is a table providing the amino acid sequences and other structural information of the compound examples and comparative compound of the present invention. For example, the amino acid sequence of compound No. 1 (GIP A) is as follows [SEQ ID NO: 10]:

[0221] And in position 34 Lys The ε-amino group of the residue carries a group. Z–Lys– Where Z is a group in the following formula:

[0222] Where R is C 18 Straight-chain alkylene; and R1 is CO2H.

[0223] The accompanying drawings also summarize the results of in vivo feeding efficacy studies of the peptides and comparative compounds of the present invention as discussed above.

[0224] As can be seen from the attached figures, compared to mice administered G7097 alone or vector control animals, mice that were fasted overnight and administered a combination of the peptide of the present invention and the GLP-1r agonist G7097 achieved reduced weight gain or weight loss.

[0225] Furthermore, Example 2 (GIP B) has the following structure [SEQ ID NO: 11]:

[0226] And in position 34 Lys The ε-amino group of the residue carries a group: Z–Lys– Where Z is a group in the following formula:

[0227] Where R is C 18 Straight-chain alkylene; and R1 is CO2H.

[0228] like Figure 2 The feeding study results showed that replacing the Ile residue at position 12 with a Lys residue improved the potency score X from 8.3 to 12.0. These results indicate that the resulting compound is particularly effective in reducing weight gain or achieving weight loss when the amino acid residue at position 12 is lysine (Lys).

[0229] The above results support the fact that the compounds of the present invention are particularly effective in improving metabolism and can be used to treat conditions such as obesity.

[0230] In the foregoing description, references to elements or components having known, obvious, or foreseeable equivalents are incorporated herein as if described separately. The true scope of the invention should be determined with reference to the claims, which should be interpreted as covering any such equivalents. The reader should also understand that elements or features of the invention described as preferred, advantageous, convenient, etc., are optional and do not limit the scope of the independent claims. Furthermore, it should be understood that such optional elements or features, while potentially beneficial in some embodiments of the invention, may be undesirable in other embodiments and therefore may not be present.

Claims

1. A compound with the following formula: Xaa1 – Xaa2 – Xaa3 – Gly4 – Thr5 – Phe6 – al23–Xaa24–Xaa25–Leu26–Xaa27–Xaa28–Xaa29–Xaa30–Xaa31–Xaa32–Xaa 33–Xaa34–Xaa35–Xaa36–Xaa37–Xaa38–Xaa39–Xaa40–Xaa41–Xaa42–Xaa43 [SEQ ID NO:1] in: Xaa1 is DTyr, His, Phe, or Tyr, or does not exist; Xaa2 is either AIB or Ala, or it does not exist; Xaa3 can be Asp, Gln, Glu, or His; Xaa7 is Ile, Thr, or Ser; Xaa10 is either Tyr or His; Xaa12 is Lys; Xaa13 is AIB, Ala, Gln, Glu, Gly, His, Pro, Ser, Thr, Tyr, Val, Asp, or Asn; Xaa14 is Leu, Met, or NLeu; Xaa17 is either Gln or Ile; Xaa18 can be Ala, Arg, or His; Xaa19 is either Ala or Gln; Xaa20 is AIB, Gln, His, or Lys; Xaa21 is Ala, Asp, or Glu; Xaa24 is either Asn, Gln, or Glu; Xaa25 is Arg, His, Trp, or Tyr; Xaa27 is either Ile or Leu; Xaa28 is either Ala or Asn; Xaa29 is Gln, Gly, or Thr; Xaa30 is Gly, Lys, or Lys Or it may not exist; Xaa31 is Arg, Gly, or Pro, or it does not exist; Xaa32 is Asn, Lys, or Lys Or it may not exist; Xaa33 represents Lys or Lys Or it may not exist; Xaa34 represents Asn or Lys Or it may not exist; Xaa35 is either an Asp or does not exist; Xaa36 is either Trp or Lys Or it may not exist; Xaa37 is Lys or Lys Or it may not exist; Xaa38 is His or does not exist; Xaa39 is either Asn or Lys Or it may not exist; Xaa40 is for Ile, Leu, or Lys Or it may not exist; Xaa41 is Thr, or it does not exist; Xaa42 is Gln, or it does not exist; Xaa43 is Lys Or it may not exist; Lys Lys with the ε-amino group substituted by the following group: Z–Xaa44–Xaa45–Xaa46–Xaa47– in: Xaa44 is Gly, Ser, Thr or does not exist; Xaa45 is Gly, Ser, or does not exist; Xaa46 is Asn, Gln, Gly, Ser, Thr or does not exist; Xaa47 is Asn, Gln, Glu, Gly, His, Lys, Pro, Ser, Thr or does not exist; And Z is a group of the following formula: (i): or (ii): , Where R is C8-C 28 An alkylene or alkenylene chain and R1 is –CO2H; And the compound said compound contains a Lys residues; Or a derivative of the compound; or a salt or solvation of the compound or its derivative.

2. The compound, derivative, salt, or solvate of claim 1, wherein the compound is a compound of formula (II): in W represents the amino acid sequence: Xaa1–Xaa2–Xaa3–Gly4–Thr5–Phe6–Xaa7–Ser8–Asp9–Xaa10–Ser11–Xaa12–Xaa13–Xaa14–Asp15–L ys16–Xaa17–Xaa18–Xaa19–Xaa20–Xaa21–Phe22–Val23–Xaa24–Xaa25–Leu26–Xaa27–Xaa28–Xaa29– [SEQ ID NO: 7] in: Xaa1 is DTyr, His, Phe, or Tyr, or does not exist; Xaa2 is either AIB or Ala, or it does not exist; Xaa3 can be Asp, Gln, Glu, or His; Xaa7 is Ile, Thr, or Ser; Xaa10 is either Tyr or His; Xaa12 is Lys; Xaa13 is AIB, Ala, Gln, Glu, Gly, His, Pro, Ser, Thr, Tyr, Val, Asp, or Asn; Xaa14 is Leu, Met, or NLeu; Xaa17 is either Gln or Ile; Xaa18 can be Ala, Arg, or His; Xaa19 is either Ala or Gln; Xaa20 is AIB, Gln, His, or Lys; Xaa21 is Ala, Asp, or Glu; Xaa24 is either Asn, Gln, or Glu; Xaa25 is Arg, His, Trp, or Tyr; Xaa27 is either Ile or Leu; Xaa28 is either Ala or Asn; and Xaa29 is Gln, Gly, or Thr; Y represents the amino acid sequence: –Xaa30–Xaa31–Xaa32–Xaa33–Xaa34 in: Xaa30 is either Gly or Lys, or it does not exist; Xaa31 is Arg, Gly, or Pro, or it does not exist; Xaa32 is either Asn or Lys, or it does not exist; Xaa33 represents Lys, Lys Or it may not exist; and Xaa34 is Lys Or it may not exist; Lys Lys with the ε-amino group substituted by the following group: Z–Xaa44–Xaa45–Xaa46–Xaa47– in: Xaa44 is Gly, Ser, or Thr, or does not exist; Xaa45 is either Gly or Ser, or it does not exist; Xaa46 is Asn, Gln, Gly, Ser, or Thr, or does not exist; Xaa47 is Asn, Gln, Glu, Gly, His, Lys, Pro, Ser, or Thr, or does not exist; And Z is a group of the following formula: (i): Or (ii): , Where R is C8-C 28 An alkylene or alkenylene chain and R1 is –CO2H; Furthermore, the compound of formula (I) or formula (II) contains a Lys residues; Or a derivative of the compound; or a salt or solvation of the compound or its derivative.

3. The compound, derivative, salt, or solvate of claim 2, wherein: Xaa1 is His, Phe, or Tyr; Xaa2 is AIB; Xaa3 is Gln, Glu, or His; Xaa7 is either Ile or Ser; Xaa10 is either Tyr or His; Xaa12 is Lys; Xaa13 is Ala, Gln, Thr, Val, Asp, or Asn; Xaa14 is either Leu or Met; Xaa17 is either Gln or Ile; Xaa18 is either Ala or His; Xaa19 is either Ala or Gln; Xaa20 is AIB, Gln, His, or Lys; Xaa21 is either Asp or Glu; Xaa24 is either Asn, Gln, or Glu; Xaa25 is a Trp; Xaa27 is Leu; Xaa28 is either Ala or Asn; and Xaa29 can be Gln, Gly, or Thr.

4. The compound, derivative, salt, or solvate of claim 3, wherein: Xaa1 is Tyr; Xaa2 is AIB; Xaa3 is either Glu or Gln; Xaa7 is either Ile or Ser; Xaa10 is either Tyr or His; Xaa12 is Lys; Xaa13 can be Ala, Asp, or Asn; Xaa14 is Leu; Xaa17 is Ile; Xaa18 is His; Xaa19 is Gln; Xaa20 is either Gln or Lys; Xaa21 is an Asp; Xaa24 is either Asn or Gln; Xaa25 is a Trp; Xaa27 is Leu; Xaa28 is Ala; and Xaa29 is either Gln or Gly.

5. The compound, derivative, salt, or solvate of claim 4, wherein: Xaa3 is Glu; Xaa20 is Gln; Xaa24 is an Asn; and Xaa29 is Gln.

6. The compound, derivative, salt or solvate of any one of claims 2 to 5, wherein the compound is a compound of formula (II).

7. The compound, derivative, salt, or solvate of claim 6, wherein: Xaa30 is either Lys or Gly; Xaa31 is either Gly or Pro; Xaa32 is either Lys or does not exist; Xaa33 represents Lys, Lys Or it may not exist; and Xaa34 is Lys Or it may not exist.

8. The compound, derivative, salt, or solvate of claim 7, wherein: Xaa30 is either Lys or Gly; Xaa31 is either Gly or Pro; Xaa32 is either Lys or does not exist; Xaa33 does not exist; and Xaa34 is Lys .

9. The compound, derivative, salt, or solvate of claim 7, wherein: Xaa30 is Lys; Xaa31 is Gly; Xaa32 is either Lys or does not exist; Xaa33 represents Lys, Lys Or it may not exist; and Xaa34 is Lys Or it may not exist.

10. The compound, derivative, salt, or solvate of claim 2, wherein: Xaa1 is Tyr; Xaa2 is AIB; Xaa3 is Glu; Xaa7 is either Ile or Ser; Xaa10 is either Tyr or His; Xaa12 is Lys; Xaa13 is Asp, Asn, Ala, or Ser; Xaa14 is Leu; Xaa17 is Ile; Xaa18 is His; Xaa19 is Gln; Xaa20 is Gln; Xaa21 is an Asp; Xaa24 is an Asn; Xaa25 is a Trp; Xaa27 is Leu; Xaa28 is Ala; Xaa29 is Gln; Xaa30 is Lys; Xaa31 is Gly; Xaa32 is Lys; Xaa33 is either Lys or does not exist; and Xaa34 is Lys ; in Lys Lys with the ε-amino group substituted by the following group: Z–Xaa44–Xaa45–Xaa46–Xaa47– in: Xaa44 does not exist; Xaa45 does not exist; Xaa46 is either Asn or does not exist; and Xaa47 is either Lys or His; Z is (i): Where R is C 18 It has an alkylene chain and R1 is –CO2H.

11. The compound, derivative, salt, or solvate of claim 10, wherein: Xaa10 is Tyr; Xaa12 is Lys; Xaa13 is either Ala or Asp; Xaa33 does not exist; Xaa34 is Lys ; Xaa46 does not exist; and Xaa47 is Lys.

12. The compound, derivative, salt, or solvate of claim 1, having an amino acid sequence corresponding to any of the amino acid sequences listed in the table of FIG1.

13. A derivative of a compound as claimed in any one of claims 1 to 12, or a salt or solvation of such a derivative, said derivative comprising one or more derivatizations selected from amidation, glycosylation, carbamylation, acylation, sulfation, phosphorylation, cyclization, lipidation, polyethylene glycolation, and fusion with another peptide or protein to form a fusion protein.

14. The compound, derivative, salt or solvate of any one of claims 1 to 13, for simultaneous, sequential or single administration together with another therapeutic agent.

15. The compound, derivative, salt, or solvate of claim 14, wherein the other therapeutic agent is a GLP-1 receptor agonist or an amylin analogue.

16. A composition comprising any one of the compounds, derivatives, salts or solvates of claims 1 to 15, and a pharmaceutically acceptable carrier.

17. The composition of claim 16, wherein the composition is contained in a syringe or other application device for subcutaneous administration to a human.

18. The compound, derivative, salt or solvate of any one of claims 1 to 15, or the composition of claim 16 or claim 17, used as a pharmaceutical.

19. A method for treating or preventing a disease or condition or other undesirable physiological state in a subject, the method comprising administering a therapeutically effective amount of any one of the compounds, derivatives, salts or solvates of claims 1 to 15 or the composition of claim 16 or 17.

20. The compound, derivative, salt or solvate of any one of claims 1 to 15, or the composition of claim 16 or claim 17, for the prevention or treatment of diabetes, obesity, heart disease, stroke and non-alcoholic fatty liver disease, to improve insulin release in a subject, to improve carbohydrate metabolism in a subject, to improve lipid profile in a subject, to reduce appetite, to reduce food intake, to reduce calorie intake, to improve glucose tolerance in a subject, and / or as a cytoprotective agent.

21. The compound, derivative, salt, or solvate or composition used as a cell protectant as claimed in claim 20, wherein the compound, derivative, salt, or composition is used to prevent or treat neurodegeneration, provide neuroprotection, and / or provide cardiac protection.

22. The compound, derivative, salt, or solvate or composition used as a cell protectant as claimed in claim 21, wherein the compound, derivative, salt, or composition is used to provide cardiac protection in a subject after myocardial infarction.

23. The compound, derivative, salt, or solvate or composition used as a cell protectant as claimed in claim 22, wherein the compound, derivative, salt, or composition is used to provide neuroprotection in subjects suffering from or diagnosed as being at risk of chronic neurodegenerative diseases.

24. The compound, derivative, salt, or solvate or composition used as described in claim 23, wherein the chronic neurodegenerative disease is selected from the group consisting of: Alzheimer's disease, Parkinson's disease, Glickman's disease (amyotrophic lateral sclerosis), Huntington's disease, multiple sclerosis, other demyelinating diseases, Alzheimer's disease, subcortical dementia, arteriosclerotic dementia, AIDS-related dementia, other dementias, cerebellar vasculitis, epilepsy, Tourette syndrome, Guillain-Barré syndrome, Wilson's disease, Pick's disease, neuroinflammatory diseases, encephalitis, encephalomyelitis, meningitis, other central nervous system infections, prions, cerebellar ataxia, cerebellar degeneration, spinocerebellar degeneration syndrome, Friedrich's ataxia, ataxia-telangiectasia, spinal muscular dystrophy, progressive supranuclear palsy, dystonia, muscle spasm, tremor, retinitis pigmentosa, striatal nigra degeneration, mitochondrial encephalomyopathy, and neuronal ceroid lipofuscin deposition disease.

25. A method for treating or preventing diabetes, obesity, heart disease, stroke, or non-alcoholic fatty liver disease in a subject, improving insulin release in a subject, improving carbohydrate metabolism in a subject, improving lipid profile in a subject, improving glucose tolerance in a subject, reducing appetite, reducing food intake, reducing calorie intake, and / or providing cellular protection in a subject, said method comprising administering a therapeutically effective amount of any one of the compounds, derivatives, salts, or solvates of claims 1 to 15, or the composition of claim 16 or 17.

26. Use of the compound, derivative, salt or solvate of any one of claims 1 to 15 for the manufacture of a medicament for the prevention or treatment of diabetes, obesity, heart disease, stroke and non-alcoholic fatty liver disease, to improve insulin release in a subject, to improve carbohydrate metabolism in a subject, to improve lipid profile in a subject, to improve glucose tolerance in a subject, to reduce appetite, to reduce food intake, to reduce calorie intake, and / or as a cytoprotective agent.

27. A method for reducing weight or preventing weight gain in a subject for cosmetic purposes, the method comprising administering an effective amount of any one of the compounds, derivatives, salts or solvates of claims 1 to 15 or the composition of claim 16 or 17.

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