TW201529598A - Derivatives of GLP-1 like peptides, and uses thereof - Google Patents

Abstract

The invention relates to derivatives of GLP-1 like peptides which are C-terminally extended analogues of native GLP-1. The derivatives comprise two side chains, one at a position corresponding to position 42, and one at a position corresponding to position 18, 23, 27, 31, 36, or 38, wherein both positions are when compared to GLP-1(7-37). The side chains comprise a C19, C20, or C22 diacid protracting moiety and optionally a linker. The invention also relates to intermediate products in the form of novel GLP-1 analogues incorporated in the derivatives of the invention, as well as pharmaceutical compositions and medical uses of the derivatives. The derivatives have very long half-lives while maintaining a satisfactory potency, which makes them potentially suitable for once-monthly administration.

Description

Derivatives of GLP-1 peptides and uses thereof

The present invention relates to derivatives of the GLP-1 peptide, which may be defined as C-terminal extension analogs of the glycoside-like peptide 1 (GLP-1). The derivative is double-purified and one of the thiol side chains is attached to the C-terminal amino acid of the GLP-1 peptide-like peptide. The invention also relates to the pharmaceutical use of such derivatives.

[inclusion of the reference to the sequence listing]

The sequence listing entitled "SEQUENCE LISTING" is 6802 bits, which was created on June 16, 2014 and incorporated herein by reference.

WO 2009/030771 A1 and WO 2011/080102 disclose various mono-deuterated GLP-1 derivatives comprising some derivatives deuterated by C12-C20 fatty diacids.

WO 2012/140117 A1, WO 2012/062803 A1 and WO 2012/062804 A1 disclose various bismuthylated GLP-1 derivatives, including some derivatives which are deuterated by C12-C18 fatty diacids.

Liraglutide is a GLP-1 derivative that is administered once a day. It is sold under the trade name VICTOZA ^® by Novo Nordisk A/S.

Semaglutide is a GLP-1 derivative that is administered once a week. It is being developed by Novo Nordisk A/S. This compound is disclosed in Example 4 of WO 2006/097537.

The present invention relates to derivatives of GLP-1 peptides having the potential to be administered once a month.

In one aspect, the invention relates to a derivative of a diterpene-like GLP-1 peptide. One of the deuteration sites is at the C-terminus, more specifically, when compared to native GLP-1 (7-37) Should be at position number 42. Another deuteration site is within the GLP-1 peptide-like peptide, more specifically, at a position corresponding to position 18, 23, 27, 31, 36 or 38 in native GLP-1 (7-37) One place. Long-chain fatty diacids are used in both deuteration.

In a second aspect, the invention is directed to pharmaceutical compositions comprising such derivatives and pharmaceutically acceptable excipients, and to the medical use of such derivatives.

In a third aspect, the invention relates to an intermediate in the form of a novel GLP-1 analog which can be incorporated into a derivative of the invention. When compared to GLP-1 (7-37) (SEQ ID NO: 1), the analogs may comprise the following amino acid changes: i) (8Aib, 22E, 26R, 27K, 34R, 38G, 39G, 40G, 41S, 42K); ii) (8Aib, 22E, 26R, 31K, 34R, 38G, 39G, 40G, 41S, 42K); iii) (8Aib, 22E, 26R, 34R, 38K, 39G, 40G, 41S, 42K); iv (8Aib, 22E, 23K, 26R, 34R, 38G, 39G, 40G, 41S, 42K); v) (8Aib, 22E, 26R, 34R, 36K, 38G, 39G, 40G, 41S, 42K); Vi) (8Aib, 18K, 22E, 26R, 34R, 38G, 39G, 40G, 41S, 42K); vii) (7Imp, 8Aib, 22E, 26R, 34R, 38K, 39G, 40G, 41S, 42K); iix) (8Aib, 22E, 26R, 34R, 36K, 38A, 39E, 40S, 41P, 42K); ix) (8Aib, 22E, 26R, 34R, 36K, 38E, 39G, 40P, 41A, 42K); x) (8Aib , 22E, 26R, 34R, 36K, 38P, 39A, 40S, 41E, 42K); xi) (8Aib, 22E, 26R, 34R, 38K, 39P, 40E, 41G, 42K) (SEQ ID NO: 12); xii (8Aib, 22E, 26R, 34R, 38K, 39S, 40A, 41E, 42K); or xiii) (8Aib, 22E, 26R, 34R, 38K, 39S, 40P, 41E, 42K).

The amino acid sequence of native human GLP-1 (7-37) is included in the sequence listing as SEQ ID NO: 1 and the specific GLP-1 of SEQ ID NO 2-14 is a GLP-1 derivative of the invention. Things.

The derivatives of the present invention represent a significant leap in the search for GLP-1 derivatives with extremely long half-lives and still excellent performance.

In the following, Greek letters may be represented by their symbols or corresponding written names, for example: α = alpha; β = beta; ε = epsilon; γ = gamma; δ = delta; ω = omega, and the like. In addition, the Greek letter μ can be represented by "u", for example, in μ l = ul or μ M = uM.

An asterisk (*) in the chemical formula indicates i) a point of attachment, ii) a radical, and/or iii) an unshared electron.

In a first aspect, the invention relates to a derivative of a GLP-1 peptide, wherein the GLP-1 peptide comprises a peptide of the following formula I: Xaa ₇ -Xaa ₈ -Glu-Gly-Thr- Xaa ₁₂ -Thr-Ser-Asp-Xaa ₁₆ -Ser-Xaa ₁₈ -Xaa ₁₉ -Xaa ₂₀ -Glu-Xaa ₂₂ -Xaa ₂₃ -Ala-Xaa ₂₅ -Xaa ₂₆ -Xaa ₂₇ -Phe-Ile-Xaa ₃₀ -Xaa _{31 -Leu-Xaa 33 -Xaa 34 -Xaa} 35 -Xaa 36 -Xaa 37 -Xaa 38 -Xaa 39 -Xaa 40 -Xaa 41 -Xaa 42, wherein Xaa ₇ is L- histidine, (S) -2- Hydroxy-3-(1H-imidazol-4-yl)-propionic acid, D-histamine acid, deaminated histidine, homohistidine, N ^α -acetyl- histidine, N ^α -methionine histidine, N ^α -methylhistamine, 3-pyridine alanine, 2-pyridine alanine or 4-pyridine alanine; Xaa ₈ is Ala, Gly, Ser, Aib, (1-amine Cyclopropyl)carboxylic acid or (1-aminocyclobutyl)carboxylic acid; Xaa ₁₂ is Phe or Leu; Xaa ₁₆ is Val or Leu; Xaa ₁₈ is Ser, Arg, Lys, Val or Leu; Xaa ₁₉ is Tyr or Gln; Xaa ₂₀ is Leu or Met; Xaa ₂₂ is Gly or Glu; Xaa ₂₃ is Gln, Glu, Lys or Arg; Xaa ₂₅ is Ala or Val; Xaa ₂₆ is Arg or Lys; Xaa ₂₇ is Glu, Lys or Leu; Xaa ₃₀ is Ala, Glu or Arg; X Aa ₃₁ is Trp, Lys or His; Xaa ₃₃ is Val, Lys or Arg; Xaa ₃₄ is Lys, Arg, His, Asn or Gln; Xaa ₃₅ is Gly or Ala; Xaa ₃₆ is Arg, Lys or Gly; Xaa ₃₇ is Gly or Pro; Xaa ₃₈ is Ser, Gly, Ala, Glu, Pro or Lys; Xaa ₃₉ is Ser, Gly, Ala, Glu or Pro; Xaa ₄₀ is Ser, Gly, Ala, Glu or Pro; Xaa ₄₁ is Ser, Gly, Ala, Glu or Pro; and Xaa ₄₂ is Lys; the restriction condition is that at least one of Xaa ₁₈ , Xaa ₂₃ , Xaa ₂₇ , Xaa ₃₁ , Xaa ₃₆ or Xaa ₃₈ is Lys; wherein Lys at Xaa ₄₂ K is the first residue, and at _{18, Xaa 23 Xaa 27, Xaa} 31, Lys Xaa, by one of the Xaa Xaa ₃₆ or K ₃₈ as a second residue; comprising the derivative of the first and respectively a first and a second extension of the second K residue, wherein the first and second extensions have the formula 1: HOOC-(CH ₂ ) ₁₈ -CO-*, and the chemical formula 1a: HOOC-(CH ₂ ) ₁₇ - CO-* or Formula 1b: HOOC-(CH ₂ ) ₂₀ -CO-*; or a pharmaceutically acceptable salt, guanamine or ester thereof.

In a second aspect, the invention relates to a pharmaceutical composition comprising a derivative of the invention and a pharmaceutically acceptable excipient; and the use of a derivative or analog of the invention as a medicament, in particular To: (i) prevent and/or treat all forms of diabetes, such as hyperglycemia, type 2 diabetes, impaired glucose tolerance, type 1 diabetes, non-insulin dependent diabetes, MODY (young adult diabetes), pregnancy Diabetes and/or reduction of HbA1C; (ii) delay or prevention of progression of diabetes, such as progression of type 2 diabetes, delaying progression of glucose tolerance (IGT) to insulin type 2 diabetes, delaying or preventing insulin resistance and/or Or delay the progression of type 2 diabetes without insulin to insulin type 2 diabetes; (iii) improve β-cell function, such as reducing beta-cell apoptosis, increasing beta-cell function and/or beta-cell mass and/or Recovering glucose sensitivity for β-cells; (iv) preventing and/or treating cognitive disorders and/or neurodegenerative disorders such as Alzheimer's disease, Parkinson's dis Ease) and/or multiple sclerosis; (v) prevention and/or treatment of eating disorders, such as obesity, for example by reducing food intake, reducing body weight, suppressing appetite, and feeling satiety; treatment or prevention By taking antipsychotics or steroid-induced bulimia, psychosis and obesity; reducing gastric motility; delaying gastric emptying; increasing body movement; and/or preventing and/or treating obesity Comorbidity, such as osteoarthritis and/or urinary incontinence; (vi) prevention and/or treatment of diabetic complications, such as vascular disease; neuropathy, including peripheral neuropathy; nephropathy; and/or retinopathy; (vii) modified lipids Parameters such as prevention and/or treatment of dyslipidemia, reduction of total serum lipids; increase of HDL; reduction of low density LDL; reduction of VLDL; reduction of triglycerides; lowering of cholesterol; reduction of lipoprotein a (Lp(a)) in humans Plasma content; inhibition of apolipoprotein a (apo(a)) production in vitro and/or in vivo; (viii) prevention and/or treatment of cardiovascular diseases such as syndrome X, atherosclerosis, myocardial infarction, coronary heart disease, Reperfusion injury, stroke Cerebral ischemia, early cardiac or early effort Tube disease, left ventricular hypertrophy, coronary artery disease, hypertension, essential hypertension, acute hypertension, cardiomyopathy, cardiac insufficiency, exercise intolerance, acute and/or chronic heart failure, arrhythmia, arrhythmia, Syncope, angina pectoris, cardiac bypass and/or stent reocclusion, atheroschlerosis oblitterens, diastolic dysfunction and/or systolic dysfunction; and/or lowering blood pressure, such as reducing systolic blood pressure; (ix) prevention and/or Treatment of gastrointestinal diseases such as inflammatory bowel disease, short bowel syndrome or Crohn's disease or colitis; dyspepsia and/or gastric ulcer; and/or inflammation, such as psoriasis, psoriatic arthritis, rheumatoid Arthritis and/or systemic lupus erythematosus; (x) prevention and/or treatment of critical illness, such as treatment of critically ill patients, critically ill multiple kidney disease (CIPNP) patients and/or potential CIPNP patients; prevention of critical illness or CIPNP Development; prevention, treatment, and/or cure of systemic inflammatory response syndrome (SIRS) in patients; prevention or reduction of bacteremia, sepsis, and/or hospitalization during hospitalization The possibility of septic shock; and/or the stabilization of blood glucose, insulin balance and, where appropriate, the presence of a patient in an intensive care unit with acute disease; (xi) prevention and/or treatment of polycystic ovary syndrome (PCOS); Preventing and/or treating brain diseases such as cerebral ischemia, cerebral hemorrhage and/or traumatic brain injury; (xiii) preventing and/or treating sleep apnea; and/or (xiv) preventing and/or treating abuse, Such as alcohol abuse and / or drug abuse.

In a third aspect, the invention relates to an intermediate in the form of a GLP-1 analog which, when compared to GLP-1 (7-37) (SEQ ID NO: 1), comprises the following amino acid changes :i) (8Aib, 22E, 26R, 27K, 34R, 38G, 39G, 40G, 41S, 42K); ii) (8Aib, 22E, 26R, 31K, 34R, 38G, 39G, 40G, 41S, 42K); (8Aib, 22E, 26R, 34R, 38K, 39G, 40G, 41S, 42K); iv (8Aib, 22E, 23K, 26R, 34R, 38G, 39G, 40G, 41S, 42K); v) (8Aib, 22E) , 26R, 34R, 36K, 38G, 39G, 40G, 41S, 42K); vi) (8Aib, 18K, 22E, 26R, 34R, 38G, 39G, 40G, 41S, 42K); vii) (7Imp, 8Aib, 22E , 26R, 34R, 38K, 39G, 40G, 41S, 42K); iix) (8Aib, 22E, 26R, 34R, 36K, 38A, 39E, 40S, 41P, 42K); ix) (8Aib, 22E, 26R, 34R, 36K, 38E, 39G, 40P, 41A, 42K); x) (8Aib, 22E, 26R, 34R, 36K, 38P, 39A, 40S, 41E, 42K); xi) (8Aib, 22E, 26R, 34R, 38K, 39P, 40E, 41G, 42K) (SEQ ID NO: 12); xii) (8Aib, 22E, 26R, 34R, 38K, 39S, 40A, 41E, 42K); or xiii) (8Aib, 22E, 26R, 34R, 38K, 39S, 40P, 41E, 42K); or an amino acid change selected from such analogs.

GLP-1 receptor agonist

A receptor agonist can be defined as an analog that binds to a receptor and elicits a typical reaction of a natural ligand. A full agonist can be defined as an agonist that elicits the same response as a natural ligand (see, for example, "Principles of Biochemistry", AL Lehninger, DL Nelson, MM Cox, Second Edition, Worth Publishers, 1993, page 763 ).

Thus, for example, a "GLP-1 receptor agonist" can be defined as a compound that is capable of binding to the GLP-1 receptor and capable of activating it. And a "complete" GLP-1 receptor agonist can be defined as a GLP-1 receptor agonist capable of eliciting a GLP-1 receptor response similar in amount to native GLP-1.

Structure GLP-1 peptides and analogs of GLP-1

The term "GLP-1 peptide" as used herein may be referred to as an analog (or variant) of human glycosidin-like peptide-1 (GLP-1 (7-37)), the sequence of which is SEQ ID NO. The :1 form is included in the sequence listing. The peptide having the sequence of SEQ ID NO: 1 can also be indicated as "native" GLP-1.

The present invention, like peptide GLP-1 may be defined by the following formula _{I: Xaa 7 -Xaa 8 -Glu-Gly} -Thr-Xaa 12 -Thr-Ser-Asp-Xaa 16 -Ser-Xaa 18 -Xaa 19 -Xaa ₂₀ -Glu-Xaa ₂₂ -Xaa ₂₃ -Ala-Xaa ₂₅ -Xaa ₂₆ -Xaa ₂₇ -Phe-Ile-Xaa ₃₀ -Xaa ₃₁ -Leu-Xaa ₃₃ -Xaa ₃₄ -Xaa ₃₅ -Xaa ₃₆ -Xaa ₃₇ -Xaa ₃₈ -Xaa ₃₉ -Xaa ₄₀ -Xaa ₄₁ -Xaa ₄₂ , wherein Xaa ₇ is L-histidine acid, (S)-2-hydroxy-3-(1H-imidazol-4-yl)-propionic acid, D-histamine Acid, deaminated histidine, high histidine, N ^α -ethyl thiohistidine, N ^α -formyl histidine, N ^α -methylhistamine, 3-pyridine alanine, 2 - Pyridylamino acid or 4-pyridylamino acid; Xaa ₈ is Ala, Gly, Ser, Aib, (1-aminocyclopropyl)carboxylic acid or (1-aminocyclobutyl)carboxylic acid; Xaa ₁₂ is Phe or Leu Xaa ₁₆ is Val or Leu; Xaa ₁₈ is Ser, Arg, Lys, Val or Leu; Xaa ₁₉ is Tyr or Gln; Xaa ₂₀ is Leu or Met; Xaa ₂₂ is Gly or Glu; Xaa ₂₃ is Gln, Glu, Lys Or Arg; Xaa ₂₅ is Ala or Val; Xaa ₂₆ is Arg or Lys; Xaa ₂₇ is Glu, Lys or Leu; Xaa ₃₀ is Ala, Glu or Arg; Xaa ₃₁ is Trp, Lys or His; Xaa ₃₃ is Val, Lys Or Arg; Xaa ₃₄ is Lys, Arg, His, Asn or Gln; Xaa ₃₅ is Gly or Ala; Xaa ₃₆ is Arg, Lys or Gly; Xaa ₃₇ is Gly or Pro; Xaa ₃₈ is Ser, Gly, Ala, Glu, Pro or Lys; Xaa ₃₉ is Ser, Gly, Ala, Glu or Pro; Xaa ₄₀ is serine, Gly, Ala, Glu or Pro; Xaa ₄₁ is Ser, Gly, Ala, Glu or Pro; and Xaa ₄₂ is Lys; with the proviso that _{Xaa 18, Xaa 23, Xaa 27} , At least one of Xaa ₃₁ , Xaa ₃₆ or Xaa ₃₈ is Lys.

In this formula, the amino acid residue numbering is followed in accordance with the convention established in the art for the natural GLP-1 establishment, that is, the first (N-terminal) amino acid residue is numbered or given to position number 7, and Subsequent downstream amino acid residues toward the C-terminus are numbered 8, 9, 10, etc., up to the last (C-terminal) amino acid residue, which is Gly number 37 in native GLP-1, however, Formula I The peptide has a C-terminal tail or extension as defined in the formula which reaches and includes position 42.

Numbering is carried out differently in the sequence listing, wherein the first amino acid residue (His) of SEQ ID NO: 1 is assigned the number 1 and the last amino acid residue (Gly) is assigned the number 31, and the sequence listing Other GLP-1 sequences are vice versa. However, in this context, we follow the numbering convention established in this technique as explained above.

Reference may be made to i) the number of amino acid residues in native GLP-1 (7-37) corresponding to the altered amino acid residue (ie, the corresponding position in native GLP-1) and ii) actual changes. Each of the GLP-1 analogs of the derivatives of the invention is described.

In other words, by reference to the native GLP-1 (7-37) peptide, that is, with its variant (wherein when compared to native GLP-1 (7-37) (SEQ ID NO: 1), multiple The amino acid residues have been altered) forms describe the GLP-1 analogs of the invention. These changes can independently represent one or more amino acid substitutions, Add and/or delete.

The following is a non-limiting example of a suitable nomenclature: a GLP-1 peptide similar to the derivative of Example 3 herein may be referred to as the following GLP-1 analog: (8Aib, 22E, 26R, 34R, 38K, 39G, 40G, 41S, 42K) GLP-1 (7-37). This means that when the analog is aligned with native GLP-1, it has i) located in the analog according to the position corresponding to position 8 in native GLP-1, ii) located in the analog corresponding to E at the position of position 22 in native GLP-1, iii) located in the analog at position corresponding to position 26 in native GLP-1, iv) located in the analog corresponding to position in native GLP-1 R, v) of the position of 34 is located in the analog which will correspond to the position of position 38 in native GLP-1 (if extended at the C-terminus), vi) located in the analog will correspond to the native GLP-1 G at position 39 (if extended at C-terminus), vii) located in the analog will correspond to the position of position 40 in native GLP-1 (if extended at C-terminus), iix) will be located in the analog Sat corresponding to the position of position 41 in native GLP-1 (if extended at C-terminus), and ix) located in the analog will correspond to the position of position 42 in native GLP-1 (if extended at C-terminus) ). All other amino acids in this analog are identical to the corresponding amino acids in native GLP-1.

As explained above, a GLP-1 peptide such as the present invention can be defined by a change in amino acid compared to native GLP-1 and as compared to native GLP-1. The amino acid changes discussed above can be considered as amino acid substitutions and amino acid additions relative to native GLP-1. In this example, it is added at the C-end, and it can therefore also be referred to as a C-terminal extension. For example, 38K refers to the amino acid K found in the immediate vicinity of the C-terminal position corresponding to position 37 in native GLP-1 when the analog is aligned with native GLP-1. Next is G in the immediate vicinity of the C-terminus at the position corresponding to position 39 of native GLP-1 in the analog; and another C-terminal position in the analog that will correspond to the position of position 40 of native GLP-1 a G; and S in the analog which will correspond to the position of the C-terminus at the position of position 41 of native GLP-1, and finally K at a position which will correspond to position 42 of native GLP-1.

The general formula I is understood in a similar manner.

In a specific embodiment, at least one of Xaa ₁₈ , Xaa ₂₃ , Xaa ₂₇ , Xaa ₃₁ , Xaa ₃₆ or Xaa ₃₈ in Formula I is Lys. The GLP-1 peptide of the present invention further comprises at least one Lys residue, i.e., at position 42 (Xaa ₄₂ ). The latter (position 42) may be referred to as a first K residue, and the former, ie, Lys at one of Xaa ₁₈ , Xaa ₂₃ , Xaa ₂₇ , Xaa ₃₁ , Xaa ₃₆ or Xaa ₃₈ may be referred to as a second K Residues. The first and second K residues constitute two deuteration sites of the diterpene derivative of the present invention. As is apparent from Formula I, a GLP-1 peptide such as the present invention may comprise other Lys residues. In a particular embodiment, a GLP-1 peptide of the invention has only two Lys residues.

When compared to SEQ ID NO: 1, analogs that "include" certain specified changes may include other alterations. In a particular embodiment, the analog "has" a specified change.

As is apparent from the above examples, the amino acid residue can be identified by the full name of the amino acid residue, its single word code and/or its three-word code. These three methods are completely equivalent.

The expression "equivalent to position" or "corresponding position" can be used to characterize a variant GLP-1 (7-37) sequence that is referenced to a reference sequence such as native GLP-1 (7-37) (SEQ ID NO: 1). The position in the middle changes. Equivalent or corresponding positions and number of changes can be easily inferred, for example, by simple handwriting and visual inspection; and/or standard protein or peptide alignment programs can be used, such as "alignment" based on the Needleman-Wunsch algorithm. In Needleman, SB and Wunsch, CD, (1970), Journal of Molecular Biology, 48: 443-453 and Myers and W. Miller in "Optimal Alignments in Linear Space" CABIOS (computer applications in the This algorithm is described in the ratio program of biosciences)) (1988) 4:11-17. For comparison, the pre-designed sub-matrix BLOSUM62 and the preset unit matrix can be used, and the penalty value of the first residue in the gap can be set to -12 or better -10, and the punishment of other residues in the gap The value is set at -2 or preferably -0.5.

An example of this alignment is inserted below, wherein SEQ ID NO: 1 is SEQ ID NO: 1, and SEQ ID NO: 2 is its analog (8Aib, 22E, 26R, 34R, 38K, 39G, 40G, 41S, 42K): #Alignment sequence: 2

#序1:1

#序2:2

#矩阵:EBLOSUM62

#间隙_罚值:10.0

#扩_刑值: 0.5

#

#length: 36

# consistency: 27/36 (75.0%)

#similarity: 29/36 (80.6%)

#间隙: 5/36 (13.9%)

#分分:143.0

When 6 is added to the position number shown in the comparison (that is, in Sequence 1 to "1" and "31", and in Sequence 2 to "1" and "37"), we have obtained as used herein. Location number. For example, in SEQ ID NO: 1 which is identical to SEQ ID NO: 1, the N-terminal amino acid (H) has position number 7 and the C-terminal amino acid (G) has the number 37. With respect to SEQ ID NO: 2, the N-terminal amino acid (H) has the number 7 and the C-terminal amino acid (K) has the number 42.

Where a particular amino acid residue of a one-letter codon (such as Aib) or the like is not included in the sequence, such residues may be replaced by X, for example as shown in the above alignment, for purposes of comparison base. If necessary, you can then manually correct X.

The following is a non-limiting example of what can be inferred from the above alignment: As an example, it can be inferred that Sequence 2 has 9 compared to Sequence 1 (ie, all periods in the alignment ("."), colon The amino acid (":") or the position of the horizontal hyphen ("-") changes.

As another example, it can be inferred that, for example, SEQ ID NO: 2 contains 38K because it has a K at a position corresponding to position 38 in the reference sequence (SEQ ID NO: 1) of the reference sequence (SEQ ID NO: 1).

And similarly, all other changes in sequence 2 of sequence 1 can be compared from the inference.

The term "peptide" as used, for example, in the context of a GLP-1 peptide, such as a derivative of the invention, refers to a compound comprising a series of amino acids interconnected by a guanamine (or peptide) bond.

The peptide of the present invention comprises at least 36 amino acids. In a specific embodiment, the peptide consists of 36 amino acids. In another specific embodiment, the peptide consists of 36 amino acids.

In another specific embodiment, the peptide consists of an amino acid interconnected by a peptide bond.

Amino acids are molecules containing an amine group and a carboxylic acid group and, where appropriate, one or more other groups commonly referred to as side chains.

The term "amino acid" includes proteinaceous (or natural) amino acids (including 20 standard amino acids) as well as non-proteinaceous (or non-natural) amino acids. A protein type amino acid is an amino acid naturally incorporated into a protein. The standard amino acid is an amino acid encoded by a gene code. Non-protein amino acids are not found in proteins or are produced by standard cellular machinery (eg, they may have been post-translationally modified). Non-limiting examples of non-protein amino acids are Aib (alpha-aminoisobutyric acid or 2-aminoisobutyric acid), deaminated histidine (alternative name imidazopropionic acid or 3-(imidazole- 5-yl)propionic acid, abbreviated as Imp) and the D-isomer of the protein type amino acid.

Hereinafter, the respective amino acids of the GLP-1 peptide which are not stated as optical isomers are understood to mean the L-isomer (unless otherwise stated).

The GLP-1 derivatives and analogs of the invention have GLP-1 activity. This term refers to the ability to bind to the GLP-1 receptor and initiate a signal transduction pathway that results in an insulinotropic effect or other physiological effects known in the art. For example, the GLP-1 activity of the analogs and derivatives of the invention can be tested using the assays described in Examples 29, 30, 32 or 33 herein.

a derivative of the GLP-1 peptide

The term "GLP-1 derivative" generally refers to a compound which can be prepared by chemical modification, in particular by covalent attachment of one or more substituents from a native GLP-1 peptide or analog thereof. Derivatives of the GLP-1 peptide of the present invention comprise two such substituents. Each of these may also or alternatively be referred to as a side chain.

In a specific embodiment, the side chain is capable of forming a non-covalent complex with albumin, thereby promoting circulation of the derivative under blood flow, and also has the effect of prolonging the action time of the derivative because The GLP-1 derivative and the albumin complex only slowly decompose to release the active pharmaceutical ingredient. Therefore, the substituent or the side chain as a whole is preferably referred to as an albumin binding moiety.

In another specific embodiment, the albumin binding moiety comprises a moiety that is particularly associated with albumin binding and thereby associated with elongation, such that the moiety can be referred to as an extension. The extension is accessible, preferably at the end (or distal or free end) of the albumin binding moiety, relative to its point of attachment to the peptide. The albumin binding moiety is linked to the peptide by deuteration of the lysine residue of the peptide, in particular by deuteration to the epsilon-amine group of the amine acid residue.

In another specific embodiment, the albumin binding moiety comprises a portion between the extension and the point of attachment to the peptide, which portion can be referred to as a linker, a linker, a spacer or the like.

The derivative of the present invention comprises the first and second extensions of Chemical Formula 1, Chemical Formula 1a or Chemical Formula 1b: Chemical Formula 1: HOOC-(CH ₂ ) ₁₈ -CO-*, Chemical Formula 1a: HOOC-(CH ₂ ) ₁₇ -CO -*, or Chemical Formula 1b: HOOC-(CH ₂ ) ₂₀ -CO-*; which may also be referred to as C20 diacid, C19 diacid and C22 diacid, respectively. The first extension is attached to the first K residue and the second extension is attached to the second K residue. The term "connected" is intended to include both direct and indirect connections. An example of an indirect linkage is via a link between a linker located between the extension and the K residue. An example of a direct connection is when the intervening linker is not present.

Thus, in a particular embodiment, the first extension is attached to the first K residue and the second extension is linked to the second K residue, as appropriate via the first and second linkers, respectively.

The first and second linkers may comprise element 1, which is a Glu diradical of formula 2:

This element may be referred to as γ-Glu, or in short gGlu, as it is an amino acid bran used herein to attach to another linking element or to the epsilon-amine group of the amine acid, as the case may be. γ carboxyl group of aminic acid.

In addition, alternatively, the first and second linkers may comprise element 2 of chemical formula 3: Wherein k is an integer in the range of 1-5, and n is an integer in the range of 1-5. In a specific embodiment, when k=1 and n=1, element 2 of Chemical Formula 3 may be indicated as OEG, or a di-radical of 8-amino-3,6-dioxaoctanoic acid. In another non-limiting specific embodiment, k=3 and n=2, in which case the element 2 group of Chemical Formula 3 can be indicated as dPEG4.

Further, alternatively, the first and second linkers may comprise element 3 of Chemical Formula 4, which may be referred to as Trx (for tranexamic acid):

Further, alternatively, the first and second linkers may comprise the element 4 of the following chemical formula 5: *-NH-(CH ₂ ) _q -CH[(CH ₂ ) _w -NH ₂ ]-CO-*, wherein q is An integer in the range of 0-5, and w is an integer in the range of 0-5, with the constraint that q is an integer in the range of 1-5 when w is 0, and w is in the case of q being 0. An integer in the range of 1-5.

In addition, alternatively, the first and second linkers may comprise element 5 of Chemical Formula 6: Wherein y is 1 or 2, z is 1 or 2, p is 0 or 1, and X represents a carbon atom or an oxygen atom.

Specific non-limiting examples of element 5 are chemical formula 7, chemical formula 8 and chemical formula 9: (TotaGlyc), (TtdSuc), and (DooaSuc).

Additionally, alternatively, the first and second linkers may comprise element 6 of chemical formula 10: (Inp).

The first and second extensions are linked to the first and second linkers, respectively, and in turn are linked to the first and second K residues of the GLP-1 peptide-like peptide via a guanamine bond, respectively.

The first and second linkers may include one or more of various elements (element 1 to element 6) as defined above, each element may appear one or more times, and the order of elements may also vary.

Whenever a linker is referred to as "including" an element, it may additionally contain other elements, although the term "incorporated" is intended to have the same meaning as "having" or "include only." Therefore, "incorporate" chemistry The linker of the two elements 2 of Formula 3 has only two of these elements in its structure.

Various specific combinations of connecting elements are described in more detail below in the section entitled "Specific Specific Examples." The order in which elements are specified herein is generally from the N-terminus to the C-terminus.

In a particular embodiment, the two albumin binding moieties (i.e., the two side chains) are similar, preferably substantially identical or optimally identical.

In another specific embodiment, the first and second extensions are similar, preferably substantially identical or optimally identical.

In another specific embodiment, the first and second linkers are similar, preferably substantially identical or optimally identical.

The term "substantially the same" includes attributable to the formation of one or more esters and/or guanamine; preferably one or more methyl esters and simple guanamine; more preferably no more than two methyl esters and/or simple guanamine; Or optimally form no more than one methyl ester and/or simple guanamine with the same difference.

In the context of compounds, such as albumin binding moieties, extensions, and linkers, similarity and/or consistency can be determined using any suitable computer program and/or algorithm known in the art.

For example, the similarity of two extensions, two linkers, and/or two intact side chains can be suitably determined using molecular fingerprints. Fingerprints are a mathematical method of representing chemical structures (see, for example, Chemoinformatics: A textbook, Johann Gasteiger and Thomas Engel (ed.), Wiley-VCH Verlag, 2003).

Examples of suitable fingerprints include, but are not limited to, UNITY fingerprints, MDL fingerprints, and/or ECFP fingerprints, such as ECFP_6 fingerprints (ECFP stands for Extended Connectivity Fingerprints).

In a particular embodiment, two extensions, two linkers, and/or two complete side chains are represented as a) ECFP_6 fingerprint; b) UNITY fingerprint; and/or c) MDL fingerprint.

Regardless of whether a), b) or c) is used, the Tanimoto coefficient is preferably used to calculate the similarity of two fingerprints.

In a particular embodiment, whether a), b) or c) is used, the two extensions, the two linkers and/or the two intact side chains each have at least 0.5 (50%); preferably at least 0.6 (60%) More preferably at least 0.7 (70%) or at least 0.8 (80%); more preferably at least 0.9 (90%); or optimally at least 0.99 (99%) similarity, such as 1.0 (100%) similarity.

The UNITY fingerprint can be calculated using the program SYBYL (available from Tripos, 1699 South Hanley Road, St. Louis, MO 63144-2319 USA). ECFP_6 and MDL fingerprints can be calculated using the program Pipeline Pilot (available from Accelrys, Inc., 10188 Telesis Court, Suite 100, San Diego, CA 92121, USA).

For further details see, for example, J. Chem. Inf. Model. 2008, 48, 542-549; J. Chem. Inf. Comput. Sci. 2004, 44, 170-178; J. Med. Chem. 2004, 47, 2743-2749 ; J. Chem. Inf. Model. 2010, 50, 742-754; and SciTegic Pipeline Pilot Chemistry Collection: Basic Chemistry User Guide, March 2008, SciTegic Pipeline Pilot Data Modeling Collection, 2008 - both from Accelrys Software, San Diego, US, and Guide http://www.tripos.com/tripos_resources/fileroot/pdfs/Unity_111408.pdf, and http://www.tripos.com/data/SYBYL/SYBYL_072505.pdf.

An example of a similarity calculation is inserted below in which the known intact side chain of a known GLP-1 derivative is compared to its methyl ester:

Using a) ECFP_6 fingerprint, the similarity was 0.798, using b) UNITY fingerprint, the similarity was 0.957; and using MDL fingerprint, the similarity was 0.905.

In the case of two identical side chains (albumin binding moieties), the derivatives can be indicated as being symmetric.

In a particular embodiment, the similarity factor is at least 0.80, preferably at least 0.85, more preferably at least 0.90, more preferably at least 0.95, or most preferably at least 0.99.

Derivatives of the invention may have the same molecular formula and bonded atomic sequence, but exist only in different stereoisomeric forms that differ in their three-dimensional orientation in space. The stereoisomerism of the exemplified derivatives of the present invention is specified by name and structure in the experimental part using standard nomenclature. Unless otherwise stated, the invention relates to all stereoisomeric forms of the claimed derivatives.

The concentration in the plasma of the GLP-1 derivative of the present invention can be determined using any suitable method. For example, LC-MS (liquid chromatography mass spectrometry) or immunoassay such as RIA (radioimmunoassay), ELISA (enzyme-linked immunosorbent assay), and LOCI (luminescence oxygen channel immunoassay) can be used. General protocols for suitable RIA and ELISA assays are found, for example, on pages 116-118 of WO 2009/030738. A preferred assay is LOCI analysis, wherein LOCI refers to luminescence oxygen channel immunoassay, which is generally described in Poulsen and Jensen, Journal of Biomolecular Screening 2007, Vol. 12, pp. 240-247, for the determination of insulin. When the acceptor beads are conjugated to a monoclonal antibody recognizing the terminal/C-terminal epitope of the peptide, the donor beads are coated with streptavidin. Another monoclonal antibody specific for the N-terminus is biotinylated. The three reactants are combined with the analyte and form a two-point immunological complex. Illumination of the complex was such that singlet oxygen atoms were released from the donor beads, which were delivered to the acceptor beads in one channel and the triggered chemiluminescence was measured with an Envision plate reader. The amount of light is proportional to the concentration of the compound.

Pharmaceutically acceptable salt, guanamine or ester

The derivatives, analogs and intermediates of the invention may be in the form of a pharmaceutically acceptable salt, guanamine or ester.

The salt is formed, for example, by a chemical reaction between a base and an acid, for example: 2NH ₃ + H ₂ SO ₄ → (NH ₄ ) ₂ SO ₄ .

The salt may be a basic salt, an acidic salt or it may not be either (i.e., a neutral salt). in In water, an alkaline salt produces hydroxide ions and an acid salt produces hydronium ions.

Salts of the derivatives of the invention may be formed from cations or anions which are respectively added between anionic or cationic groups. Such groups may be located in the peptide moiety, and/or in the side chain of the derivative of the invention.

Non-limiting examples of anionic groups of the derivatives of the invention include side chains (if present) as well as free carboxyl groups in the peptide moiety. The peptide moiety typically includes a free carboxylic acid group at the C-terminus, and it may also include a free carboxyl group at an internal acidic amino acid residue, such as Asp and Glu.

Non-limiting examples of cationic groups in the peptide moiety include free amine groups at the N-terminus (if present), as well as internal basic amino acid residues, such as any free amine group of His, Arg, and Lvs.

In a particular embodiment, the derivatives and analogs of the invention are basic salts. The salts can be formed, for example, between an anionic group in the peptide moiety and an added sodium or potassium cation.

The ester of the derivative of the present invention can be formed, for example, by the reaction of a free carboxylic acid group with an alcohol or a phenol which results in the replacement of at least one hydroxyl group by an alkoxy group or an aryloxy group.

Ester formation can involve a free carboxyl group at the C-terminus of the peptide, and/or any free carboxyl group in the side chain.

The indoleamine of the derivative of the present invention can be formed, for example, by the reaction of a free carboxylic acid group with an amine or a substituted amine or by the reaction of a free or substituted amine group with a carboxylic acid.

Indoleamine formation may involve the free carboxyl group at the C-terminus of the peptide, any free carboxyl group in the side chain, the free amine group at the N-terminus of the peptide, and/or any free or substituted amine group of the peptide and/or the peptide in the side chain. .

In a particular embodiment, the peptide or derivative is in the form of a pharmaceutically acceptable salt. In another specific embodiment, the derivative is in the form of a pharmaceutically acceptable guanamine, preferably having a guanamine group at the C-terminus of the peptide. In another specific embodiment, the peptide or derivative is in the form of a pharmaceutically acceptable ester.

Functional characteristics

In a particular embodiment, the derivatives of the invention have an extremely long half-life and at the same time have excellent in vitro and in vivo potency, which makes such derivatives potentially suitable for monthly administration.

Therefore, in the first functional aspect, the derivative of the present invention has good performance. In addition, or in the second aspect, it binds optimally to the GLP-1 receptor, for example at high albumin concentrations. Preferably, it is a potent GLP-1 receptor agonist as reflected by its ability to bind strongly to the GLP-1 receptor and the ability to activate the receptor. In addition, or in a third functional aspect, it has improved pharmacokinetic properties.

Biological activity - in vitro efficiency

According to a first functional aspect, the derivatives of the invention as well as the group-classified GLP-1 peptide are thus biologically active or potent.

In a particular embodiment, potency and/or activity refers to in vitro potency, i.e., potency in a functional GLP-1 receptor assay, and more specifically, the ability to activate a human GLP-1 receptor.

In vitro efficacy can be determined, for example, in a membrane-containing medium that exhibits the human GLP-1 receptor and/or in an assay with whole cells that exhibit the human GLP-1 receptor.

For example, in a reporter gene assay, for example, in the expression of the human GLP-1 receptor and containing the DNA for the cAMP response element (CRE) coupled to the promoter and for firefly luciferase (CRE luciferin) The gene of the enzyme) was stably transfected into the BHK cell line to measure the response of the human GLP-1 receptor. When cAMP is produced due to activation of the GLP-1 receptor, this in turn causes luciferase to be expressed. Luciferase can be assayed by the addition of luciferin, which is converted to oxyluciferin by an enzyme and produces bioluminescence, which is measured and measured as an in vitro potency. One non-limiting example of this analysis is described in Example 29.

The term half-maximal effective concentration (EC ₅₀₎ generally refers to the reference maximum value halfway between the baseline and the dose response curve of the concentration-response evoked. EC ₅₀ used as a measure of the potency of the compound and represents the concentration observed in 50% of the maximum effect.

It may be determined as described above in-vitro potency of the derivatives of the present invention, and the derivative of the measured EC _50. The lower the EC ₅₀ value, the better the performance.

In a particular embodiment, the derivatives of the invention are extremely strong, regardless of the fact that they have an extremely long half-life. In one particular embodiment, the derivatives of the present invention has determined using the method of Example 29 of the embodiment corresponds to the in vitro efficacy at 400pM 400pM or less of EC _50.

Biological activity - in vivo pharmacology

In another specific embodiment, the derivatives of the invention, as well as the group-classified GLP-1 peptides, are therefore potent in vivo, which can be determined in any suitable animal model, as well as in clinical trials such techniques. .

Diabetic db/db mice are an example of a suitable animal model, and blood glucose and/or weight loss effects can be measured in vivo in such mice, for example, as described in Example 32. In a particular embodiment, the derivatives of the invention are capable of reducing blood glucose and body weight of db/db mice for at least 96 hours.

LYD pigs are another example of a suitable animal model, and a reduction in food intake can be determined in vivo in such pigs, for example, as described in Example 33.

In a particular embodiment, the derivatives of the present invention are in vivo and are extremely potent over a long period of time, as evidenced by the results found in the experimental section and also referred to in the section entitled "Specific Specific Examples".

Biological activity - in vitro receptor binding

According to a second functional aspect, the derivatives of the invention as well as the group-classified GLP-1 peptides, for example, bind to the GLP-1 receptor very well, for example, at high concentrations of albumin. This can be determined as described in Example 30.

In general, corresponding to the IC ₅₀ value is low, at a low albumin concentration and GLP-1 receptor binding should be as good as possible.

Under the IC ₅₀ values reflect the higher concentrations of albumin serum albumin binding derivatives of GLP-1 to affect receptor. As is known, GLP-1 derivatives can bind to serum albumin and, if this is the case, the IC ₅₀ values of the serum albumin is higher than the IC ₅₀ values at low albumin. The increase in the IC ₅₀ values represent high serum albumin to bind to the GLP-1 receptor serum albumin binding competition to reduce GLP-1 receptor caused.

In a particular embodiment, the derivatives of the invention bind very well to the GLP-1 receptor at low albumin concentrations, but they also bind very well at high albumin concentrations.

The derivatives of the present invention as an example, in a particular embodiment, at low concentrations of HSA (low albumin) in the presence of GLP-1 receptor binding affinity (IC ₅₀₎ located 5.0nM or 5.0nM or less.

Pharmacokinetic characteristics

According to a third functional aspect, the derivatives of the invention have improved pharmacokinetic properties, such as increased terminal half-life and/or reduced clearance.

Increasing the terminal half-life and/or decreasing the clearance means that the compound itself is eliminated more slowly. For the derivatives of the invention, this requires an extended duration of pharmacological effects.

The pharmacokinetic properties of the derivatives of the invention can be suitably determined in vivo in pharmacokinetic (PK) studies. These studies are conducted to assess how pharmaceutical compounds are absorbed, distributed, and eliminated in the body, and how such processes affect the concentration of the compound in the body over time.

In the discovery and preclinical phase of drug discovery, animal models such as mice, rats, monkeys, dogs or pigs can be used to perform this characterization. Any of these models can be used to test the pharmacokinetic properties of the derivatives of the invention.

In these studies, a single dose of the drug is typically administered to the animal intravenously (i.v.), subcutaneously (s.c.) or orally (p.o.) in the relevant formulation. Blood samples were taken at predefined time points after dosing and the drug concentration of the samples was analyzed by correlation quantitative analysis. Based on these measurements, the time-plasma concentration characteristics of the studied compounds were plotted and the so-called non-compartmental pharmacokinetic analysis of the data was performed.

For most compounds, the end portion of the plasma-concentration profile will be linear when plotted in a semi-logarithmic curve, reflecting that the body removes the drug at a constant fraction after initial absorption and distribution. The rate (λ Z or λ _z ) is equal to the negative slope of the end portion of the curve. The terminal half-life can also be calculated from this rate as t1⁄2=ln(2)/λ _z (see, for example, Johan Gabrielsson and Daniel Weiner: Pharmacokinetics and Pharmacodynamic Data Analysis. Concepts & Applications, 3rd edition, Swedish Pharmaceutical Press, Stockholm (2000) ).

The clearance can be determined after intravenous administration and is defined as the dose (D) divided by the area under the curve of the plasma concentration versus time profile (AUC) (Rowland, M and Tozer TN: Clinical Pharmacokinetics: Concepts and Applications, 3rd Edition) , 1995 Williams Wilkins).

The assessment of terminal half-life and/or clearance is related to the assessment of the dosing regimen and is an important parameter for drug development and evaluation of novel drug compounds.

Pharmacokinetic characteristics - in vivo half-life of minipigs

According to a third functional aspect, the derivatives of the invention have improved pharmacokinetic properties.

In a particular embodiment, the pharmacokinetic profile can be determined as the in vivo terminal half-life ( _T1⁄2 ) of a minipigs after intravenous administration, for example as described in Example 31 herein.

In a particular embodiment, the derivatives of the invention have an excellent terminal half-life in minipigs which renders the derivatives suitable for once-monthly administration. In a particular embodiment, the derivative of the invention in minipigs after intravenous administration has a terminal half-life of at least 90 hours.

Other specific examples of the derivatives of the present invention are described in the section entitled "Specific Specific Examples" preceding the experimental section.

Production process

It is well known in the art to produce peptide-like GLP-1 (7-37) and GLP-1 analogs.

The GLP-1 peptide moiety (or a fragment thereof) of the derivative of the present invention can be produced, for example, by classical peptide synthesis using t-Boc or Fmoc chemical reactions or other established techniques, such as solid phase peptide synthesis. See, for example, Greene and Wuts, "Protective Groups in Organic Synthesis", John Wiley & Sons, 1999, Florencio Zaragoza Dörwald, "Organic Synthesis on solid Phase", Wiley-VCH Verlag Ltd., 2000 and "Fmoc Solid Phase Peptide" Synthesis, edited by W.C. Chan and P.D. White, Oxford University Press, 2000.

Alternatively, or alternatively, it can be produced by a recombinant method, i.e., by culturing a host cell containing a coding analog and capable of expressing the DNA sequence of the peptide in a suitable nutrient medium under conditions permitting expression of the peptide. Non-limiting examples of host cells suitable for expressing such peptides are: E. coli, S. cerevisiae, and mammalian BHK or CHO cell lines.

Such derivatives of the invention may be produced, for example, as described in the experimental section, including unnatural amino acids and/or covalently linked N-terminal monopeptides or dipeptide mimics. Or see, for example, Hodgson et al.: "The synthesis of peptides and proteins containing non-natural amino acids", Chemical Society Reviews, Vol. 33, No. 7 (2004), pp. 422-430; and the name "Semi-recombinant Preparation of GLP-1 analogues" WO 2009/083549 A1.

Specific examples of methods for preparing various derivatives of the present invention are included in the experimental section.

Pharmaceutical composition

The invention also relates to pharmaceutical compositions comprising a derivative of the invention, or a pharmaceutically acceptable salt, guanamine or ester thereof, and a pharmaceutically acceptable excipient. Such compositions can be prepared as known in the art.

The term "excipient" generally refers to any component other than the active therapeutic ingredient. The excipient can be an inert substance, an inactive substance, and/or a non-pharmaceutically active substance.

The excipients can be used for various purposes, for example as carriers, vehicles, diluents, lozenges and/or to improve the administration and/or absorption of the active substance.

Formulations of pharmaceutically active ingredients with various excipients are known in the art, see, for example, Remington: The Science and Practice of Pharmacy (e.g., 19th Edition (1995), and any subsequent versions).

Non-limiting examples of excipients are solvents, diluents, buffers, preservatives, tonicity adjusting agents, chelating agents, and stabilizers.

Examples of formulations include liquid formulations, that is, aqueous formulations comprising water. Liquid blending The substance can be a solution or a suspension. Aqueous formulations typically comprise at least 50% w/w water or at least 60%, 70%, 80% or even at least 90% w/w water.

Alternatively, the pharmaceutical composition can be a solid formulation, such as a lyophilized or spray dried composition, which can be used as is or added to the physician or patient prior to use to add a solvent and/or diluent thereto.

The pH in the aqueous formulation can be any value between pH 3 and pH 10, such as from about 7.0 to about 9.5; or from about 3.0 to about 7.0.

The pharmaceutical composition can include a buffer. The buffering agent may, for example, be selected from the group consisting of sodium acetate, sodium carbonate, citrate, glycine glycine, histidine, glycine, lysine, arginine, sodium dihydrogen phosphate, disodium hydrogen phosphate, phosphoric acid Sodium and ginseng (hydroxymethyl)-aminomethane, diglycine, flavonoids, malic acid, succinate, maleic acid, fumaric acid, tartaric acid, aspartic acid, and mixtures thereof.

The pharmaceutical composition may contain a preservative. The preservative may, for example, be selected from the group consisting of phenol, o-cresol, m-cresol, p-cresol, methyl p-hydroxybenzoate, propyl p-hydroxybenzoate, 2-phenoxyethanol, butyl p-hydroxybenzoate, 2- Phenylethanol, benzyl alcohol, chlorobutanol and thimerosal, bronopol, benzoic acid, imidazolidinyl urea, chlorhexidine, sodium dehydroacetate, chlorocresol, ethyl p-hydroxybenzoate, benzethonium chloride, chlorphenesine (3-p-chlorophenoxypropane-1,2-diol) and mixtures thereof. The preservative can be present in a concentration from 0.1 mg/ml to 20 mg/ml. The pharmaceutical composition can include an isotonic agent. The isotonic agent may, for example, be selected from salts (eg, sodium chloride), sugars or sugar alcohols, amino acids (eg, glycine, histidine, arginine, lysine, isoleucine, aspartic acid) , tryptophan, threonine, aldol (eg glycerol (glycerol), 1,2-propanediol (propylene glycol), 1,3-propanediol, 1,3-butanediol), polyethylene glycol ( For example PEG400) and mixtures thereof. Any sugar may be used, such as a monosaccharide, a disaccharide or a polysaccharide or a water-soluble glucan, including, for example, sugar, glucose, mannose, sorbose, xylose, maltose, lactose, sucrose, trehalose, polydextrose, pullulan. (pullulan), dextrin, cyclodextrin, alpha and beta HPCD, soluble starch, hydroxyethyl starch and sodium carboxymethylcellulose. A sugar alcohol is defined as a C4-C8 hydrocarbon having at least one -OH group and includes, for example, mannitol, sorbitol, inositol, galactitol, dulcitol, Xylitol and arabitol. In one embodiment, the sugar alcohol additive is mannitol.

The pharmaceutical composition can comprise a chelating agent. The chelating agent can, for example, be selected from the group consisting of ethylenediaminetetraacetic acid (EDTA), citric acid and aspartic acid, and mixtures thereof.

The pharmaceutical composition can include a stabilizer. The stabilizer can be, for example, one or more oxidation inhibitors, aggregation inhibitors, surfactants, and/or one or more protease inhibitors. Non-limiting examples of such various stabilizers are disclosed below.

The term "aggregate formation" refers to the physical interaction between polypeptide molecules that result in the formation of larger visible aggregates that retain soluble oligomers or precipitate from solution. The formation of aggregates of polypeptides during storage of a liquid pharmaceutical composition can adversely affect the biological activity of the polypeptide, resulting in a loss of therapeutic efficacy of the pharmaceutical composition. In addition, aggregate formation can cause other problems, such as clogging a tube, membrane, or pump when a perfusion-containing system is used to administer a polypeptide-containing pharmaceutical composition.

The pharmaceutical composition can comprise an amino acid base sufficient to reduce the formation of aggregates of the polypeptide during storage of the composition. The term "amino acid base" means one or more amino acids (such as methionine, histidine, imidazole, arginine, lysine, isoleucine, aspartic acid, tryptophan, Threonic acid) or an analogue thereof. Any amino acid may be present in its free base form or in its salt form. Any stereoisomer of the amino acid base (i.e., L, D or a mixture thereof) may be present.

Methionine (or other thiol-containing acid or amino acid analog) may be added to inhibit methylthioamide when the polypeptide acting as a therapeutic agent is a polypeptide comprising at least one methionine residue susceptible to the oxidation The acid residue is oxidized to arsenic amide. Any stereoisomer (L or D) of methionine or a combination thereof can be used.

The pharmaceutical composition may comprise a stabilizer selected from the group consisting of high molecular weight polymers or low molecular weight compounds. The stabilizer may, for example, be selected from polyethylene glycol (eg PEG 3350), polyvinyl alcohol (PVA), polyvinylpyrrolidone, carboxy-/hydroxycellulose or derivatives thereof (eg HPC, HPC-SL, HPC-L) And HPMC), cyclodextrin, sulfur-containing substances such as monothioglycerol, thioglycolic acid and 2-methylthioethanol and different salts (such as sodium chloride). The pharmaceutical composition may contain other stabilizers such as (but not limited to Methionine and EDTA, which protects the polypeptide from methionine oxidation, and a nonionic surfactant that protects the polypeptide from aggregation associated with freeze-thaw or mechanical shear.

The pharmaceutical composition can include one or more surfactants. The term "surfactant" refers to any molecule or ion comprising a water soluble (hydrophilic) moiety and a fat soluble (lipophilic) moiety. The surfactant can be selected, for example, from an anionic surfactant, a cationic surfactant, a nonionic surfactant, and/or a zwitterionic surfactant.

The pharmaceutical composition may comprise one or more protease inhibitors such as EDTA (ethylenediaminetetraacetic acid) and/or benzamidine hydrochloride.

Other optional components of the pharmaceutical composition include, for example, wetting agents, emulsifiers, antioxidants, bulking agents, metal ions, oily vehicles, proteins (eg, human serum albumin, gelatin), and/or zwitterions (eg, amines) Base acids such as betaines, taurine, arginine, glycine, lysine and histidine.

As described above, the present invention also relates to a pharmaceutical composition comprising the derivative of the present invention or a pharmaceutically acceptable salt thereof, a guanamine or an ester, and a pharmaceutically acceptable excipient.

In a particular embodiment, the excipient comprises a phosphate buffer and an isotonic agent.

In another specific embodiment, the excipient comprises a phosphate buffer and a propylene glycol supplemented to isotonicity.

In another specific embodiment, the invention relates to a single dose pharmaceutical composition for subcutaneous injection comprising (i) a GLP-1 derivative of the invention at a suitable concentration or a pharmaceutically acceptable thereof a salt, a guanamine or an ester, (ii) an 8 mM phosphate buffer (such as 1.42 mg/mL disodium phosphate dihydrate), (iii) an uplifting propylene glycol and (iv) a pH of 7.4.

The term "suitable concentration" refers to a pharmaceutically relevant concentration which can be determined as known in the art.

A non-limiting example of a suitable concentration corresponding to the dosage administered when included in a 1 mL composition is mentioned hereinafter (ie, for example, a suitable concentration may range from 0.1 mg/mL to 100 of the composition) Mg/mL).

In a particular embodiment, a suitable concentration is 3 mg/mL.

In another specific embodiment, a suitable concentration is 30 mg/mL.

In another specific embodiment, the GLP-1 derivative is (a) a compound of Example 1, (b) a compound of Example 2, (c) a compound of Example 3, (d) a compound of Example 5, Or a pharmaceutically acceptable salt, guanamine or ester of any of (a)-(d).

Further, the pharmaceutical composition can be formulated, for example, by any one or more of the formulations described in WO 2008/145728, as is known in the art of oral formulations of insulinotropic compounds.

The dosage administered may contain from 0.1 mg to 100 mg of the derivative, from 1 to 100 mg of the derivative or from 1 to 50 mg of the derivative.

The derivative can be administered in the form of a pharmaceutical composition. It can be at several sites, such as at a local site, such as a skin or mucosal site; in a site that bypasses absorption, such as in an artery, in a vein, or in the heart; and in a site involving absorption, such as in the skin, Subcutaneous, intramuscular, or abdomen is administered to a patient in need.

The route of administration can be, for example, translingual; sublingual; buccal; oral; oral; intragastric; intestinal; nasal; transpulmonary, such as via bronchioles, alveoli or a combination thereof; parenteral; transepidermal; Dermis; transdermal; transconjunctival; transurethral; transvaginal; transrectal; and/or transocular. The composition may be an oral composition, and the route of administration is oral.

Several dosage forms, for example, solutions; suspensions; emulsions; microemulsions; multiple emulsions; foams; ointments; pastes; ointments; ointments; lozenges; coated lozenges; chewable tablets; lotions; Such as hard or soft gelatin capsules; suppositories; transrectal capsules; drops; gels; sprays; powders; aerosols; inhalants; eye drops; ophthalmic ointments; ophthalmic lotions; vaginal pessaries; Vaginal ointment; injection solution; in situ conversion solution, such as in situ gelation, styling, precipitation, and in situ crystallization; in the form of a perfusion solution; or administration of the composition as an implant.

The composition can be a coated tablet, capsule or chewable tablet as appropriate.

The composition may be further compounded in a pharmaceutical carrier or drug delivery system, for example to improve stability, bioavailability and/or solubility. In a particular embodiment, the composition can be attached to the system via covalent, hydrophobic, and/or electrostatic interactions. The purpose of the compounding can be, for example, to reduce adverse effects, achieve time therapy, and/or increase patient compliance.

The composition can also be used to formulate controlled, sustained, extended, delayed, and/or sustained release drug delivery systems.

Parenteral administration can be carried out by subcutaneous, intramuscular, intraperitoneal or intravenous injection via a syringe, optionally as a pen-like syringe or via a perfusion pump.

The composition can be administered nasally in the form of a solution, suspension or powder; or it can be administered pulmonaryly in the form of a liquid or powder spray.

Transdermal administration is another option, for example, by needle-free injection, from a patch such as an iontophoresis patch, or via a transmucosal route, such as a buccal.

The composition can be a stabilizing formulation. The term "stabilized formulation" refers to a formulation having increased physical and/or chemical stability, preferably both. In general, the formulation must be stable during use and storage (in accordance with recommended use and storage conditions) until the expiration date is reached.

The term "physical stability" refers to the tendency of a polypeptide to form biologically inactive and/or insoluble aggregates due to exposure to thermo-mechanical stress and/or interaction with destabilizing interfaces and surfaces such as hydrophobic surfaces. The physical stability of the aqueous polypeptide formulation can be assessed by visual inspection after various periods of exposure to mechanical/physical stress (e.g., agitation) at different temperatures and/or by turbidity measurements. Alternatively, physical stability can be assessed using spectroscopic agents or probes of the conformational state of the polypeptide, such as thioflavin T or "hydrophobic patch" probes.

The term "chemical stability" refers to a chemical (specifically, covalently) change in the structure of a polypeptide that results in the formation of a chemical degradation product that has potentially reduced bioavailability and/or increased immunogenic effect compared to the intact polypeptide. The chemical stability can be assessed by measuring the amount of chemical degradation products at various time points after exposure to different environmental conditions, such as by SEC-HPLC and/or RP-HPLC.

Treatment with a derivative of the invention may also be combined with one or more other pharmacologically active substances, Such as selected from the group consisting of an anti-diabetic agent, an anti-obesity agent, an appetite regulating agent, an antihypertensive agent, an agent for treating and/or preventing complications caused by or associated with diabetes, and for treating and/or preventing by obesity A combination of agents that produce or are associated with complications and conditions. Examples of such pharmacologically active substances are: insulin, sulfonyl urea, biguanide, meglitinide, glucosidase inhibitor, glycoside agonist, glycosidic antagonist, DPP-IV (two Peptidyl peptidase-IV) inhibitors, inhibitors of liver enzymes associated with stimulation of glucose and/or hepatic glycosemia, glucose uptake modulators, compounds that modify lipid metabolism, such as HMG CoA inhibitors (statin) (statin) anti-hyperlipidemic agent, gastric inhibitory polypeptide (GIP analog), compound that reduces food intake, RXR agonist and agent acting on β-cell-dependent ATP-dependent potassium channel; cholestyramine Colestipol, clofibrate, gemfibrozil, lovastatin, pravastatin, simvastatin, probucol, dextrothyroxine , neteglinide, repaglinide; beta-blockers, such as aprenolol, atenolol, timolol, pindo Pindolol, propranolol and metoprolol, ACE (angiotensin) Inhibitors, such as benazepril, captopril, enalapril, fosinopril, lisinopril, alapril (alatriopril), quinapril and ramipril, calcium channel blockers such as nifedipine, felodipine, nicardipine, y Isradipine, nimodipine, diltiazem and verapamil, and alpha-blockers such as doxazosin, urapidil, prazosin and Terazosin; CART (cocaine amphetamine-regulated transcript) agonist, NPY (neuropeptide Y) antagonist, PYY agonist, Y2 receptor agonist, Y4 receptor agonist, mixed Y2/Y4 receptor Agonist, MC4 (melanocortin 4) agonist, appetite hormone receptor antagonist, TNF (tumor necrosis factor) agonist, CRF (corticotropin releasing factor) agonist, CRF BP (corticotropin releasing factor binding) Protein) antagonist, urinary agonist, β 3 Agonists, acid modulators and analogues, MSH (melanocyte stimulating hormone) agonists, MCH (melanocyte aggregation hormone) antagonists, CCK (cholecystokinin) agonists, serotonin reuptake inhibitors, serotonin and nail Adrenergic reuptake inhibitors, mixed serotonin and norepinephrine activating compounds, 5HT (serotonin) agonists, bombesin agonists, fibroblast growth factor 21 (FGF-21), aglycone antagonists, Growth hormone, growth hormone releasing compound, TRH (thyroid stimulating hormone releasing hormone) agonist, UCP 2 or 3 (decoupled protein 2 or 3) modulator, leptin agonist, DA agonist (bromocriptin) , doprexin), lipase/amylase inhibitor, RXR (retinoid X receptor) modulator, TR beta agonist; histamine H3 antagonist, gastric inhibitor polypeptide agonist or antagonist (GIP analog), Gastrin and gastrin analogs.

Treatment with a derivative according to the invention may also be combined with surgery affecting glucose content and/or lipid homeostasis, such as gastric pouch surgery or gastric bypass.

Medical indications

The invention also relates to a derivative of the invention for use as a medicament.

In a particular embodiment, the derivatives of the invention are useful in the treatment of (i) prevention and/or treatment of all forms of diabetes, such as hyperglycemia, type 2 diabetes, abnormal glucose tolerance, type 1 diabetes, non- Insulin-dependent diabetes mellitus, MODY (young adult diabetes), gestational diabetes and/or reduction of HbA1C; (ii) delay or prevention of diabetes progression, such as progression of type 2 diabetes, delaying glucose tolerance abnormality (IGT) progression to Insulin type 2 diabetes is required, delaying or preventing insulin resistance and/or delaying the progression of type 2 diabetes requiring insulin to insulin type 2 diabetes; (iii) improving β-cell function, such as reducing beta-cell apoptosis, Increasing β-cell function and/or β-cell mass and/or restoring glucose sensitivity to β-cells; (iv) preventing and/or treating cognitive disorders and/or neurodegenerative disorders such as Alzheimer's disease ( Alzheimer's disease), Parkinson's disease and/or multiple sclerosis; (v) prevention and/or treatment of eating disorders, such as obesity, for example by reducing food intake, Reduce weight, suppress appetite, induce satiety; treat or prevent by taking antipsychotics or steroid-induced bulimia, psychosis and obesity; reduce gastric motility; delay gastric emptying; Increase body movement; and/or prevent and/or treat obesity comorbidities such as osteoarthritis and/or urinary incontinence; (vi) prevent and/or treat diabetic complications such as vascular disease; neuropathy, including peripheral neuropathy (nephropathy; and/or retinopathy; (vii) improved lipid parameters such as prevention and/or treatment of dyslipidemia, reduction of total serum lipids; increased HDL; decreased low density LDL; decreased VLDL; decreased triglycerides; Decreasing the plasma content of lipoprotein a (Lp(a)) in the human body; inhibiting the production of apolipoprotein a (apo(a)) in vitro and/or in vivo; (viii) preventing and/or treating cardiovascular diseases, such as Syndrome X, atherosclerosis, myocardial infarction, coronary heart disease, reperfusion injury, stroke, cerebral ischemia, early cardiac or early cardiovascular disease, left ventricular hypertrophy, coronary artery disease, hypertension, essential hypertension, acute Hypertensive emergency, cardiomyopathy, cardiac insufficiency, exercise intolerance, acute and/or chronic heart failure, arrhythmia, arrhythmia, syncope, angina pectoris, cardiac bypass and/or stent reocclusion, atheroschlerosis oblitterens , diastolic dysfunction and / or systolic dysfunction; and / or lower blood pressure, such as reducing systolic blood pressure; (ix) prevention and / or treatment of gastrointestinal diseases, such as inflammatory bowel disease, short bowel syndrome or Crohn's disease (Crohn's Disease or colitis; indigestion and/or gastric ulcer; and/or inflammation, such as psoriasis, psoriatic arthritis, rheumatoid arthritis and/or systemic lupus erythematosus; (x) prevention and/or treatment of critical illness Diseases, such as treatment of critically ill patients, critically ill patients with multiple kidney disease (CIPNP) and/or potential CIPNP patients; prevention of the development of critical illness or CIPNP; prevention, treatment and/or cure of systemic inflammatory response syndrome (SIRS) in patients; prevention Or reduce the likelihood of bacteremia, sepsis, and/or septic shock during hospitalization; and/or blood in patients with intensive care units with acute illness , The presence of insulin metabolic balance and optionally stabilized; (xi) prevention and/or treatment of polycystic ovary syndrome (PCOS); (xii) prevention and/or treatment of brain diseases such as cerebral ischemia, cerebral hemorrhage and/or traumatic brain injury; (xiii) prevention and/or prevention Treat sleep apnea; and/or (xiv) prevent and/or treat abuse, such as alcohol abuse and/or substance abuse.

In a particular embodiment, the indication is selected from the group consisting of (i)-(xiv), such as indications (i)-(viii), (x)-(xiii), and/or (xiv), and One or the other way associated with diabetes.

In another specific embodiment, the indication is selected from the group consisting of: (i)-(iii) and (v)-(viii), such as indications (i), (ii), and/or (iii) Or indication (v), indication (vi), indication (vii) and/or indication (viii).

In another specific embodiment, the indication is (i). In another specific embodiment, the indication is (v). In another specific embodiment, the indication is (viii).

The following indications are particularly good: type 2 diabetes and/or obesity.

Specific specific example

The following are specific examples of the invention:

A derivative of a GLP-1 peptide, wherein the GLP-1 peptide comprises a peptide of the following formula I: Formula I: Xaa ₇ -Xaa ₈ -Glu-Gly-Thr-Xaa ₁₂ -Thr-Ser -Asp-Xaa ₁₆ -Ser-Xaa ₁₈ -Xaa ₁₉ -Xaa ₂₀ -Glu-Xaa ₂₂ -Xaa ₂₃ -Ala-Xaa ₂₅ -Xaa ₂₆ -Xaa ₂₇ -Phe-Ile-Xaa ₃₀ -Xaa ₃₁ -Leu-Xaa ₃₃ -Xaa ₃₄ -Xaa ₃₅ -Xaa ₃₆ -Xaa ₃₇ -Xaa ₃₈ -Xaa ₃₉ -Xaa ₄₀ -Xaa ₄₁ -Xaa ₄₂ , wherein Xaa ₇ is L-histamine, (S)-2-hydroxy-3-(1H - imidazol-4-yl) - propionic acid, D- histidine, histidine amino group to the high-histidine, N ^[alpha] - acetylsalicylic histidine, N ^[alpha] - methyl acyl histidine, N ^Α -methylhistamine, 3-pyridinealanine, 2-pyridinealanine or 4-pyridinealanine; Xaa ₈ is Ala, Gly, Ser, Aib, (1-aminocyclopropyl)carboxylic acid or (1) -Aminocyclobutyl)carboxylic acid; Xaa ₁₂ is Phe or Leu; Xaa ₁₆ is Val or Leu; Xaa ₁₈ is Ser, Arg, Lys, Val or Leu; Xaa ₁₉ is Tyr or Gln; Xaa ₂₀ is Leu or Met; Xaa ₂₂ is Gly or Glu; Xaa ₂₃ is Gln, Glu, Lys or Arg; Xaa ₂₅ is Ala or Val; Xaa ₂₆ is Arg or Lys; Xaa ₂₇ is Glu, Lys or Leu; Xaa ₃₀ is Ala, Glu or Arg; Xaa ₃₁ is Trp, Lys or His; Xaa ₃₃ is Val, Lys Or Arg; Xaa ₃₄ is Lys, Arg, His, Asn or Gln; Xaa ₃₅ is Gly or Ala; Xaa ₃₆ is Arg, Lys or Gly; Xaa ₃₇ is Gly or Pro; Xaa ₃₈ is Ser, Gly, Ala, Glu, Pro or Lys; Xaa ₃₉ is Ser, Gly, Ala, Glu or Pro; Xaa ₄₀ is Ser, Gly, Ala, Glu or Pro; Xaa ₄₁ is Ser, Gly, Ala, Glu or Pro; and Xaa ₄₂ is Lys; The restriction condition is that at least one of Xaa ₁₈ , Xaa ₂₃ , Xaa ₂₇ , Xaa ₃₁ , Xaa ₃₆ or Xaa ₃₈ is Lys; wherein Lys at Xaa ₄₂ is the first K residue, and is in Xaa ₁₈ , Xaa ₂₃ , Lys at one of Xaa ₂₇ , Xaa ₃₁ , Xaa ₃₆ or Xaa ₃₈ is a second K residue; the derivative comprises first and second extensions respectively linked to the first and second K residues, wherein the first and the second extension portion is selected from chemical formula 1, chemical chemical formula 1a and formula 1b: chemical formula _{1: HOOC- (CH 2) 18} -CO- *, the formula _{1a: HOOC- (CH 2) 17} -CO- * And Chemical Formula 1b: HOOC-(CH ₂ ) ₂₀ -CO-*; or a pharmaceutically acceptable salt thereof, guanamine or ester.

2. The derivative of embodiment 1, wherein the GLP-1 peptide comprises at least two Lys residues.

3. The derivative of any one of embodiments 1 to 2, wherein the GLP-1 peptide comprises two Lys residues.

4. The derivative of any one of embodiments 1 to 3, wherein the GLP-1 peptide has two Lys residues.

5. The derivative of any of embodiments 1 to 4, wherein the GLP-1 peptide has only two Lys residues.

6. The derivative according to any one of embodiments 1 to 5, wherein one of Xaa ₁₈ , Xaa ₂₃ , Xaa ₂₇ , Xaa ₃₁ , Xaa ₃₆ or Xaa ₃₈ is Lys.

7. The derivative according to any one of embodiments 1 to 6, wherein one of Xaa ₁₈ , Xaa ₂₃ , Xaa ₂₇ , Xaa ₃₁ , Xaa ₃₆ or Xaa ₃₈ is Lys.

8. The derivative of any of embodiments 1 to 7, wherein Lys at Xaa ₁₈ is the second K residue.

9. The derivative of any of embodiments 1 to 8, wherein Lys at Xaa ₂₃ is the second K residue.

10. The derivative of any of embodiments 1 to 9, wherein Lys at Xaa ₂₇ is the second K residue.

11. The derivative of any one of embodiments 1 to 10, wherein Lys at Xaa ₃₁ is the second K residue.

12. The derivative of any of embodiments 1 to 11, wherein Lys at Xaa ₃₆ is the second K residue.

13. The derivative of any of embodiments 1 to 12, wherein Lys at Xaa ₃₈ is the second K residue.

14. The derivative of any of embodiments 1 to 4, wherein Xaa ₇ is His.

15. The derivative of any of embodiments 1 to 14, wherein Xaa ₇ is a deaminoglycolic acid.

16. The derivative of any of embodiments 1 to 15, wherein Xaa ₈ is Aib.

17. The derivative of any of embodiments 1 to 16, wherein Xaa ₁₂ is Phe.

The derivative of any one of embodiments 1 to 17, wherein Xaa ₁₆ is Val.

The derivative according to any one of embodiments 1 to 18, wherein Xaa ₁₈ is Ser or Lys.

The derivative according to any one of embodiments 1 to 19, wherein Xaa ₁₈ is Ser.

The derivative according to any one of embodiments 1 to 19, wherein Xaa ₁₈ is Lys.

The derivative according to any one of embodiments 1 to 21, wherein Xaa ₁₉ is Tyr.

The derivative according to any one of embodiments 1 to 22, wherein Xaa ₂₀ is Leu.

The derivative of any one of embodiments 1 to 23, wherein Xaa ₂₂ is Glu.

The derivative according to any one of embodiments 1 to 24, wherein Xaa ₂₃ is Gln or Lys.

The derivative according to any one of embodiments 1 to 25, wherein Xaa ₂₃ is Gln.

27. The derivative of any one of embodiments 1 to 25, wherein Xaa ₂₃ is Lys.

The derivative according to any one of embodiments 1 to 27, wherein Xaa ₂₅ is Ala.

The derivative according to any one of embodiments 1 to 28, wherein Xaa ₂₆ is Arg.

The derivative according to any one of embodiments 1 to 29, wherein Xaa ₂₇ is Glu or Lys.

The derivative of any one of embodiments 1 to 30, wherein Xaa ₂₇ is Glu.

The derivative according to any one of embodiments 1 to 30, wherein Xaa ₂₇ is Lys.

The derivative of any one of embodiments 1 to 32, wherein Xaa ₃₀ is Ala.

The derivative of any one of embodiments 1 to 33, wherein Xaa ₃₁ is Trp or Lys.

The derivative of any one of embodiments 1 to 34, wherein Xaa ₃₁ is Lys.

The derivative of any one of embodiments 1 to 34, wherein Xaa ₃₁ is Trp.

The derivative of any one of embodiments 1 to 36, wherein Xaa ₃₃ is Val.

The derivative of any one of embodiments 1 to 37, wherein Xaa ₃₄ is Arg.

The derivative of any one of embodiments 1 to 38, wherein Xaa ₃₅ is Gly.

The derivative of any one of embodiments 1 to 39, wherein Xaa ₃₆ is Arg or Lys.

The derivative of any one of embodiments 1 to 40, wherein Xaa ₃₆ is Arg.

The derivative of any one of embodiments 1 to 40, wherein Xaa ₃₆ is Lys.

43. The derivative of any of embodiments 1 to 42, wherein Xaa ₃₇ is Gly.

The derivative of any one of embodiments 1 to 43, wherein Xaa ₃₈ is Gly, Ala, Glu, Pro or Lys.

The derivative of any of embodiments 1 to 44, wherein Xaa ₃₈ is Gly.

The derivative of any one of embodiments 1 to 44, wherein Xaa ₃₈ is Ala.

The derivative of any one of embodiments 1 to 44, wherein Xaa ₃₈ is Glu.

The derivative of any one of embodiments 1 to 44, wherein Xaa ₃₈ is Pro.

The derivative of any one of embodiments 1 to 44, wherein Xaa ₃₈ is Lys.

The derivative of any one of embodiments 1 to 49, wherein Xaa ₃₉ is Ser, Gly, Ala, Glu or Pro.

The derivative of any one of embodiments 1 to 50, wherein Xaa ₃₉ is Ser.

The derivative of any one of embodiments 1 to 50, wherein Xaa ₃₉ is Gly.

The derivative of any one of embodiments 1 to 50, wherein Xaa ₃₉ is Ala.

The derivative of any one of embodiments 1 to 50, wherein Xaa ₃₉ is Glu.

The derivative of any one of embodiments 1 to 50, wherein Xaa ₃₉ is Pro.

The derivative of any one of embodiments 1 to 55, wherein Xaa ₄₀ is Ser, Gly, Ala, Glu or Pro.

The derivative of any one of embodiments 1 to 56, wherein Xaa ₄₀ is Ser.

The derivative of any one of embodiments 1 to 56, wherein Xaa ₄₀ is Gly.

The derivative of any one of embodiments 1 to 56, wherein Xaa ₄₀ is Ala.

The derivative of any one of embodiments 1 to 56, wherein Xaa ₄₀ is Glu.

The derivative of any one of embodiments 1 to 56, wherein Xaa ₄₀ is Pro.

The derivative of any one of embodiments 1 to 62, wherein Xaa ₄₁ is Ser, Gly, Ala, Glu or Pro.

The derivative of any one of embodiments 1 to 63, wherein Xaa ₄₁ is Ser.

The derivative of any one of embodiments 1 to 63, wherein Xaa ₄₁ is Gly.

The derivative of any one of embodiments 1 to 63, wherein Xaa ₄₁ is Ala.

The derivative of any one of embodiments 1 to 63, wherein Xaa ₄₁ is Glu.

The derivative of any one of embodiments 1 to 63, wherein Xaa ₄₁ is Pro.

The derivative of any one of embodiments 1 to 68, wherein the GLP-1 peptide is a peptide of formula I.

The derivative according to any one of embodiments 1 to 69, wherein in the formula I, Xaa ₇ is L-histamine acid, (S)-2-hydroxy-3-(1H-imidazol-4-yl) -propionic acid, D-histamine, deaminoglycolic acid, N ^α -ethinyl histidine, N ^α -formyl histidine, N ^α -methylhistamine; Xaa ₈ is Ala , Gly, Ser, Aib, (1-aminocyclopropyl)carboxylic acid or (1-aminocyclobutyl)carboxylic acid; Xaa ₁₂ is Phe; Xaa ₁₆ is Val or Leu; Xaa ₁₈ is Ser, Arg or Lys; Xaa ₁₉ is Tyr or Gln; Xaa ₂₀ is Leu or Met; Xaa ₂₂ is Gly or Glu; Xaa ₂₃ is Gln, Glu, Lys or Arg; Xaa ₂₅ is Ala or Val; Xaa ₂₆ is Arg or Lys; Xaa ₂₇ is Glu Lys or Leu; Xaa ₃₀ is Ala or Glu; Xaa ₃₁ is Trp, Lys or His; Xaa ₃₃ is Val, Lys or Arg; Xaa ₃₄ is Lys, Arg or Asn; Xaa ₃₅ is Gly; Xaa ₃₆ is Arg, Lys Or Gly; Xaa ₃₇ is Gly or Pro; Xaa ₃₈ is Gly, Ala, Glu, Pro or Lys; Xaa ₃₉ is Ser, Gly, Ala, Glu or Pro; Xaa ₄₀ is Ser, Gly, Ala, Glu or Pro; Xaa ₄₁ is Ser, Gly, Ala, Glu or Pro; and Xaa ₄₂ is Lys.

The derivative according to any one of embodiments 1 to 70, wherein in the formula I, Xaa ₇ is L-histamine acid, deaminoglycolic acid; Xaa ₈ is Aib; Xaa ₁₂ is Phe; Xaa ₁₆ Is Val; Xaa ₁₈ is Ser or Lys; Xaa ₁₉ is Tyr; Xaa ₂₀ is Leu; Xaa ₂₂ is Glu; Xaa ₂₃ is Gln or Lys; Xaa ₂₅ is Ala; Xaa ₂₆ is Arg; Xaa ₂₇ is Glu or Lys; Xaa ₃₀ is Ala; Xaa ₃₁ is Trp or Lys; Xaa ₃₃ is Val; Xaa ₃₄ is Arg; Xaa ₃₅ is Gly; Xaa ₃₆ is Arg or Lys; Xaa ₃₇ is Gly; Xaa ₃₈ is Gly, Ala, Glu, Pro or Lys Xaa ₃₉ is Ser, Gly, Ala, Glu or Pro; Xaa ₄₀ is Ser, Gly, Ala, Glu or Pro; Xaa ₄₁ is Ser, Gly, Ala, Glu or Pro; and Xaa ₄₂ is Lys.

The derivative of any one of embodiments 1 to 71, wherein the GLP-1 peptide has up to 12 amine groups when compared to GLP-1 (7-37) (SEQ ID NO: 1) The acid changes.

The derivative of any one of embodiments 1 to 72, wherein the GLP-1 peptide has up to 11 amine groups when compared to GLP-1 (7-37) (SEQ ID NO: 1) The acid changes.

The derivative of any one of embodiments 1 to 73, wherein the GLP-1 peptide has up to 10 amine groups when compared to GLP-1 (7-37) (SEQ ID NO: 1) The acid changes.

The derivative of any one of embodiments 1 to 74, wherein the GLP-1 peptide has up to 9 amine groups when compared to GLP-1 (7-37) (SEQ ID NO: 1) The acid changes.

The derivative of any one of embodiments 1 to 75, wherein the GLP-1 peptide has up to 8 amine groups when compared to GLP-1 (7-37) (SEQ ID NO: 1) The acid changes.

77. The derivative of any of embodiments 1 to 76, wherein the GLP-1 peptide has up to 7 amine groups when compared to GLP-1 (7-37) (SEQ ID NO: 1) The acid changes.

78. The derivative of any one of embodiments 1 to 77, wherein the GLP-1 peptide is in phase There are up to 6 amino acid changes compared to GLP-1 (7-37) (SEQ ID NO: 1).

The derivative of any one of embodiments 1 to 78, wherein the GLP-1 peptide has up to 5 amine groups when compared to GLP-1 (7-37) (SEQ ID NO: 1) The acid changes.

The derivative of any one of embodiments 1 to 79, wherein the GLP-1 peptide has a minimum of 5 amine groups when compared to GLP-1 (7-37) (SEQ ID NO: 1) The acid changes.

The derivative of any one of embodiments 1 to 80, wherein the GLP-1 peptide has a minimum of 6 amine groups when compared to GLP-1 (7-37) (SEQ ID NO: 1) The acid changes.

The derivative of any one of embodiments 1 to 81, wherein the GLP-1 peptide has a minimum of 7 amine groups when compared to GLP-1 (7-37) (SEQ ID NO: 1) The acid changes.

The derivative of any one of embodiments 1 to 82, wherein the GLP-1 peptide has a minimum of 8 amine groups when compared to GLP-1 (7-37) (SEQ ID NO: 1) The acid changes.

The derivative of any one of embodiments 1 to 83, wherein the GLP-1 peptide has at least 9 amine groups when compared to GLP-1 (7-37) (SEQ ID NO: 1) The acid changes.

The derivative of any one of embodiments 1 to 84, wherein the GLP-1 peptide has a minimum of 10 amine groups when compared to GLP-1 (7-37) (SEQ ID NO: 1) The acid changes.

The derivative of any one of embodiments 1 to 85, wherein the GLP-1 peptide has 5 amino acids when compared to GLP-1 (7-37) (SEQ ID NO: 1) change.

The derivative of any one of embodiments 1 to 85, wherein the GLP-1 peptide has 6 amino acids when compared to GLP-1 (7-37) (SEQ ID NO: 1) change.

The derivative of any one of embodiments 1 to 85, wherein the GLP-1 peptide has 7 amino acids when compared to GLP-1 (7-37) (SEQ ID NO: 1) change.

The derivative of any one of embodiments 1 to 85, wherein the GLP-1 peptide has 8 amino acids when compared to GLP-1 (7-37) (SEQ ID NO: 1) change.

90. The derivative of any one of embodiments 1 to 85, wherein the GLP-1 peptide has 9 amino acids when compared to GLP-1 (7-37) (SEQ ID NO: 1) change.

The derivative of any one of embodiments 1 to 85, wherein the GLP-1 peptide has 10 amino acids when compared to GLP-1 (7-37) (SEQ ID NO: 1) change.

The derivative of any one of embodiments 1 to 85, wherein the GLP-1 peptide is selected from the group consisting of the following analogues of GLP-1 (7-37) (SEQ ID NO: 1): i) 8Aib, 22E, 26R, 27K, 34R, 38G, 39G, 40G, 41S, 42K) (SEQ ID NO: 2); ii) (8Aib, 22E, 26R, 31K, 34R, 38G, 39G, 40G, 41S, 42K (SEQ ID NO: 3); iii) (8Aib, 22E, 26R, 34R, 38K, 39G, 40G, 41S, 42K) (SEQ ID NO: 4); iv (8Aib, 22E, 23K, 26R, 34R, 38G, 39G, 40G, 41S, 42K) (SEQ ID NO: 5); v) (8Aib, 22E, 26R, 34R, 36K, 38G, 39G, 40G, 41S, 42K) (SEQ ID NO: 6); (8Aib, 18K, 22E, 26R, 34R, 38G, 39G, 40G, 41S, 42K) (SEQ ID NO: 7); vii) (7Imp, 8Aib, 22E, 26R, 34R, 38K, 39G, 40G, 41S) , 42K) (SEQ ID NO: 8); iix) (8Aib, 22E, 26R, 34R, 36K, 38A, 39E, 40S, 41P, 42K) (SEQ ID NO: 9); ix) (8Aib, 22E, 26R , SEQ ID NO: 10) (xAib, 22E, 26R, 34R :11);xi)(8Aib, 22E, 26R, 34R, 38K, 39P, 40E, 41G, 42K) (SEQ ID NO: 12); xii) (8Aib, 22E, 26R, 34R, 38K, 39S, 40A, 41E, 42K) (SEQ ID NO: 13); and xiii) (8Aib, 22E, 26R, 34R, 38K, 39S, 40P, 41E, 42K) (SEQ ID NO: 14).

The derivative of any one of embodiments 1 to 92, wherein each of the first and second extensions is Chemical Formula 1.

The derivative of any of embodiments 1 to 92, wherein each of the first and second extensions is of Formula 1a.

The derivative of any one of embodiments 1 to 92, wherein each of the first and second extensions is of Formula 1b.

The derivative of any one of embodiments 1 to 95, wherein the first and the second extension Each of the sub-portions is connected to the first and second K residues, respectively, via the first and second linkers, respectively.

97. The derivative of embodiment 96, wherein each of the first and second extensions are, respectively, ligated to the first and second K residues via a first and second linker, respectively.

98. The derivative of any one of embodiments 96 to 97, wherein the first and second linkers each have a *-NH or *-N group and a *-CO group.

The derivative of any one of embodiments 96 to 98, wherein each of the first and the second linker comprises element 1 of formula 2:

100. The derivative of any one of embodiments 96 to 99, wherein each of the first and second linkers has an element 1 of formula 2.

The derivative of any one of embodiments 99 to 100, wherein the chemical formula 2 represents a gGlu residue.

The derivative according to any one of embodiments 99 to 101, wherein the element 1 is an L-gGlu residue.

The derivative of any one of the examples 96 to 102, wherein each of the first and the second linker comprises element 2 of chemical formula 3: Wherein k is an integer in the range of 1-5, and n is an integer in the range of 1-5.

104. The derivative of embodiment 103, wherein each of the first and the second linker One contains at least one element 2 of Chemical Formula 3.

The derivative of any one of the examples 103 to 104, wherein each of the first and the second linkers comprises at least two element 2 of the chemical formula 3.

106. The derivative of any one of embodiments 103 to 105, wherein each of the first and second linkers comprises two elements 2 of formula 3.

The derivative of any one of the examples 103 to 106, wherein each of the first and the second linker has two elements 2 of the chemical formula 3.

The derivative of any one of the examples 103 to 107, wherein each of the first and the second linker comprises four elements 2 of the chemical formula 3.

The derivative of any one of the examples 103 to 108, wherein each of the first and the second linker has four element 2 of the chemical formula 3.

The derivative of any one of embodiments 103 to 109, wherein each of the first and the second linker comprises five element 2 of formula 3.

The derivative of any one of the examples 103 to 110, wherein each of the first and the second linker has five element 2 of the chemical formula 3.

The derivative of any one of the examples 103 to 111, wherein each of the first and the second linker comprises six element 2 of the chemical formula 3.

The derivative of any one of the examples 103 to 112, wherein each of the first and the second linker has six element 2 of the chemical formula 3.

The derivative of any one of embodiments 103 to 113, wherein k=1 and n=1.

The derivative according to any one of the examples 103 to 114, wherein the chemical formula 3 represents OEG.

116. The derivative of any one of embodiments 103 to 104, wherein each of the first and second linkers comprises element 2 of formula 3.

117. The derivative of any one of embodiments 103 to 104 and 116, wherein the first Each of the second links has an element 2 of Chemical Formula 3.

The derivative of any one of embodiments 116 to 117, wherein k=3 and n=2.

119. The derivative of any one of embodiments 116 to 118, wherein the chemical formula 3 represents dPEG4.

120. The derivative of any one of embodiments 96 to 119, wherein each of the first and the second linker comprises element 3 of formula 4:

The derivative of any one of the examples 96 to 120, wherein each of the first and second linkers has an element 3 of the chemical formula 4.

The derivative according to any one of embodiments 120 to 121, wherein the chemical formula 4 represents Trx.

The derivative of any one of the examples 96 to 122, wherein each of the first and the second linker comprises element 4 of Chemical Formula 5: Chemical Formula 5: *-NH-(CH ₂ ) _q -CH[(CH ₂ ) _w -NH ₂ ]-CO-*, where q is an integer in the range 0-5, and w is an integer in the range 0-5, with the constraint that when w is 0 , q is an integer in the range of 1-5, and when q is 0, w is an integer in the range of 1-5.

124. The derivative of embodiment 123, wherein each of the first and second linkers comprises at least one element 4 of Formula 5.

The derivative of any one of embodiments 123 to 124, wherein each of the first and second linkers comprises at least two element 4 of formula 5.

126. The derivative of any one of embodiments 123 to 125, wherein each of the first and second linkers comprises two elements 4 of formula 5.

127. The derivative of any one of embodiments 123 to 126, wherein each of the first and second linkers has two element 4 of formula 5.

The derivative of any one of embodiments 123 to 127, wherein q is 4 and w is 0.

129. The derivative of any one of embodiments 123 to 127, wherein w is 4 and q is 0.

The derivative according to any one of the examples 123 to 129, wherein the chemical formula 5 represents an eps-Lys residue.

The derivative according to any one of embodiments 123 to 130, wherein the element 4 is an L-eps-Lys residue.

The derivative of any one of embodiments 96 to 131, wherein each of the first and the second linker comprises element 5 of chemical formula 6: Wherein y is 1 or 2, z is 1 or 2, p is 0 or 1, and X represents a carbon atom-oxygen atom.

133. The derivative of embodiment 132, wherein each of the first and second linkers has an element 5 of formula 6.

134. The derivative of any one of embodiments 132 to 133, wherein y is 2, z is 2, p is 1, and X represents an oxygen atom.

135. The derivative of embodiment 134, wherein formula 6 represents a TotaGlyc residue of formula 7:

136. The derivative of any one of embodiments 132 to 133, wherein y is 2 and z is 2. p is 0 and X represents a carbon atom.

137. The derivative of embodiment 136, wherein the chemical formula 6 represents a TtdSuc. residue of Chemical Formula 8:

138. The derivative of any one of embodiments 132 to 133, wherein y is 1, z is 1, p is 0, and X represents a carbon atom.

139. The derivative of embodiment 138, wherein the chemical formula 6 represents a DooaSuc residue of formula 9:

The derivative of any one of embodiments 96 to 139, wherein each of the first and the second linker comprises element 6 of formula 10:

141. The derivative of any one of embodiments 96 to 140, wherein each of the first and second linkers has a factor 6 of formula 10.

142. The derivative of any one of embodiments 140 to 141, wherein the chemical formula 10 represents an Inp residue.

144. The derivative of any one of embodiments 1 to 142, which comprises the following connecting elements At least one of: element 1, element 2, element 3, element 4, element 5, and element 6.

145. The derivative of embodiment 144, wherein each of the linking elements is defined in any one of the specific examples 99 to 142.

146. The derivative of any one of embodiments 1 to 145, wherein each of the first and second linkers consists of element 3 of formula 4, element 1 of formula 2, and two formula 3 Element 2 consists of k=1 and n=1, which are interconnected via a guanamine bond and in the specified order.

147. The derivative of any one of embodiments 1 to 145, wherein each of the first and second linkers consists of element 3 of formula 4, element 1 of formula 2, and four chemical formula 3 Element 2 consists of k=1 and n=1, which are interconnected via a guanamine bond and in the specified order.

148. The derivative of any one of embodiments 1 to 145, wherein each of the first and second linkers consists of element 3 of a chemical formula 4, element 1 of a chemical formula 2, and six chemical formula 3 Element 2 consists of k=1 and n=1, which are interconnected via a guanamine bond and in the specified order.

149. The derivative of any of embodiments 1 to 145, wherein each of the first and second linkers consists of a factor 3 of formula 4, an element 1 of formula 2, and a formula 3 Element 2 consists of k=3 and n=2, which are interconnected via a guanamine bond and in the specified order.

The derivative of any one of the first to the second, wherein each of the first and the second linker is an element 3 of the chemical formula 4, an element 1 of the chemical formula 2, and two chemical formulas 5 Element 4 consists of where q = 4 and w = 0 (or w = 4 and q = 0), the elements are interconnected via a guanamine bond and in the specified order.

151. The derivative of any one of embodiments 1 to 145, wherein each of the first and second linkers consists of element 3 of a chemical formula 4, element 1 of a chemical formula 2, and a Element 5 of Chemical Formula 9 is composed, which are interconnected via a guanamine bond and in the specified order.

152. The derivative of any of embodiments 1 to 145, wherein each of the first and second linkers consists of element 1 of formula 2 and element 4 of two formula 5, wherein q = 4 and w = 0 (or w = 4 and q = 0), the elements are interconnected via a guanamine bond and in the specified order.

153. The derivative of any one of embodiments 1 to 145, wherein each of the first and second linkers consists of element 1 of formula 2 and element 2 of four chemical formula 3, wherein k =1 and n=1, the elements are interconnected via a guanamine bond and in the specified order.

154. The derivative of any of embodiments 1 to 145, wherein each of the first and second linkers consists of element 1 of formula 2 and element 5 of formula 7, the elements Interconnected via a guanamine bond and in the specified order.

155. The derivative of any one of embodiments 1 to 145, wherein each of the first and second linkers consists of two element 4 of formula 5 and four element 2 of formula 3, wherein k=1 and n=1, the elements are interconnected via a guanamine bond and in the specified order.

156. The derivative of any one of embodiments 1 to 145, wherein each of the first and second linkers consists of two element 4 of formula 5 and five element 2 of formula 3, wherein k=1 and n=1, the elements are interconnected via a guanamine bond and in the specified order.

157. The derivative of any of embodiments 1 to 145, wherein each of the first and second linkers consists of two element 4 of formula 5 and element 2 of six chemical formula 3, wherein k=1 and n=1, the elements are interconnected via a guanamine bond and in the specified order.

158. The derivative of any one of embodiments 1 to 145, wherein each of the first and second linkers is a factor 6 of a chemical formula 10, an element 1 of a chemical formula 2, and a chemical formula 8 Element 5 consists of the elements interconnected via a guanamine bond and in the specified order.

159. The derivative of any one of embodiments 1 to 158, wherein the first and second extensions, such as each of the chemical formula 1, formula 1a or formula 1b, of the CO-* group are respectively considered a case in which the ε of the first and second K residues are respectively connected via the first and second linkers Amine.

The derivative according to any one of the preceding claims 1 to 159, wherein the first and second extensions, such as each of the chemical formula 1, the chemical formula 1a or the chemical formula 1b, of the CO-* group are respectively considered The condition is linked to the epsilon amine group of the first and second K residues, respectively, via the first and second linkers.

161. The derivative of any one of embodiments 1 to 160, wherein each of the first and second extensions are separately connected via a first and a second linker under the formation of a guanamine bond, as appropriate The epsilon amine group to the first and second K residues is linked via the first and second extensions and the first amine and the second K residue.

162. The derivative of any one of embodiments 1 to 161, wherein each of the first and second extensions are separately connected via a first and a second linker under the formation of a guanamine bond, as appropriate The epsilon amine group to the first and second K residues is linked via the first and second extensions and the first amine and the second K residue.

163. The derivative of any one of embodiments 1 to 162, wherein the CO-* group of each of the first and the second extensions is linked to the first and second linkers, respectively a *-NH or *-N group, and the *-CO group of each of the first and second linkers is attached to the epsilon amine group of the first and second K residues, respectively .

164. The derivative of any of embodiments 1 to 163 which is in the form of an acidic or basic salt.

165. The derivative of any of embodiments 1 to 164 which is in the form of an acid salt.

166. The derivative of any one of embodiments 1 to 165 which is in the form of an acetate.

167. The derivative of any of embodiments 1 to 163 which is in the form of a basic salt.

168. The derivative of any of embodiments 1 to 167, which is in the form of a sodium or potassium salt.

169. The derivative of any one of embodiments 1 to 168 which is in the form of a sodium salt.

170. The derivative of any of embodiments 1 to 169 which is in the form of a potassium salt.

171. The derivative of any one of embodiments 1 to 170 which is a GLP-1 receptor agonist.

172. The derivative of any of embodiments 1 to 171 which is a full GLP-1 receptor agonist.

173. The derivative of any of embodiments 1 to 172 which is biologically active in vitro.

174. The derivative of any of embodiments 1 to 173 which is potent in vitro.

175. The derivative of any one of embodiments 1 to 174, which is capable of activating the human GLP-1 receptor.

176. The derivative of any one of embodiments 1 to 175, which is capable of activating the human GLP-1 receptor by analysis of whole cells expressing the human GLP-1 receptor, wherein in the absence of HSA (0) % HSA) and/or in the presence of HSA (1% HSA), preferably in the absence of HSA.

177. The derivative of any one of embodiments 1 to 176, wherein the human GLP-1 receptor response is measured by a reporter gene assay, such as the analysis of Example 29.

178. The derivative of any one of embodiments 1 to 177, wherein the in vitro bioactivity or potency is determined substantially as described in Example 29.

179. Specific examples of a derivative of any of 1 to 178, having an in vitro potency corresponding to 400pM 400pM or less of the EC _50.

180. Specific examples of a derivative of any of 1 to 179, which corresponds to an inner tube 300pM 300pM or less of the potency EC _50.

181. Specific examples of a derivative of any of 1 to 180, which corresponds to having an in-vitro efficacy of 100pM 100pM or less, or ₅₀ EC.

182. Specific examples of a derivative of any of 1 to 181, which corresponds to an inner tube 75pM 75pM or less of the potency EC _50.

Effectiveness 183. As specific examples 1 to 182 to any of a derivative, which corresponds to the inner tube having 55pM 55pM or less of the EC _50.

184. Specific examples of a derivative of any of 1 to 183, having an in vitro potency corresponding to 40pM 40pM or less of the EC _50.

185. Specific examples of the effectiveness of a derivative according to any one of 184, which corresponds to the inner tube having 25pM 25pM or less of the EC _50.

186. Specific examples of a derivative of any of 1 to 183, which corresponds to having an in-vitro efficacy 15pM 15pM or less of EC _50.

187. Specific examples of a derivative of any of 1 to 183, which corresponds to having an in-vitro efficacy 10pM 10pM or less of EC _50.

179 to 188. Specific examples of a derivative of any one of 187, wherein said substantially the EC ₅₀ was determined as described in Example 29.

189. Specific examples of a derivative of any of 1 to 188, which corresponds to less than an inner tube semaglutide of the EC ₅₀ of 50 times the potency of EC _50, wherein the EC ₅₀ of semaglutide system It was determined in the same manner as the EC _{50 of} the derivative.

190. Specific examples of a derivative of any of 1 to 189, which corresponds to less than an inner tube semaglutide of the EC ₅₀ of 40 times the potency of EC _50, wherein the EC ₅₀ of semaglutide system It was determined in the same manner as the EC _{50 of} the derivative.

191. Specific examples of a derivative of any of 1 to 190, with in vitro efficacy corresponds to less than the semaglutide of times the EC 30 EC ₅₀ of _50, wherein the EC ₅₀ of semaglutide system It was determined in the same manner as the EC _{50 of} the derivative.

192. Derivative according to any of the specific examples 1 to 191, which corresponds to less than an inner tube semaglutide of the EC 20 is ₅₀ times the potency of the EC _50, wherein the EC ₅₀ of semaglutide system It was determined in the same manner as the EC _{50 of} the derivative.

193. Specific examples of a derivative of any of 1 to 192, with in vitro efficacy corresponds to less than semaglutide. 8 times the EC of the EC ₅₀ of _50, wherein the EC ₅₀ of semaglutide system It was determined in the same manner as the EC _{50 of} the derivative.

194. Specific examples of a derivative of any of 1 to 193, with in vitro efficacy corresponds to less than semaglutide. 5 times the EC of the EC ₅₀ of _50, wherein the EC ₅₀ of semaglutide system It was determined in the same manner as the EC _{50 of} the derivative.

195. Specific examples of a derivative of any of 1 to 194, which corresponds to less than an inner tube semaglutide of 3.5 of the EC ₅₀ EC ₅₀ times the potency of, wherein the EC ₅₀ of semaglutide system It was determined in the same manner as the EC _{50 of} the derivative.

196. Specific examples of a derivative of any of 1 to 195, with in vitro efficacy corresponds to less than semaglutide 2 times the EC of the EC ₅₀ of _50, wherein the EC ₅₀ of semaglutide system It was determined in the same manner as the EC _{50 of} the derivative.

189 to 197. Specific examples of the derivatives according to any one of 196, wherein said substantially the EC ₅₀ was determined as described in Example 29.

198. The derivative of any one of embodiments 1 to 197, which is capable of binding to the GLP-1 receptor.

199. The derivative of any of embodiments 1 to 198, which is capable of binding to the GLP-1 receptor at a low concentration of HSA (maximum 0.001% final assay concentration).

200. The derivative of any of embodiments 1 to 199 which is capable of binding to the GLP-1 receptor at a high concentration of HSA (2.0% final assay concentration).

The derivative of any one of embodiments 1 to 200, wherein the binding to the human GLP-1 receptor is measured by a competitive binding assay, such as the analysis of Example 30.

The derivative of any one of embodiments 1 to 201, wherein the in vitro binding to the human GLP-1 receptor is determined substantially as described in Example 30.

203. Specific examples of a derivative according to any one of 202, which is capable of binding to the human GLP-1 receptor in the case of 5.0nM or 5.0nM or less of IC ₅₀ is at a low concentration of HSA.

204. Specific examples of a derivative according to any one of 203, which is capable of binding to the human GLP-1 receptor in the case of 4.0nM or 4.0nM or less of IC ₅₀ is at a low concentration of HSA.

205. Specific examples of a derivative according to any one of 204, which is capable of binding to the human GLP-1 receptor in the case of 3.0nM or 3.0nM or less of IC ₅₀ is at a low concentration of HSA.

206. Specific examples of a derivative according to any one of 205, which is capable of binding to the human GLP-1 receptor in the case of 2.0nM or 2.0nM or less of IC ₅₀ is at a low concentration of HSA.

207. Specific examples of a derivative according to any one of 206, which is capable of binding to the human GLP-1 receptor in the case of 1.0nM or 1.0nM or less of IC ₅₀ is at a low concentration of HSA.

208. Specific examples of a derivative according to any one of 207, which is capable of binding to the human GLP-1 receptor in the case of 0.8nM or 0.8nM or less of IC ₅₀ is at a low concentration of HSA.

Specific examples of the reaction was determined as 203 to 209. 208 derivative according to any of which the IC ₅₀ substantially as described in Example 30, having a maximum 0.001% HSA (final assay concentration) in the.

The derivative according to any one of embodiments 1 to 209, which is capable of binding to the human GLP-1 receptor having an IC ₅₀ which is less than 8 times the IC ₅₀ of the semaglutide at a low concentration of HSA wherein the IC ₅₀ semaglutide measured in the same derivative of the IC ₅₀ of the embodiment.

211. Specific examples of a derivative according to any one of 210, which is capable of binding at low concentrations of HSA to the human receptor of the GLP-1 ₅₀ has less than semaglutide of the IC _50. 6 times the IC wherein the IC ₅₀ semaglutide measured in the same derivative of the IC ₅₀ of the embodiment.

The derivative of any one of embodiments 1 to 211, which is capable of binding to the human GLP-1 receptor having an IC ₅₀ of less than 4.5 times the IC ₅₀ of the semaglutide at a low concentration of HSA wherein the IC ₅₀ semaglutide measured in the same derivative of the IC ₅₀ of the embodiment.

213. Specific examples of a derivative according to any one of 212, which is capable of binding at low concentrations of HSA to the human receptor of the GLP-1 ₅₀ has less than semaglutide of the IC _50. 3 times the IC wherein the IC ₅₀ semaglutide measured in the same derivative of the IC ₅₀ of the embodiment.

214. Specific examples of a derivative according to any one of 213, which is capable of binding at low concentrations of HSA to the human receptor of the GLP-1 ₅₀ has less than the semaglutide of 2 times the IC ₅₀ of the IC wherein the IC ₅₀ semaglutide measured in the same derivative of the IC ₅₀ of the embodiment.

215. Specific examples of a derivative according to any one of 214, which is capable of binding at low concentrations of HSA to the human receptor of the GLP-1 ₅₀ has less than semaglutide of the IC ₅₀ for 1.5 times the IC wherein the IC ₅₀ semaglutide measured in the same derivative of the IC ₅₀ of the embodiment.

216. Specific examples of a derivative according to any one of 215, which is capable of binding at low concentrations of HSA to the human receptor of the GLP-1 ₅₀ has less than semaglutide of the IC ₅₀ of 1 times the IC wherein the IC ₅₀ semaglutide measured in the same derivative of the IC ₅₀ of the embodiment.

Specific examples of the reaction was determined as 210 to 217. 216 derivative according to any of which the IC ₅₀ substantially as described in Example 30, having a maximum 0.001% HSA (final assay concentration) in the.

218. Specific examples of a derivative according to any one of 217, to which 2.0% HSA (final assay concentration) is capable of binding at 950nM or 950nM to have less of IC the human GLP-1 receptor _50.

219. Specific examples of a derivative according to any one of 218, to which 2.0% HSA (final assay concentration) is capable of binding at 650nM or 650nM to have less of IC the human GLP-1 receptor _50.

220. Specific examples of a derivative according to any one of 219, to which 2.0% HSA (final assay concentration) is capable of binding at 550nM or 550nM to have less of IC the human GLP-1 receptor _50.

221. Specific examples of a derivative according to any one of 220, to which 2.0% HSA (final assay concentration) is capable of binding at 500nM or 500nM to have less of IC the human GLP-1 receptor _50.

222. Specific examples of a derivative according to any one of 221, to which 2.0% HSA (final assay concentration) is capable of binding at 400nM or 400nM to have less of IC the human GLP-1 receptor _50.

223. Specific examples of a derivative according to any one of 222, to which 2.0% HSA (final assay concentration) is capable of binding at 300nM or 300nM to have less of IC the human GLP-1 receptor _50.

224. Specific examples of a derivative according to any one of 223, to which 2.0% HSA (final assay concentration) is capable of binding at 200nM or 200nM to have less of IC the human GLP-1 receptor _50.

225. Specific examples of a derivative according to any one of 224, to which 2.0% HSA (final assay concentration) is capable of binding at 150nM or 150nM to have less of IC the human GLP-1 receptor _50.

Specific examples of the reaction was determined 218 to 226. The derivative according to any of 225, wherein the IC ₅₀ substantially as described in Example 30, in a 2.0% HSA (final assay concentration) in the.

227. Specific examples of a derivative according to any one of 226, in which the 2.0% HSA (final assay concentration) capable of binding to the human of ₅₀ less than the GLP semaglutide of the IC _50. 3 times the IC 1 receptor, wherein the IC ₅₀ semaglutide of the same derivative of the IC ₅₀ of the embodiment was measured.

228. Specific examples of a derivative according to any one of 227, in which the 2.0% HSA (final assay concentration) capable of binding to the human of ₅₀ less than the GLP semaglutide of the IC ₅₀ of 2 times the IC 1 receptor, wherein the IC ₅₀ semaglutide of the same derivative of the IC ₅₀ of the embodiment was measured.

229. Specific examples of a derivative according to any one of 228, in which the 2.0% HSA (final assay concentration) capable of binding to the human of ₅₀ less than the GLP semaglutide of the IC ₅₀ for 1.5 times the IC 1 receptor, wherein the IC ₅₀ semaglutide of the same derivative of the IC ₅₀ of the embodiment was measured.

230. Specific examples of a derivative according to any one of 229, in which the 2.0% HSA (final assay concentration) capable of binding to the human of ₅₀ less than the GLP semaglutide of the IC ₅₀ of 1 times the IC 1 receptor, wherein the IC ₅₀ semaglutide of the same derivative of the IC ₅₀ of the embodiment was measured.

231. Specific examples of a derivative according to any one of 230, in which the 2.0% HSA (final assay concentration) capable of binding to the human of ₅₀ less than the GLP semaglutide of the IC ₅₀ of 0.8 times the IC 1 receptor, wherein the IC ₅₀ semaglutide of the same derivative of the IC ₅₀ of the embodiment was measured.

232. Specific examples of a derivative according to any one of 231, in which the 2.0% HSA (final assay concentration) capable of binding to the human of ₅₀ less than the GLP semaglutide of the IC ₅₀ of 0.35 times the IC 1 receptor, wherein the IC ₅₀ semaglutide of the same derivative of the IC ₅₀ of the embodiment was measured.

Specific examples of the reaction was determined as 227 to 233. 232 derivative according to any of which the IC ₅₀ substantially as described in Example 30, in a 2.0% HSA (final assay concentration) in the.

234. The derivative of any of embodiments 1 to 233 which has improved pharmacokinetic properties.

235. The derivative of any of embodiments 1 to 234 which has an increased half-life and/or reduced clearance.

236. The derivative of any of embodiments 1 to 235, which is suitable for administration once a month.

237. The derivative of any of embodiments 1 to 236 for subcutaneous administration.

238. The derivative of any of embodiments 1 to 237, wherein the derivative is tested in vivo in a pharmacokinetic (PK) study.

239. The derivative of any one of embodiments 1 to 238, wherein the derivative is tested in any suitable animal model, such as a mouse, rat, monkey, dog or pig.

240. The derivative of any of embodiments 1 to 239 which is compared to semaglutide.

241. The derivative of any of embodiments 1 to 240 which has an improved in vivo terminal half-life (T1⁄2) compared to semaglutide in minipigs after intravenous administration.

242. The derivative of any one of embodiments 1 to 241, wherein the terminal half-life is intravenously administered using any suitable research protocol, such as the one described in Example 31. After the administration, it was measured in vivo in a small pig.

243. The derivative of any one of embodiments 1 to 242, wherein the terminal half-life is determined in vivo in a mini-pigs substantially as described in Example 31 after intravenous administration.

244. The derivative of any one of embodiments 1 to 243 which has an in vivo terminal half-life (T1⁄2) in a mini-pig after intravenous administration.

245. The derivative of any one of embodiments 1 to 244 which has an in vivo terminal half-life (T1⁄2) in a mini-pig after intravenous administration.

246. The derivative of any of embodiments 1 to 245 which has an in vivo terminal half-life (T1⁄2) in a mini-pig after intravenous administration.

247. The derivative of any one of embodiments 1 to 246 which has an in vivo terminal half-life (T1⁄2) in a mini-pig after intravenous administration.

248. The derivative of any one of embodiments 1 to 247, which has an in vivo terminal half-life of at least 1.5 times the terminal half-life of semaglutide determined in the same manner after intravenous administration (in a mini-pig) ( T1⁄2).

249. The derivative according to any one of embodiments 1 to 248, which has an in vivo terminal half-life of at least 2 times the terminal half-life of semaglutide determined in the same manner after intravenous administration in a mini-pigs ( T1⁄2).

The derivative according to any one of embodiments 1 to 249, which has an in vivo terminal half-life of at least 2.3 times the terminal half-life of the semaglutide measured in the same manner after intravenous administration in the mini-pigs ( T1⁄2).

251. The derivative of any one of embodiments 1 to 250, which has an in vivo terminal half-life of at least 2.6 times the terminal half-life of the semaglutide determined in the same manner after intravenous administration in the mini-pigs ( T1⁄2).

252. The derivative of any of embodiments 1 to 251 which is potent in vivo.

253. A derivative according to any one of embodiments 1 to 252, when in any suitable animal Models, such as those measured in mice or pigs, are potent in vivo.

254. The derivative of any one of embodiments 1 to 253, wherein the animal model is a db/db mouse.

255. The derivative of any one of embodiments 1 to 254, wherein the blood glucose lowering effect is determined.

256. The derivative of any of embodiments 1 to 255, wherein the weight loss effect is determined.

257. The derivative of any one of embodiments 1 to 256, wherein the blood glucose lowering effect is measured in vivo in db/db mice using any suitable research protocol and method, for example, as described in Example 32. Weight loss effect.

258. The derivative of any one of embodiments 1 to 257, wherein the blood glucose lowering effect and/or the weight loss reducing effect is measured in vivo in db/db mice substantially as described in Example 32.

259. The derivative of any of embodiments 1 to 258, which has an in vivo effect of reducing blood glucose after 48 hours as determined in a single dose study in a db/db mouse model.

260. The derivative of any of embodiments 1 to 259, wherein the blood glucose is reduced by at least 15% compared to the blood glucose level prior to administration of the derivative.

261. The derivative of any of embodiments 1 to 260, wherein the blood glucose is reduced by at least 25% compared to the blood glucose level prior to administration of the derivative.

262. The derivative of any one of embodiments 1 to 261, wherein the blood glucose is reduced by at least 35% compared to the blood glucose level prior to administration of the derivative.

263. The derivative of any of embodiments 1 to 262, wherein the blood glucose is reduced by at least 50% compared to the blood glucose level prior to administration of the derivative.

264. The derivative of any of embodiments 1 to 263, which has an in vivo effect of reducing blood glucose after 72 hours as determined in a single dose study in a db/db mouse model.

265. The derivative of any one of embodiments 1 to 264, which has a mouse model in db/db The in vivo effect of reducing blood glucose after 96 hours as determined in a single dose study.

266. The derivative of any of embodiments 1 to 265, wherein the blood glucose is reduced by at least 3% compared to the blood glucose level prior to administration of the derivative.

267. The derivative of any of embodiments 1 to 266, wherein the blood glucose is reduced by at least 5% compared to the blood glucose level prior to administration of the derivative.

268. The derivative of any of embodiments 1 to 267, wherein the blood glucose is reduced by at least 10% compared to the blood glucose level prior to administration of the derivative.

269. The derivative of any of embodiments 1 to 268, wherein the blood glucose is reduced by at least 15% compared to the blood glucose level prior to administration of the derivative.

270. The derivative of any of embodiments 1 to 269, wherein the blood glucose is reduced by at least 20% compared to the blood glucose level prior to administration of the derivative.

271. The derivative of any of embodiments 1 to 270, wherein the blood glucose is reduced by at least 25% compared to the blood glucose level prior to administration of the derivative.

272. The derivative of any of embodiments 1 to 271, which has an in vivo effect of reducing body weight after 48 hours as determined in a single dose study in a db/db mouse model.

273. The derivative of any one of embodiments 1 to 272, wherein the body weight is reduced by at least 3% compared to the body weight prior to administration of the derivative.

274. The derivative of any of embodiments 1 to 273, wherein the body weight is reduced by at least 4% compared to the body weight prior to administration of the derivative.

275. The derivative of any of embodiments 1 to 274, wherein the body weight is reduced by at least 5% compared to the body weight prior to administration of the derivative.

276. The derivative of any of embodiments 1 to 275, wherein the body weight is reduced by at least 6% compared to the body weight prior to administration of the derivative.

277. The derivative of any of embodiments 1 to 276, which has an in vivo effect of reducing body weight after 72 hours as determined in a single dose study in a db/db mouse model.

278. The derivative of any of embodiments 1 to 277, which has an in vivo effect of reducing body weight after 96 hours as determined in a single dose study in a db/db mouse model.

279. The derivative of any of embodiments 1 to 278, wherein the body weight is reduced by at least 1% compared to the body weight prior to administration of the derivative.

280. The derivative of any one of embodiments 1 to 279, wherein the body weight is reduced by at least 2% compared to the body weight prior to administration of the derivative.

281. The derivative of any one of embodiments 1 to 280, wherein the body weight is reduced by at least 3% compared to the body weight prior to administration of the derivative.

282. The derivative of any of embodiments 1 to 281, wherein the body weight is reduced by at least 4% compared to the body weight prior to administration of the derivative.

283. The derivative of any one of embodiments 1 to 282, wherein the animal model is a pig.

284. The derivative of any one of embodiments 1 to 283, wherein the animal model is a LYD pig.

285. The derivative of any of embodiments 1 to 284, wherein the reduction in food intake is determined in an in vivo pharmacodynamic (PD) study.

286. The derivative of any one of embodiments 1 to 285, wherein the reduction in food intake is determined in vivo in a pig using any suitable research protocol and method, for example, as described in Example 33.

287. The derivative of any one of embodiments 1 to 286, wherein the reduction in food intake is determined in vivo in pigs substantially as described in Example 33 using any suitable research protocol and method.

288. The derivative of any one of embodiments 1 to 287, which has an in vivo reduction in food intake during a first 24-hour period (0-24 hours) after administration of a single dose of the derivative Effect, where food intake was determined in a single dose study in the LYD pig model.

289. The derivative of any one of embodiments 1 to 288, which has a single dose administered The in vivo effect of food intake was reduced during the second 24-hour period (24-48 hours) following the derivative, wherein food intake was determined in a single dose study in the LYD pig model.

290. The derivative of any one of embodiments 1 to 289, which has a reduced food intake during a third 24-hour period (48-72 hours) after administration of a single dose of the derivative. Effect, where food intake was determined in a single dose study in the LYD pig model.

291. The derivative of any one of embodiments 1 to 290, which has a reduced food intake during a fourth 24-hour period (72-96 hours) after administration of a single dose of the derivative. Effect, where food intake was determined in a single dose study in the LYD pig model.

292. A GLP-1 derivative selected from the group consisting of Chemical Formula 21, Chemical Formula 22, Chemical Formula 23, Chemical Formula 24, Chemical Formula 25, Chemical Formula 26, Chemical Formula 27, Chemical Formula 28, Chemical Formula 29, Chemical Formula 30, Chemical Formula 31, Chemical Formula 32, Chemical Formula 33, Chemical Formula 34, Chemical Formula 35, Chemical Formula 36, Chemical Formula 37, Chemical Formula 38, Chemical Formula 39, Chemical Formula 40, Chemical Formula 41, Chemical Formula 42, Chemical Formula 43, Chemical Formula 44, Chemical Formula 45, Chemical Formula 46, Chemical Formula 47, and Chemical Formula 48; A pharmaceutically acceptable salt, guanamine or ester.

293. A GLP-1 derivative selected from the group consisting of the chemical structures shown in any one of Examples 1 to 28; or a pharmaceutically acceptable salt, guanamine or ester thereof.

294. A GLP-1 derivative selected from the group consisting of the GLP-1 derivative names shown in any one of Examples 1 to 28; or a pharmaceutically acceptable salt, guanamine or ester thereof.

295. The derivative of any one of embodiments 292 to 294 which is a derivative according to any one of embodiments 1 to 291.

296. An intermediate in the form of a GLP-1 analog which, when compared to GLP-1 (7-37) (SEQ ID NO: 1), comprises the following amino acid changes: i) (8Aib, 22E, 26R, 27K, 34R, 38G, 39G, 40G, 41S, 42K); ii) (8Aib, 22E, 26R, 31K, 34R, 38G, 39G, 40G, 41S, 42K); iii) (8Aib, 22E, 26R, 34R, 38K, 39G, 40G, 41S, 42K); iv (8Aib, 22E, 23K, 26R, 34R, 38G, 39G, 40G, 41S, 42K); v) (8Aib, 22E, 26R, 34R, 36K, 38G, 39G, 40G, 41S, 42K); vi) (8Aib, 18K, 22E, 26R, 34R, 38G, 39G, 40G, 41S, 42K); vii) (7Imp, 8Aib, 22E, 26R, 34R, 38K, 39G, 40G, 41S, 42K); iix) (8Aib, 22E, 26R, 34R, 36K, 38A, 39E, 40S, 41P, 42K); ix) (8Aib, 22E, 26R, 34R, 36K, 38E, 39G, 40P, 41A, 42K); x) (8Aib, 22E, 26R, 34R, 36K, 38P, 39A, 40S, 41E, 42K);xi)(8Aib, 22E, 26R, 34R, 38K, 39P, 40E, 41G, 42K) (SEQ ID NO: 12); xii) (8Aib, 22E, 26R, 34R, 38K, 39S, 40A, 41E) , 42K); or xiii) (8Aib, 22E, 26R, 34R, 38K, 39S, 40P, 41E, 42K).

297. An intermediate in the form of a GLP-1 analog selected from the group consisting of the following analogs of GLP-1 (7-37) (SEQ ID NO: 1): i) (8Aib, 22E, 26R, 27K, 34R, 38G, 39G, 40G, 41S, 42K) (SEQ ID NO: 2); ii) (8Aib, 22E, 26R, 31K, 34R, 38G, 39G, 40G, 41S, 42K) (SEQ ID NO: 3); (8Aib, 22E, 26R, 34R, 38K, 39G, 40G, 41S, 42K) (SEQ ID NO: 4); iv (8Aib, 22E, 23K, 26R, 34R, 38G, 39G, 40G, 41S, 42K) (SEQ ID NO: 5); v) (8Aib, 22E, 26R, 34R, 36K, 38G, 39G, 40G, 41S, 42K) (SEQ ID NO: 6); vi) (8Aib, 18K, 22E, 26R, 34R, 38G, 39G, 40G, 41S, 42K) (SEQ ID NO: 8), vii) (7Imp, 8Aib, 22E, 26R, 34R, 38K, 39G, 40G, 41S, 42K) (SEQ ID NO: 8) ; iix) (8Aib, 22E, 26R, 34R, 36K, 38A, 39E, 40S, 41P, 42K) (SEQ ID NO: 9); ix) (8Aib, 22E, 26R, 34R, 36K, 38E, 39G, 40P) , 41A, 42K) (SEQ ID NO: 10); x) (8Aib, 22E, 26R, 34R, 36K, 38P, 39A, 40S, 41E, 42K) (SEQ ID NO: 11); xi) (8Aib, 22E , 26R, 34R, 38K, 39P, 40E, 41G, 42K) (SEQ ID NO: 12); xii) (8Aib 22E, 26R, 34R, 38K, 39S, 40A, 41E, 42K) (SEQ ID NO: 13); and xiii) (8Aib, 22E, 26R, 34R, 38K, 39S, 40P, 41E, 42K) (SEQ ID NO) :14).

298. A pharmaceutical composition comprising the derivative of any one of embodiments 1 to 295 Or an analog of any one of Examples 296 to 297 and a pharmaceutically acceptable excipient.

299. The derivative of any one of embodiments 1 to 295, or the analog of any one of embodiments 296 to 297, for use as a medicament.

300. The derivative of any of embodiments 1 to 295, or the analog of any one of embodiments 296 to 297, for use in (i) preventing and/or treating all forms of diabetes, such as hyperglycemia Symptoms, type 2 diabetes, abnormal glucose tolerance, type 1 diabetes, non-insulin-dependent diabetes mellitus, MODY (young adult diabetes), gestational diabetes and/or reduction of HbA1C; (ii) delay or prevention of diabetes progression, such as Advances in type 2 diabetes, delaying the progression of impaired glucose tolerance (IGT) into type 2 diabetes requiring insulin, delaying or preventing insulin resistance, and/or delaying progression of type 2 diabetes requiring insulin to insulin type 2 diabetes requiring insulin; (iii) improving β-cell function, such as reducing β-cell apoptosis, increasing β-cell function and/or β-cell mass and/or restoring glucose sensitivity to β-cells; (iv) preventing and/or treating cognition Obstacle and/or neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease and/or multiple sclerosis; (v) prevention and/or treatment of eating disorders such as obesity Case Such as by reducing food intake, reducing body weight, suppressing appetite, and feeling satiety; treating or preventing by eating antipsychotics or steroid-induced bulimia, psychosis and obesity; Stomach movement; delaying gastric emptying; increasing body movement; and/or preventing and/or treating comorbidities of obesity, such as osteoarthritis and/or urinary incontinence; (vi) preventing and/or treating diabetic complications, such as Vascular disease; neuropathy, including peripheral neuropathy; nephropathy; and/or retinopathy; (vii) improved lipid parameters such as prevention and/or treatment of dyslipidemia, reduction of total serum lipids; increased HDL; decreased low density LDL; decreased VLDL; Triglyceride; lowers cholesterol; lowers plasma content of lipoprotein a (Lp(a)) in humans; inhibits in vitro and/or in vivo production Apolipoprotein a (apo(a)); (viii) prevention and/or treatment of cardiovascular diseases such as syndrome X, atherosclerosis, myocardial infarction, coronary heart disease, reperfusion injury, stroke, cerebral ischemia, early heart Or early cardiovascular disease, left ventricular hypertrophy, coronary artery disease, hypertension, essential hypertension, acute hypertension, cardiomyopathy, cardiac insufficiency, exercise intolerance, acute and/or chronic heart failure, arrhythmia, Arrhythmia, syncope, angina pectoris, cardiac bypass and/or stent reocclusion, atheroschlerosis oblitterens, diastolic dysfunction and/or systolic dysfunction; and/or lowering blood pressure, such as reducing systolic blood pressure; (ix) prevention And/or treating gastrointestinal disorders such as inflammatory bowel disease, short bowel syndrome or Crohn's disease or colitis; dyspepsia and/or gastric ulcer; and/or inflammation, such as psoriasis, psoriatic arthritis, Rheumatoid arthritis and/or systemic lupus erythematosus; (x) prevention and/or treatment of critical illness, such as treatment of critically ill patients, critically ill multiple kidney disease (CIPNP) patients and/or latent In patients with CIPNP; prevention of development of critical illness or CIPNP; prevention, treatment and/or cure of systemic inflammatory response syndrome (SIRS) in patients; prevention or reduction of bacteremia, sepsis and/or septic shock during hospitalization Possibility; and/or stabilization of blood glucose, insulin balance, and optionally metabolism in patients with intensive care units with acute illness; (xi) prevention and/or treatment of polycystic ovary syndrome (PCOS); (xii) prevention and / or treatment of brain diseases such as cerebral ischemia, cerebral hemorrhage and / or traumatic brain injury; (xiii) prevention and / or treatment of sleep apnea; and / or (xiv) prevention and / or treatment abuse, such as alcohol abuse And / or drug abuse.

301. Use of a derivative according to any one of embodiments 1 to 208, or an analogue according to any one of embodiments 209 to 210, for the manufacture of a medicament for: (i) prevention and/or Or treat all forms of diabetes, such as hyperglycemia, type 2 diabetes, impaired glucose tolerance, type 1 diabetes, non-insulin dependent diabetes, MODY Type 2 diabetes), gestational diabetes and/or reduction of HbA1C; (ii) delay or prevention of progression of diabetes, such as progression of type 2 diabetes, delaying progression of glucose tolerance (IGT) to insulin type 2 diabetes, delay or Preventing insulin resistance and/or delaying the progression of insulin-free type 2 diabetes to type 2 diabetes requiring insulin; (iii) improving beta-cell function, such as reducing beta-cell apoptosis, increasing beta-cell function and/or beta - cell mass and/or recovery of glucose sensitivity for β-cells; (iv) prevention and/or treatment of cognitive disorders and/or neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease ( Parkinson's disease and/or multiple sclerosis; (v) prevention and/or treatment of eating disorders, such as obesity, for example by reducing food intake, losing weight, suppressing appetite, and feeling satiety; treatment or prevention By administering antipsychotics or steroid-induced bulimia, psychogenic eclipse and/or obesity; reducing gastric motility; delaying gastric emptying; increasing body movement; and/or preventing and/or treating obesity Diseased, such as osteoarthritis and/or urinary incontinence; (vi) prevention and/or treatment of diabetic complications, such as vascular disease; neuropathy, including peripheral neuropathy; nephropathy; and/or retinopathy; (vii) improved lipid parameters, Such as preventing and / or treating dyslipidemia, reducing total serum lipids; increasing HDL; lowering low density LDL; lowering VLDL; lowering triglyceride; lowering cholesterol; lowering plasma content of lipoprotein a (Lp(a)) in humans Inhibiting the production of apolipoprotein a (apo(a)) in vitro and/or in vivo; (viii) preventing and/or treating cardiovascular diseases such as syndrome X, atherosclerosis, myocardial infarction, coronary heart disease, reperfusion Injury, stroke, cerebral ischemia, early heart or early cardiovascular disease, left ventricular hypertrophy, coronary artery disease, hypertension, essential hypertension, acute hypertension, cardiomyopathy, cardiac insufficiency, exercise intolerance, acute And/or chronic heart failure, arrhythmia, arrhythmia, syncope, angina pectoris, cardiac bypass and/or stent reocclusion, atheroschlerosis oblitterens, diastolic dysfunction and/or contraction Dysfunction; and / or lowering blood Pressure, such as reduced systolic blood pressure; (ix) prevention and/or treatment of gastrointestinal diseases such as inflammatory bowel disease, short bowel syndrome or Crohn's disease or colitis; dyspepsia and/or gastric ulcer; Or inflammation, such as psoriasis, psoriatic arthritis, rheumatoid arthritis and/or systemic lupus erythematosus; (x) prevention and/or treatment of critical illness, such as treatment of critically ill patients, critically ill multiple nephropathy (CIPNP) Patients and/or potential CIPNP patients; prevention of critical illness or development of CIPNP; prevention, treatment, and/or cure of systemic inflammatory response syndrome (SIRS) in patients; prevention or reduction of bacteremia, sepsis, and septicemia during hospitalization / or the possibility of septic shock; and / or stabilize the blood glucose, insulin balance and optionally the presence of a patient in an intensive care unit with acute disease; (xi) prevent and/or treat polycystic ovary syndrome (PCOS); (xii) preventing and/or treating brain diseases such as cerebral ischemia, cerebral hemorrhage and/or traumatic brain injury; (xiii) preventing and/or treating sleep apnea; and/or (xiv) preventing and/or treating abuse , such as alcohol abuse and / or drug abuse.

302. A method for (i) preventing and/or treating all forms of diabetes, such as hyperglycemia, type 2 diabetes, abnormal glucose tolerance, type 1 diabetes, non-insulin dependent diabetes, MODY (young Adult diabetes), gestational diabetes and/or reduction of HbA1C; (ii) delay or prevention of progression of diabetes, such as progression of type 2 diabetes, delaying progression of glucose tolerance (IGT) to insulin type 2 diabetes, delay or Preventing insulin resistance and/or delaying the progression of insulin-free type 2 diabetes to type 2 diabetes requiring insulin; (iii) improving beta-cell function, such as reducing beta-cell apoptosis, increasing beta-cell function and/or beta - cell mass and/or recovery of glucose sensitivity for β-cells; (iv) prevention and/or treatment of cognitive disorders and/or neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease ( Parkinson's disease) and / or multiple sclerosis; (v) preventing and/or treating eating disorders, such as obesity, for example by reducing food intake, losing weight, suppressing appetite, and feeling satiety; treating or preventing by injecting antipsychotics or steroids Bulimia, psychotic eclipse and/or obesity; reducing gastric motility; delaying gastric emptying; increasing body movement; and/or preventing and/or treating obesity comorbidities such as osteoarthritis and/or urine Incontinence; (vi) prevention and/or treatment of diabetic complications, such as vascular disease; neuropathy, including peripheral neuropathy; nephropathy; and/or retinopathy; (vii) improved lipid parameters, such as prevention and/or treatment of dyslipidemia, reduction of total Serum lipids; increase HDL; reduce low-density LDL; lower VLDL; lower triglycerides; lower cholesterol; lower plasma levels of lipoprotein a (Lp(a)) in humans; inhibit in vitro and/or in vivo production Lipoprotein a (apo(a)); (viii) prevention and/or treatment of cardiovascular diseases such as syndrome X, atherosclerosis, myocardial infarction, coronary heart disease, reperfusion injury, stroke, cerebral ischemia, early heart or Early efforts Disease, left ventricular hypertrophy, coronary artery disease, hypertension, essential hypertension, acute hypertension emergency, cardiomyopathy, cardiac insufficiency, exercise intolerance, acute and/or chronic heart failure, arrhythmia, arrhythmia, syncope , angina pectoris, cardiac bypass and/or stent reocclusion, atheroschlerosis oblitterens, diastolic dysfunction and/or systolic dysfunction; and/or lowering blood pressure, such as reducing systolic blood pressure; (ix) prevention and/or treatment Gastrointestinal diseases such as inflammatory bowel disease, short bowel syndrome or Crohn's disease or colitis; indigestion and/or gastric ulcer; and/or inflammation, such as psoriasis, psoriatic arthritis, rheumatoid joints Inflammatory and/or systemic lupus erythematosus; (x) prevention and/or treatment of critical illness, such as treatment of critically ill patients, critically ill multiple kidney disease (CIPNP) patients and/or potential CIPNP patients; prevention of critical illness or CIPNP Development; prevention, treatment, and/or cure of systemic inflammatory response syndrome (SIRS) in patients; prevention or reduction of bacteremia, sepsis, and/or septicemia during hospitalization The possibility of hemorrhagic shock; and / or acutely Blood glucose, insulin balance and metabolic stabilization of patients in intensive care unit; (xi) prevention and/or treatment of polycystic ovary syndrome (PCOS); (xii) prevention and/or treatment of brain diseases such as the brain (xiii) prevention and/or treatment of sleep apnea; and/or (xiv) prevention and/or treatment abuse, such as alcohol abuse and/or substance abuse; A pharmaceutically active amount of a derivative according to any one of the specific examples 1 to 295, or an analog of any one of the specific examples 296 to 297.

Other specific examples

The following are other specific examples of the invention:

A derivative of a GLP-1 peptide such as Formula I: Formula I: Xaa ₇ -Xaa ₈ -Glu-Gly-Thr-Xaa ₁₂ -Thr-Ser-Asp-Xaa ₁₆ - Ser-Xaa ₁₈ -Xaa ₁₉ -Xaa ₂₀ -Glu-Xaa ₂₂ -Xaa ₂₃ -Ala-Xaa ₂₅ -Xaa ₂₆ -Xaa ₂₇ -Phe-Ile-Xaa ₃₀ -Xaa ₃₁ -Leu-Xaa ₃₃ -Xaa ₃₄ -Xaa ₃₅ -Xaa ₃₆ -Xaa ₃₇ - Xaa ₃₈ -Xaa ₃₉ -Xaa ₄₀ -Xaa ₄₁ -Xaa ₄₂ , wherein Xaa ₇ is L-histamine, (S)-2-hydroxy-3-(1H-imidazol-4-yl)-propionic acid, D- histidine, histidine amino group to the high-histidine, N α ^- acetyl group histidine, N α ^- methyl acyl histidine, N α ^- methyl-histidine, 3-pyridyl-alanine , 2-pyridylamino acid or 4-pyridylalanine; Xaa ₈ is Ala, Gly, Ser, Aib, (1-aminocyclopropyl)carboxylic acid or (1-aminocyclobutyl)carboxylic acid; Xaa ₁₂ is Phe Or Leu; Xaa ₁₆ is Val or Leu; Xaa ₁₈ is Ser, Arg, Lys, Val or Leu; Xaa ₁₉ is Tyr or Gln; Xaa ₂₀ is Leu or Met; Xaa ₂₂ is Gly or Glu; Xaa ₂₃ is Gln, Glu , Lys or Arg; Xaa ₂₅ is Ala or Val; Xaa ₂₆ is Arg or Lys; Xaa ₂₇ is Glu, Lys or Leu; Xaa ₃₀ is Ala, Glu or Arg; Xaa ₃₁ is Trp, Lys or His; Xaa ₃₃ is Val , Lys or Arg; Xaa ₃₄ is Lys, Arg, His, Asn or Gln; Xaa ₃₅ is Gly or Ala; Xaa ₃₆ is Arg, Lys or Gly; Xaa ₃₇ is Gly or Pro; Xaa ₃₈ is Ser, Gly, Ala, Glu, Pro or Lys; Xaa ₃₉ is Ser, Gly, Ala, Glu Or Pro; Xaa ₄₀ is Ser, Gly, Ala, Glu or Pro; Xaa ₄₁ is Ser, Gly, Ala, Glu or Pro; and Xaa ₄₂ is Lys; the restrictions are Xaa ₁₈ , Xaa ₂₃ , Xaa ₂₇ , Xaa ₃₁ At least one of Xaa ₃₆ or Xaa ₃₈ is Lys; wherein Lys at Xaa ₄₂ is the first K residue, and one of Xaa ₁₈ , Xaa ₂₃ , Xaa ₂₇ , Xaa ₃₁ , Xaa ₃₆ or Xaa ₃₈ Lys is a second K residue; the derivative comprises first and second extensions respectively linked to the first and second K residues, wherein the first and second extensions have the chemical formula 1: chemical formula 1: HOOC-(CH ₂ ) ₁₈ -CO-*; or a pharmaceutically acceptable salt, guanamine or ester thereof.

2. The derivative of embodiment 1, wherein each of the first and second extensions are independently linked to the first and second K residues, respectively, via the first and second linkers, respectively.

3. The derivative of embodiment 2, wherein the first and second linkers each have a *-NH group and a *-CO group.

4. The derivative of any one of embodiments 2 to 3, wherein each of the first and the second linker comprises element 1 of formula 2:

5. The derivative of embodiment 4, wherein each of the first and second linkers has an element 1 of formula 2.

6. The derivative according to any one of embodiments 4 to 5, wherein the chemical formula 2 represents a gGlu residue.

7. The derivative according to any one of embodiments 4 to 6, wherein the element 1 is an L-gGlu residue.

8. The derivative of any one of embodiments 2 to 7, wherein each of the first and the second linker comprises element 2 of formula 3: Wherein k is an integer in the range of 1-5, and n is an integer in the range of 1-5.

9. The derivative of embodiment 8, wherein each of the first and second linkers comprises at least one element 2 of formula 3.

10. The derivative of any one of embodiments 8 to 9, wherein each of the first and second linkers comprises at least two element 2 of formula 3.

11. The derivative of any one of embodiments 8 to 10, wherein the first and the second linker Each of them contains two elements 2 of Chemical Formula 3.

12. The derivative of any of embodiments 8 to 11, wherein each of the first and second linkers has two elements 2 of formula 3.

13. The derivative of any of embodiments 8 to 12, wherein k=1 and n=1.

14. The derivative according to any one of embodiments 8 to 13, wherein the chemical formula 3 represents OEG.

15. The derivative of any one of embodiments 2 to 14, wherein each of the first and the second linker comprises element 3 of formula 4:

16. The derivative of any one of embodiments 2 to 15, wherein each of the first and second linkers has a factor 3 of formula 4.

17. The derivative according to any one of embodiments 15 to 16, wherein the chemical formula 4 represents Trx.

The derivative according to any one of embodiments 2 to 17, wherein each of the first and second linkers comprises element 4 of Chemical Formula 5: Chemical Formula 5: *-NH-(CH ₂ ) _q -CH[(CH ₂ ) _w -NH ₂ ]-CO-*, where q is an integer in the range 0-5, and w is an integer in the range 0-5, with the constraint that when w is 0 , q is an integer in the range of 1-5, and when q is 0, w is an integer in the range of 1-5.

19. The derivative of embodiment 18, wherein each of the first and second linkers comprises at least one element 4 of formula 5.

The derivative of any one of embodiments 18 to 19, wherein each of the first and second linkers comprises at least two element 4 of formula 5.

The derivative of any one of embodiments 18 to 20, wherein each of the first and second linkers comprises two elements 4 of formula 5.

The derivative according to any one of embodiments 18 to 21, wherein each of the first and second linkers has two elements 4 of the chemical formula 5.

The derivative of any one of embodiments 18 to 22, wherein q is 4 and w is 0.

The derivative of any one of embodiments 18 to 22, wherein w is 4 and q is 0.

The derivative according to any one of embodiments 18 to 24, wherein the chemical formula 5 represents an eps-Lys residue.

The derivative according to any one of embodiments 18 to 25, wherein the element 4 is an L-eps-Lys residue.

26. The derivative of any one of embodiments 2 to 25, wherein each of the first and second linkers consists of element 3 of formula 4, element 1 of formula 2, and two formula 3 Element 2 consists of k=1 and n=1, which are interconnected via a guanamine bond and in the specified order.

27. The derivative according to any one of embodiments 2 to 25, wherein each of the first and second linkers consists of element 3 of a chemical formula 4, element 1 of a chemical formula 2, and two chemical formulas 5 Element 4 consists of where q = 4 and w = 0 (or w = 4 and q = 0), the elements are interconnected via a guanamine bond and in the specified order.

28. The derivative of any one of embodiments 2 to 25, wherein each of the first and second linkers consists of element 1 of formula 2 and element 4 of two formula 5, wherein q = 4 and w = 0 (or w = 4 and q = 0), the elements are interconnected via a guanamine bond and in the specified order.

29. The derivative of any one of embodiments 1 to 28, wherein the CO-* group of Chemical Formula 1 of each of the first and second extensions is via the first and second, respectively, as appropriate A linker is attached to the epsilon amine group of the first and second K residues, respectively.

The derivative of any one of the first to second embodiments, wherein each of the first and second extensions is separately connected to the respective guanamine bond via the first and second linkers, respectively. The epsilon amine group of the first and second K residues, via the first and second extensions, and the The first and the second K residues are linked by a guanamine bond.

31. The derivative of any one of embodiments 1 to 30, wherein the CO-* group of Chemical Formula 1 of each of the first and second extensions is linked to the first and the a *-NH group of the two linkers, and the *-CO groups of each of the first and second linkers are attached to the epsilon amine group of the first and second K residues, respectively.

The derivative according to any one of embodiments 1 to 31, wherein one of Xaa ₁₈ , Xaa ₂₃ , Xaa ₂₇ , Xaa ₃₁ , Xaa ₃₆ or Xaa ₃₈ is Lys.

The derivative according to any one of embodiments 1 to 31, wherein only one of Xaa ₁₈ , Xaa ₂₃ , Xaa ₂₇ , Xaa ₃₁ , Xaa ₃₆ or Xaa ₃₈ is Lys.

The derivative of any one of embodiments 1 to 31b, wherein Lys at Xaa ₁₈ is the second K residue.

The derivative of any one of embodiments 1 to 31b, wherein Lys at Xaa ₂₃ is the second K residue.

The derivative of any one of embodiments 1 to 31b, wherein Lys at Xaa ₂₇ is the second K residue.

The derivative of any one of embodiments 1 to 31b, wherein Lys at Xaa ₃₁ is the second K residue.

The derivative of any one of embodiments 1 to 31b, wherein Lys at Xaa ₃₆ is the second K residue.

The derivative of any of embodiments 1 to 31b, wherein Lys at Xaa ₃₈ is the second K residue.

The derivative according to any one of embodiments 1 to 37, wherein Xaa ₇ is His.

The derivative of any one of embodiments 1 to 38, wherein Xaa ₈ is Aib.

The derivative of any one of embodiments 1 to 39, wherein Xaa ₁₂ is Phe.

The derivative of any one of embodiments 1 to 40, wherein Xaa ₁₆ is Val.

The derivative according to any one of embodiments 1 to 41, wherein Xaa ₁₈ is Ser or Lys.

The derivative of any one of embodiments 1 to 42, wherein Xaa ₁₈ is Ser.

The derivative of any one of embodiments 1 to 42, wherein Xaa ₁₈ is Lys.

The derivative of any one of embodiments 1 to 44, wherein Xaa ₁₉ is Tyr.

The derivative of any one of embodiments 1 to 45, wherein Xaa ₂₀ is Leu.

The derivative of any one of embodiments 1 to 46, wherein Xaa ₂₂ is Glu.

The derivative of any one of embodiments 1 to 47, wherein Xaa ₂₃ is Gln or Lys.

The derivative of any one of embodiments 1 to 25, wherein Xaa ₂₃ is Gln.

The derivative of any one of embodiments 1 to 48, wherein Xaa ₂₃ is Lys.

The derivative of any one of embodiments 1 to 50, wherein Xaa ₂₅ is Ala.

The derivative of any one of embodiments 1 to 51, wherein Xaa ₂₆ is Arg.

The derivative of any one of embodiments 1 to 52, wherein Xaa ₂₇ is Glu or Lys.

The derivative of any one of embodiments 1 to 53, wherein Xaa ₂₇ is Glu.

The derivative of any one of embodiments 1 to 54, wherein Xaa ₂₇ is Glu or Lys.

The derivative of any one of embodiments 1 to 54, wherein Xaa ₂₇ is Lys.

57. Specific examples of the derivative according to any one of 1 to 56, wherein Xaa ₃₀ Ala. [

The derivative of any one of embodiments 1 to 57, wherein Xaa ₃₁ is Trp or Lys.

The derivative of any one of embodiments 1 to 58, wherein Xaa ₃₁ is Lys.

The derivative of any one of embodiments 1 to 58, wherein Xaa ₃₁ is Trp.

The derivative of any one of embodiments 1 to 60, wherein Xaa ₃₃ is Val.

The derivative of any one of embodiments 1 to 61, wherein Xaa ₃₄ is Arg.

The derivative of any one of embodiments 1 to 62, wherein Xaa ₃₅ is Gly.

64. Specific examples of the derivative of any one of to 63, wherein Xaa ₃₆ is Arg or Lys.

The derivative of any one of embodiments 1 to 64, wherein Xaa ₃₆ is Arg.

The derivative of any one of embodiments 1 to 64, wherein Xaa ₃₆ is Lys.

The derivative of any one of embodiments 1 to 66, wherein Xaa ₃₇ is Gly.

The derivative of any one of embodiments 1 to 70, wherein Xaa ₃₇ is Lys.

73. Derivative according to any of the specific examples 1 to 72, wherein Xaa ₃₈ is Gly or Lys.

The derivative of any one of embodiments 1 to 73, wherein Xaa ₃₈ is Gly.

The derivative of any one of embodiments 1 to 73, wherein Xaa ₃₈ is Lys.

The derivative of any one of embodiments 1 to 75, wherein Xaa ₃₉ is Gly.

77. The derivative of any of embodiments 1 to 76, wherein Xaa ₄₀ is Gly.

The derivative of any one of embodiments 1 to 77, wherein Xaa ₄₁ is Ser.

The derivative of any one of embodiments 1 to 78, wherein the GLP-1 peptide has up to 12 amine groups when compared to GLP-1 (7-37) (SEQ ID NO: 1) The acid changes.

The derivative of any one of embodiments 1 to 79, wherein the GLP-1 peptide has up to 11 amine groups when compared to GLP-1 (7-37) (SEQ ID NO: 1) The acid changes.

The derivative of any one of embodiments 1 to 80, wherein the GLP-1 peptide has up to 10 amine groups when compared to GLP-1 (7-37) (SEQ ID NO: 1) The acid changes.

The derivative of any one of embodiments 1 to 81, wherein the GLP-1 peptide has up to 9 amine groups when compared to GLP-1 (7-37) (SEQ ID NO: 1) The acid changes.

The derivative of any one of embodiments 1 to 82, wherein the GLP-1 peptide has up to 8 amine groups when compared to GLP-1 (7-37) (SEQ ID NO: 1) The acid changes.

The derivative of any one of embodiments 1 to 83, wherein the GLP-1 peptide has up to 7 amine groups when compared to GLP-1 (7-37) (SEQ ID NO: 1) The acid changes.

The derivative of any one of embodiments 1 to 84, wherein the GLP-1 peptide has up to 6 amine groups when compared to GLP-1 (7-37) (SEQ ID NO: 1) The acid changes.

The derivative of any one of embodiments 1 to 85, wherein the GLP-1 peptide has up to 5 amine groups when compared to GLP-1 (7-37) (SEQ ID NO: 1) The acid changes.

87. The derivative of any one of embodiments 1 to 86, wherein the GLP-1 peptide is in phase There is a minimum of 5 amino acid changes compared to GLP-1 (7-37) (SEQ ID NO: 1).

The derivative of any one of embodiments 1 to 87, wherein the GLP-1 peptide has a minimum of 6 amine groups when compared to GLP-1 (7-37) (SEQ ID NO: 1) The acid changes.

The derivative of any one of embodiments 1 to 88, wherein the GLP-1 peptide has a minimum of 7 amine groups when compared to GLP-1 (7-37) (SEQ ID NO: 1) The acid changes.

The derivative of any one of embodiments 1 to 89, wherein the GLP-1 peptide has a minimum of 8 amine groups when compared to GLP-1 (7-37) (SEQ ID NO: 1) The acid changes.

The derivative of any one of embodiments 1 to 90, wherein the GLP-1 peptide has at least 9 amine groups when compared to GLP-1 (7-37) (SEQ ID NO: 1) The acid changes.

The derivative of any one of embodiments 1 to 91, wherein the GLP-1 peptide has a minimum of 10 amine groups when compared to GLP-1 (7-37) (SEQ ID NO: 1) The acid changes.

The derivative of any one of embodiments 1 to 92, wherein the GLP-1 peptide has 5 amino acids when compared to GLP-1 (7-37) (SEQ ID NO: 1) change.

The derivative of any one of embodiments 1 to 92, wherein the GLP-1 peptide has 6 amino acids when compared to GLP-1 (7-37) (SEQ ID NO: 1) change.

The derivative of any one of embodiments 1 to 92, wherein the GLP-1 peptide has 7 amino acids when compared to GLP-1 (7-37) (SEQ ID NO: 1) change.

The derivative of any one of embodiments 1 to 92, wherein the GLP-1 peptide has 8 amino acids when compared to GLP-1 (7-37) (SEQ ID NO: 1) change.

97. The derivative of any one of embodiments 1 to 92, wherein the GLP-1 peptide has 9 amino acids when compared to GLP-1 (7-37) (SEQ ID NO: 1) change.

98. The derivative of any one of embodiments 1 to 92, wherein the GLP-1 peptide has 10 amino acids when compared to GLP-1 (7-37) (SEQ ID NO: 1) change.

The derivative of any one of embodiments 1 to 98, wherein the GLP-1 peptide comprises at least two Lys residues.

The derivative of any one of embodiments 1 to 99, wherein the GLP-1 peptide comprises two Lys residues.

99b. The derivative of any of embodiments 1 to 99a, wherein the GLP-1 peptide has two Lys residues.

99c. The derivative of any one of embodiments 1 to 99b, wherein the GLP-1 peptide has only two Lys residues.

100. The derivative of any one of embodiments 1 to 99, wherein the GLP-1 peptide is selected from the group consisting of GLP-1 (7-37) (SEQ ID NO: 1): i) 8Aib, 22E, 26R, 27K, 34R, 38G, 39G, 40G, 41S, 42K); ii) (8Aib, 22E, 26R, 31K, 34R, 38G, 39G, 40G, 41S, 42K); iii) (8Aib, 22E, 26R, 34R, 38K, 39G, 40G, 41S, 42K); iv (8Aib, 22E, 23K, 26R, 34R, 38G, 39G, 40G, 41S, 42K); v) (8Aib, 22E, 26R, 34R) , 36K, 38G, 39G, 40G, 41S, 42K); and vi) (8Aib, 18K, 22E, 26R, 34R, 38G, 39G, 40G, 41S, 42K).

101. The derivative of any one of embodiments 1 to 100 which is in the form of its sodium or potassium salt.

The derivative of any one of embodiments 1 to 101 which is a GLP-1 receptor agonist.

103. The derivative of embodiment 102 which is a full GLP-1 receptor agonist.

104. The derivative of any of embodiments 1 to 103 which is biologically active in vitro.

105. The derivative of any of embodiments 1 to 104 which is potent in vitro.

106. The derivative of any of embodiments 1 to 105, which is capable of activating the human GLP-1 receptor.

107. The derivative of any of embodiments 1 to 106, which is capable of activating the human GLP-1 receptor by analysis of whole cells expressing the human GLP-1 receptor, wherein in the absence of HSA (0% HSA) and/or the analysis was performed in the presence of HSA (1% HSA).

108. The derivative of embodiment 107, wherein the reaction of the human GLP-1 receptor is measured by reporter gene analysis, such as the analysis of Example 9.

109. The derivative of any one of embodiments 104 to 108, wherein the in vitro bioactivity or potency is determined substantially as described in Example 9.

110. Derivative according to any of the specific examples 1 to 109, which corresponds to an inner tube 400pM 400pM or less of the potency EC _50.

111. Derivative according to any of the specific examples 1 to 110, which corresponds to a test tube having 300pM 300pM or less of the potency EC _50.

112. Specific examples of a derivative of any of 1 to 111, which corresponds to having an in-vitro efficacy of 100pM 100pM or less, or ₅₀ EC.

113. Derivative according to any of the specific examples 1 to 112, with a corresponding 75pM, or 75pM in vitro EC ₅₀ of less efficacy.

114. Specific examples of a derivative of any of 1 to 113, with a corresponding inner tube 55pM 55pM or less of the potency EC _50.

115. Specific examples of a derivative of any of 1 to 114, with a corresponding inner tube 40pM 40pM or less of the potency EC _50.

116. Specific examples of a derivative of any one of 110 to 115, wherein said substantially the EC ₅₀ was determined as described in Example 9.

117. Specific examples of a derivative according to any one of 116, which corresponds to the inner tube 40 having a factor of ₅₀ less than the EC ₅₀ of the potency of the semaglutide EC, wherein semaglutide to ₅₀ of the EC It was determined in the same manner as the EC _{50 of} the derivative.

118. Specific examples of a derivative of any of 1 to 117, which corresponds to having an in-vitro potency of less than semaglutide of the 30 times the EC ₅₀ of the EC _50, wherein the EC semaglutide of ₅₀ It was determined in the same manner as the EC _{50 of} the derivative.

119. Derivative according to any of the specific examples 1 to 118, which corresponds to a test tube having less than semaglutide of the EC 20 is ₅₀ times the potency of the EC _50, wherein the EC semaglutide of ₅₀ It was determined in the same manner as the EC _{50 of} the derivative.

120. Specific examples of a derivative of any of 1 to 119, which corresponds to having an in-vitro potency of less than semaglutide. 8 times the EC of the EC ₅₀ of _50, wherein the EC semaglutide of ₅₀ It was determined in the same manner as the EC _{50 of} the derivative.

121. Derivative according to any of the specific examples 1 to 120, which corresponds to a test tube having less than semaglutide of the EC _50. 5 times the potency of the EC _50, wherein the EC semaglutide of ₅₀ It was determined in the same manner as the EC _{50 of} the derivative.

The derivative according to any one of embodiments 1 to 121, which has an in vitro activity corresponding to an EC ₅₀ of less than 3.5 times the EC ₅₀ of semaglutide, wherein the EC ₅₀ system of semaglutide It was determined in the same manner as the EC _{50 of} the derivative.

The derivative of any one of embodiments 117 to 122, wherein the EC ₅₀ is determined substantially as described in Example 9.

124. The derivative of any one of embodiments 1 to 123 which is capable of binding to the GLP-1 receptor.

125. The derivative of any of embodiments 1 to 124 which is capable of binding to the GLP-1 receptor at a low concentration of HSA (maximum 0.001% final assay concentration).

126. The derivative of any of embodiments 1 to 125, which is capable of binding to the GLP-1 receptor at a high concentration of HSA (2.0% final assay concentration).

127. The derivative of any one of embodiments 124 to 126, wherein the binding to the human GLP-1 receptor is measured by a competitive binding assay, such as the assay of Example 10.

128. The derivative of any one of embodiments 124 to 127, wherein the in vitro binding to the human GLP-1 receptor is determined substantially as described in Example 10.

129. Specific examples of a derivative according to any one of 128, which is capable of binding to the human GLP-1 receptor in a case where the IC 3.0nM 3.0nM or less, or ₅₀ at a very low concentration of the HSA.

130. Specific examples of a derivative according to any one of 129, which is capable of binding to the human GLP-1 receptor in a case where the IC 2.0nM 2.0nM or less, or ₅₀ at a very low concentration of the HSA.

The derivative according to any one of embodiments 1 to 130, which is capable of binding to the human GLP-1 receptor at an IC ₅₀ of 1.0 nM or less at a very low concentration of HSA.

132. Specific examples of a derivative according to any one of 131, which is capable of binding to the human GLP-1 receptor in the case of 0.8nM 0.8nM or less of IC ₅₀ is at a very low concentration of HSA.

133. The assay reaction derivative according to any one of the specific examples 129-132, wherein the IC ₅₀ substantially as described in Example 10, having a maximum 0.001% HSA (final assay concentration) in the.

134. Specific examples of a derivative according to any one of 133, which is capable of binding to less than semaglutide. 3 times the IC of the IC ₅₀ is at a very low concentration of the HSA human subject of GLP-1 ₅₀ , wherein the IC ₅₀ semaglutide measured in the same derivative of the IC ₅₀ of the embodiment.

135. Specific examples of a derivative according to any one of 134, which is capable of binding to less than semaglutide 2 times the IC of the IC ₅₀ is at a very low concentration of the HSA human subject of GLP-1 ₅₀ , wherein the IC ₅₀ semaglutide measured in the same derivative of the IC ₅₀ of the embodiment.

136. Specific examples of a derivative according to any one of 135, which is capable of binding to less than semaglutide for 1.5 times the IC of the IC ₅₀ is at a very low concentration of the HSA human subject of GLP-1 ₅₀ , wherein the IC ₅₀ semaglutide measured in the same derivative of the IC ₅₀ of the embodiment.

137. Specific examples of a derivative according to any one of 136, which is capable of binding to less than semaglutide of the IC 1 times the IC ₅₀ is at a very low concentration of the HSA human subject of GLP-1 ₅₀ , wherein the IC ₅₀ semaglutide measured in the same derivative of the IC ₅₀ of the embodiment.

138. Specific examples of the reaction was determined 134 to 137 derivative according to any of which the IC ₅₀ substantially as described in Example 10, having a maximum 0.001% HSA (final assay concentration) in the.

139. As the specific examples 1 to 138 to any of a derivative, in which 2.0% HSA (final assay concentration) capable of binding to having 400nM 400nM or less of IC or the human GLP-1 receptor _50.

140. As the specific examples 1 to 139 to any of a derivative, in which 2.0% HSA (final assay concentration) capable of binding to having 300nM 300nM or less of IC or the human GLP-1 receptor _50.

141. Derivative according to any of the specific examples 1 to 140, in which 2.0% HSA (final assay concentration) capable of binding to having at 200nM 200nM or less of IC or the human GLP-1 receptor _50.

142. As the specific examples 1 to 141 to any of a derivative, in which 2.0% HSA (final assay concentration) capable of binding to having 150nM 150nM or less of IC or the human GLP-1 receptor _50.

143. Specific examples of the reaction was determined 139 to 142 derivative according to any of which the IC ₅₀ substantially as described in Example 10, with 2.0% HSA (final assay concentration) in the.

144. As the specific examples 1 to 143 to any of a derivative, in which 2.0% HSA (final assay concentration) capable of binding to the human of ₅₀ less than the GLP semaglutide of the IC ₅₀ for 1.5 times the IC 1 receptor, wherein the IC ₅₀ semaglutide of the same derivative of the IC ₅₀ of the embodiment was measured.

145. As the specific examples 1 to 144 to any of a derivative, in which 2.0% HSA (final assay concentration) capable of binding to the human of ₅₀ less than the GLP semaglutide of the IC ₅₀ of 1 times the IC 1 receptor, wherein the IC ₅₀ semaglutide of the same derivative of the IC ₅₀ of the embodiment was measured.

146. As the specific examples 1 to 145 to any of a derivative, in which 2.0% HSA (final assay concentration) capable of binding to the human of ₅₀ less than the GLP semaglutide of the IC ₅₀ of 0.8 times the IC 1 receptor, wherein the IC ₅₀ semaglutide of the same derivative of the IC ₅₀ of the embodiment was measured.

147. As the specific examples 1 to 146 to any of a derivative, in which 2.0% HSA (final assay concentration) capable of binding to the human of ₅₀ less than the GLP semaglutide of the IC ₅₀ of 0.35 times the IC 1 receptor, wherein the IC ₅₀ semaglutide of the same derivative of the IC ₅₀ of the embodiment was measured.

148. Specific examples of a derivative of 144 to 147, wherein IC ₅₀ substantially as described in Example 10, with 2.0% HSA in the reaction of the assay (final assay concentration).

149. The derivative of any of embodiments 1 to 148 which has improved pharmacokinetic properties.

150. The derivative of any of embodiments 1 to 149 which has an increased half-life and/or reduced clearance.

151. The derivative of any of embodiments 1 to 150 which is suitable for administration once a month.

152. A derivative of embodiment 151 for subcutaneous administration.

153. The derivative of any one of embodiments 149 to 152, wherein the derivative is tested in vivo in a pharmacokinetic (PK) study.

154. The derivative of embodiment 153, wherein the derivative is tested in any suitable animal model, such as a mouse, rat, monkey, dog or pig.

155. The derivative of any one of embodiments 149 to 154 which is compared to semaglutide.

156. The derivative of any of embodiments 1 to 155 which has an improved in vivo terminal half-life (T1⁄2) compared to semaglutide in minipigs after intravenous administration.

157. The derivative of any one of embodiments 149 to 156, wherein the terminal half-life is in a mini-pig after intravenous administration using any suitable research protocol, such as the study protocol described in Example 11. In vivo measurement.

158. The derivative of any one of embodiments 149 to 157, wherein the terminal half-life is determined in vivo in a mini-pigs substantially as described in Example 11 after intravenous administration.

159. The derivative of any one of embodiments 1 to 158, which is administered intravenously It has a terminal half-life (T1⁄2) in vivo for at least 90 hours in small pigs.

160. The derivative of any of embodiments 1 to 159 which has an in vivo terminal half-life (T1⁄2) in a mini-pig after intravenous administration.

161. The derivative of any one of embodiments 1 to 160 which has an in vivo terminal half-life (T1⁄2) of at least 125 hours in a mini-pig after intravenous administration.

162. The derivative of any one of embodiments 1 to 161 which has an in vivo terminal half-life (T1⁄2) in a mini-pig after intravenous administration.

163. The derivative of any one of embodiments 1 to 162, which has an in vivo terminal half-life of at least 1.5 times the terminal half-life of semaglutide determined in the same manner after intravenous administration (in a mini-pig) ( T1⁄2).

164. The derivative of any one of embodiments 1 to 163 which has an in vivo terminal half-life of at least 2 times the terminal half-life of semaglutide determined in the same manner in minipigs after intravenous administration ( T1⁄2).

165. The derivative of any one of embodiments 1 to 164, which has an in vivo terminal half-life of at least 2.3 times the terminal half-life of semaglutide determined in the same manner after intravenous administration (in a mini-pig) ( T1⁄2).

166. The derivative of any one of embodiments 1 to 165, which has an in vivo terminal half-life of at least 2.6 times the terminal half-life of semaglutide determined in the same manner after intravenous administration (in a mini-pig) ( T1⁄2).

167. The derivative of any of embodiments 1 to 166 which is potent in vivo.

168. The derivative of any of embodiments 1 to 167 which is potent in vivo when assayed in any suitable animal model, such as a mouse or pig.

169. The derivative of embodiment 168, wherein the animal model is a db/db mouse.

The derivative according to any one of embodiments 167 to 169, wherein the blood sugar lowering effect is determined.

171. The derivative of any one of embodiments 167 to 170, wherein the weight loss effect is determined.

172. The derivative of any one of embodiments 1 to 171, wherein the blood glucose lowering effect is measured in vivo in db/db mice using any suitable research protocol and method, for example, as described in Example 12 Weight loss effect.

173. The derivative of any one of embodiments 1 to 172, wherein the blood glucose lowering effect and/or the weight loss reducing effect is measured in vivo in db/db mice substantially as described in Example 12.

174. The derivative of any of embodiments 1 to 173, which has an in vivo effect of reducing blood glucose after 48 hours as determined in a single dose study in a db/db mouse model.

175. The derivative of embodiment 174, wherein the blood glucose is reduced by at least 15% compared to the blood glucose level prior to administration of the derivative.

176. The derivative of any one of embodiments 174 to 175, wherein the blood glucose is reduced by at least 25% compared to the blood glucose level prior to administration of the derivative.

177. The derivative of any one of embodiments 174 to 176, wherein the blood glucose is reduced by at least 35% compared to the blood glucose level prior to administration of the derivative.

178. The derivative of any one of embodiments 174 to 177, wherein the blood glucose is reduced by at least 50% compared to the blood glucose level prior to administration of the derivative.

179. The derivative of any of embodiments 1 to 178, which has an in vivo effect of reducing blood glucose after 72 hours as determined in a single dose study in a db/db mouse model.

180. The derivative of any of embodiments 1 to 179, which has an in vivo effect of reducing blood glucose after 96 hours as determined in a single dose study in a db/db mouse model.

181. The derivative of embodiment 180, wherein the blood glucose is reduced by at least 5% compared to the blood glucose level prior to administration of the derivative.

182. The derivative of any one of embodiments 180 to 181, wherein the blood glucose is reduced by at least 10% compared to the blood glucose level prior to administration of the derivative.

183. The derivative of any one of embodiments 180 to 182, wherein the blood glucose is reduced by at least 15% compared to the blood glucose level prior to administration of the derivative.

184. The derivative of any one of embodiments 180 to 183, wherein the blood glucose is reduced by at least 20% compared to the blood glucose level prior to administration of the derivative.

185. The derivative of any one of embodiments 180 to 184, wherein the blood glucose is reduced by at least 25% compared to the blood glucose level prior to administration of the derivative.

186. The derivative of any of embodiments 1 to 185, which has an in vivo effect of reducing body weight after 48 hours as determined in a single dose study in a db/db mouse model.

187. The derivative of embodiment 186, wherein the body weight is reduced by at least 3% compared to the body weight prior to administration of the derivative.

188. The derivative of any one of embodiments 186 to 187, wherein the body weight is reduced by at least 4% compared to the body weight prior to administration of the derivative.

189. The derivative of any one of embodiments 186 to 188, wherein the body weight is reduced by at least 5% compared to the body weight prior to administration of the derivative.

190. The derivative of any one of embodiments 186 to 184, wherein the body weight is reduced by at least 6% compared to the body weight prior to administration of the derivative.

191. The derivative of any one of embodiments 1 to 190, which has an in vivo effect of reducing body weight after 72 hours as determined in a single dose study in a db/db mouse model.

192. The derivative of any of embodiments 1 to 191, which has an in vivo effect of reducing body weight after 96 hours as determined in a single dose study in a db/db mouse model.

193. The derivative of embodiment 192, wherein the body weight is reduced by at least 2% compared to the body weight prior to administration of the derivative.

194. The derivative of any one of embodiments 192 to 193, wherein the body weight is reduced by at least 3% compared to the body weight prior to administration of the derivative.

195. The derivative of any one of embodiments 192 to 194, wherein The body weight before the derivative is reduced by at least 4%.

196. The derivative of embodiment 168, wherein the animal model is a pig.

197. The derivative of embodiment 196, wherein the animal model is a LYD pig.

198. The derivative of any one of embodiments 196 to 197, wherein the reduction in food intake is determined in an in vivo pharmacodynamic (PD) study.

199. The derivative of any one of embodiments 196 to 198, wherein the reduction in food intake is determined in vivo in a pig using any suitable research protocol and method, for example, as described in Example 13.

200. The derivative of any one of embodiments 196 to 199, wherein the reduction in food intake is determined in vivo in pigs substantially as described in Example 13, using any suitable research protocol and method.

201. The derivative of any one of embodiments 1 to 200, which has an in vivo reduction in food intake during a first 24-hour period (0-24 hours) after administration of a single dose of the derivative Effect, where food intake was determined in a single dose study in the LYD pig model.

The derivative according to any one of embodiments 1 to 201, which has an in vivo reduction in food intake during a second 24-hour period (24-48 hours) after administration of a single dose of the derivative Effect, where food intake was determined in a single dose study in the LYD pig model.

203. The derivative of any one of embodiments 1 to 202, which has a reduced food intake during a third 24-hour period (48-72 hours) after administration of a single dose of the derivative. Effect, where food intake was determined in a single dose study in the LYD pig model.

The derivative of any one of embodiments 1 to 203, which has an in vivo reduction in food intake during a fourth 24-hour period (72-96 hours) after administration of a single dose of the derivative Effect, where food intake was determined in a single dose study in the LYD pig model.

205. A GLP-1 derivative selected from the group consisting of Chemical Formula 21, Chemical Formula 22, Chemical Formula 23, Chemical Formula 24, Chemical Formula 25, Chemical Formula 26, Chemical Formula 27, and Chemical Formula 28; A pharmaceutically acceptable salt, guanamine or ester.

206. A GLP-1 derivative selected from the group consisting of the chemical structures shown in any one of Examples 1 to 8; or a pharmaceutically acceptable salt, guanamine or ester thereof.

207. A GLP-1 derivative selected from the group consisting of the GLP-1 derivative names shown in any one of Examples 1 to 8; or a pharmaceutically acceptable salt, guanamine or ester thereof.

208. The derivative of any one of embodiments 205 to 207, which is a derivative according to any one of the specific examples 1 to 204.

209. An intermediate in the form of a GLP-1 analog which, when compared to GLP-1 (7-37) (SEQ ID NO: 1), comprises the following amino acid changes: i) (8Aib, 22E, 26R, 27K, 34R, 38G, 39G, 40G, 41S, 42K); ii) (8Aib, 22E, 26R, 31K, 34R, 38G, 39G, 40G, 41S, 42K); iii) (8Aib, 22E, 26R, 34R, 38K, 39G, 40G, 41S, 42K); iv (8Aib, 22E, 23K, 26R, 34R, 38G, 39G, 40G, 41S, 42K); v) (8Aib, 22E, 26R, 34R, 36K, 38G) , 39G, 40G, 41S, 42K); or vi) (8Aib, 18K, 22E, 26R, 34R, 38G, 39G, 40G, 41S, 42K).

210. An intermediate in the form of a GLP-1 analog selected from the group consisting of the following analogs of GLP-1 (7-37) (SEQ ID NO: 1): i) (8Aib, 22E, 26R, 27K, 34R, 38G, 39G, 40G, 41S, 42K); ii) (8Aib, 22E, 26R, 31K, 34R, 38G, 39G, 40G, 41S, 42K); iii) (8Aib, 22E, 26R, 34R, 38K, 39G, 40G, 41S, 42K); iv (8Aib, 22E, 23K, 26R, 34R, 38G, 39G, 40G, 41S, 42K); v) (8Aib, 22E, 26R, 34R, 36K, 38G, 39G, 40G, 41S) , 42K); and vi) (8Aib, 18K, 22E, 26R, 34R, 38G, 39G, 40G, 41S, 42K).

211. A pharmaceutical composition comprising a derivative of any one of embodiments 1 to 208 or an analog of any one of embodiments 209 to 210 and a pharmaceutically acceptable excipient.

The derivative of any one of the specific examples 1 to 208, or the analog of any one of the specific examples 209 to 210, for use as a medicament.

213. The derivative of any one of embodiments 1 to 208, or the analog of any one of embodiments 209 to 210, for (i) preventing and/or treating all forms of diabetes, such as hyperglycemia Symptoms, type 2 diabetes, abnormal glucose tolerance, type 1 diabetes, non-insulin-dependent diabetes mellitus, MODY (young adult diabetes), gestational diabetes and/or reduction of HbA1C; (ii) delay or prevention of diabetes progression, such as Advances in type 2 diabetes, delaying the progression of impaired glucose tolerance (IGT) into type 2 diabetes requiring insulin, delaying or preventing insulin resistance, and/or delaying progression of type 2 diabetes requiring insulin to insulin type 2 diabetes requiring insulin; (iii) improving β-cell function, such as reducing β-cell apoptosis, increasing β-cell function and/or β-cell mass and/or restoring glucose sensitivity to β-cells; (iv) preventing and/or treating cognition Obstacle and/or neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease and/or multiple sclerosis; (v) prevention and/or treatment of eating disorders such as obesity Case Such as by reducing food intake, reducing body weight, suppressing appetite, and feeling satiety; treating or preventing by eating antipsychotics or steroid-induced bulimia, psychosis and obesity; Stomach movement; delaying gastric emptying; increasing body movement; and/or preventing and/or treating comorbidities of obesity, such as osteoarthritis and/or urinary incontinence; (vi) preventing and/or treating diabetic complications, such as Vascular disease; neuropathy, including peripheral neuropathy; nephropathy; and/or retinopathy; (vii) improved lipid parameters such as prevention and/or treatment of dyslipidemia, reduction of total serum lipids; increased HDL; decreased low density LDL; decreased VLDL; Triglyceride; lowers cholesterol; lowers plasma content of lipoprotein a (Lp(a)) in human body; inhibits production of apolipoprotein a (apo(a)) in vitro and/or in vivo; (viii) Prevention and/or treatment of cardiovascular diseases such as syndrome X, atherosclerosis, myocardial infarction, coronary heart disease, reperfusion injury, stroke, cerebral ischemia, early cardiac or early cardiovascular disease, left ventricular hypertrophy, coronary Arterial disease, hypertension, essential hypertension, acute hypertension, cardiomyopathy, cardiac insufficiency, exercise intolerance, acute and/or chronic heart failure, arrhythmia, arrhythmia, syncope, angina, cardiac bypass and / or stent reocclusion, atheroschlerosis oblitterens, diastolic dysfunction and / or systolic dysfunction; and / or lower blood pressure, such as reducing systolic blood pressure; (ix) prevention and / or treatment of gastrointestinal diseases, such as inflammatory bowel Disease, short bowel syndrome or Crohn's disease or colitis; dyspepsia and / or gastric ulcer; and / or inflammation, such as psoriasis, psoriatic arthritis, rheumatoid arthritis and / or systemic erythema Lupus; (x) prevention and/or treatment of critical illness, such as treatment of critically ill patients, critically ill multiple kidney disease (CIPNP) patients and/or potential CIPNP patients; prevention Development of a serious illness or CIPNP; prevention, treatment, and/or cure of a patient's systemic inflammatory response syndrome (SIRS); prevention or reduction of the likelihood of bacteremia, sepsis, and/or septic shock during hospitalization; and/ Or stabilize blood glucose, insulin balance, and optionally metabolism in patients with intensive care units with acute disease; (xi) prevent and/or treat polycystic ovary syndrome (PCOS); (xii) prevent and/or treat brain diseases , such as cerebral ischemia, cerebral hemorrhage and/or traumatic brain injury; (xiii) prevention and/or treatment of sleep apnea; and/or (xiv) prevention and/or treatment abuse, such as alcohol abuse and/or substance abuse.

214. Use of a derivative according to any one of embodiments 1 to 208, or an analogue according to any one of embodiments 209 to 210, for the manufacture of a medicament for: (i) prevention and/or Or treating all forms of diabetes, such as hyperglycemia, type 2 diabetes, abnormal glucose tolerance, type 1 diabetes, non-insulin dependent diabetes, MODY (young adult diabetes), gestational diabetes, and/or reduced HbA1C; (ii) Delaying or preventing the progression of diabetes, such as progression of type 2 diabetes, delaying the progression of impaired glucose tolerance (IGT) to type 2 diabetes requiring insulin, delaying or preventing insulin resistance, and/or delaying type 2, which does not require insulin Diabetes progresses to type 2 diabetes requiring insulin; (iii) improves β-cell function, such as reducing beta-cell apoptosis, increasing beta-cell function and/or beta-cell mass and/or restoring glucose sensitivity to beta-cells (iv) prevention and/or treatment of cognitive disorders and/or neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease and/or multiple sclerosis; (v) Preventing and/or treating eating disorders, such as obesity, for example, by reducing food intake, reducing body weight, suppressing appetite, and feeling satiety; treating or preventing by eating an antipsychotic or steroid-induced bulimia, Cardiac bulimia and/or obesity; reducing gastric motility; delaying gastric emptying; increasing body movement; and/or preventing and/or treating comorbidities of obesity, such as osteoarthritis and/or urinary incontinence; Vi) prevention And/or treating diabetic complications, such as vascular diseases; neuropathy, including peripheral neuropathy; nephropathy; and/or retinopathy; (vii) improving lipid parameters, such as preventing and/or treating dyslipidemia, reducing total serum lipids; increasing HDL; Lowering low-density LDL; lowering VLDL; lowering triglyceride; lowering cholesterol; lowering plasma levels of lipoprotein a (Lp(a)) in humans; inhibiting apolipoprotein a (apo) in vitro and/or in vivo a)); (viii) prevention and/or treatment of cardiovascular diseases such as syndrome X, atherosclerosis, myocardial infarction, coronary heart disease, reperfusion injury, stroke, cerebral ischemia, early heart or early cardiovascular disease, left Ventricular hypertrophy, coronary artery disease, hypertension, essential hypertension, acute hypertension, cardiomyopathy, cardiac insufficiency, exercise intolerance, acute and/or chronic heart failure, arrhythmia, arrhythmia, syncope, angina, Cardiac bypass and/or stent reocclusion, atheroschlerosis oblitterens, diastolic dysfunction, and/or systolic dysfunction; and/or lowering blood pressure, such as reducing systolic blood pressure (ix) prevention and/or treatment of gastrointestinal diseases such as inflammatory bowel disease, short bowel syndrome or Crohn's disease or colitis; dyspepsia and/or gastric ulcer; and/or inflammation, such as psoriasis, psoriasis Arthritis, rheumatoid arthritis and/or systemic lupus erythematosus; (x) prevention and/or treatment of critical illness, such as treatment of critically ill patients, critically ill multiple kidney disease (CIPNP) patients and/or potential CIPNP Patients; prevention of the development of critical illness or CIPNP; prevention, treatment and/or cure of systemic inflammatory response syndrome (SIRS) in patients; prevention or reduction of the likelihood of bacteremia, sepsis and/or septic shock during hospitalization And/or stabilize blood glucose, insulin balance and, where appropriate, the presence of a patient in an intensive care unit with acute disease; (xi) prevent and/or treat polycystic ovary syndrome (PCOS); (xii) preventive and/or Treatment of brain diseases such as cerebral ischemia, cerebral hemorrhage and/or traumatic brain injury; (xiii) prevention and/or treatment of sleep apnea; and/or (xiv) prevention and/or treatment abuse, such as alcohol abuse and/or or Substance abuse.

215. A method for (i) preventing and/or treating all forms of diabetes, such as hyperglycemia, type 2 diabetes, abnormal glucose tolerance, type 1 diabetes, non-insulin dependent diabetes, MODY (younger Adult diabetes), gestational diabetes and/or reduction of HbA1C; (ii) delay or prevention of progression of diabetes, such as progression of type 2 diabetes, delaying progression of glucose tolerance (IGT) to insulin type 2 diabetes, delay or Preventing insulin resistance and/or delaying the progression of insulin-free type 2 diabetes to type 2 diabetes requiring insulin; (iii) improving beta-cell function, such as reducing beta-cell apoptosis, increasing beta-cell function and/or beta - cell mass and/or recovery of glucose sensitivity for β-cells; (iv) prevention and/or treatment of cognitive disorders and/or neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease ( Parkinson's disease and/or multiple sclerosis; (v) prevention and/or treatment of eating disorders, such as obesity, for example by reducing food intake, losing weight, suppressing appetite, and inducing satiety; Treatment or prevention by administration of anti-psychotic Drug or steroid-induced bulimia, psychogenic eclipse and/or obesity; reducing gastric motility; delaying gastric emptying; increasing body movement; and/or preventing and/or treating comorbidities of obesity, such as bone and joint Inflammation and/or urinary incontinence; (vi) prevention and/or treatment of diabetic complications such as vascular disease; neuropathy, including peripheral neuropathy; nephropathy; and/or retinopathy; (vii) improved lipid parameters such as prevention and/or treatment Dyslipidemia, lowering total serum lipids; increasing HDL; lowering low-density LDL; lowering VLDL; lowering triglyceride; lowering cholesterol; lowering plasma content of lipoprotein a (Lp(a)) in human body; inhibiting in vitro and/or Or in vivo production of apolipoprotein a (apo(a)); (viii) prevention and/or treatment of cardiovascular diseases such as syndrome X, atherosclerosis, myocardial infarction, coronary heart disease, reperfusion injury, stroke, brain deficiency Blood, early heart or early cardiovascular disease, left ventricular hypertrophy, coronary artery disease, hypertension, essential hypertension, acute hypertension, cardiomyopathy, cardiac insufficiency, exercise intolerance, acute and/or chronic heart failure Arrhythmia, arrhythmia, syncope, angina pectoris, cardiac bypass and/or stent reocclusion, atheroschlerosis oblitterens, diastolic dysfunction and/or systolic dysfunction; and/or lowering blood pressure, such as reducing systolic blood pressure; Ix) prevention and/or treatment of gastrointestinal diseases such as inflammatory bowel disease, short bowel syndrome or Crohn's disease or colitis; dyspepsia and / or gastric ulcer; and / or inflammation, such as psoriasis, psoriasis Arthritis, rheumatoid arthritis and/or systemic lupus erythematosus; (x) prevention and/or treatment of critical illness, such as treatment of critically ill patients, critically ill multiple kidney disease (CIPNP) patients and/or potential CIPNP patients Prevention of the development of critical illness or CIPNP; prevention, treatment and/or cure of systemic inflammatory response syndrome (SIRS) in patients; prevention or reduction of the likelihood of bacteremia, sepsis and/or septic shock during hospitalization And/or stabilize blood glucose, insulin balance and, where appropriate, the presence of a patient in an intensive care unit with acute disease; (xi) prevent and/or treat polycystic ovary Waiting group (PCOS); (xii) preventing and/or treating brain diseases such as cerebral ischemia, cerebral hemorrhage and/or traumatic brain injury; (xiii) preventing and/or treating sleep apnea; and/or (xiv) preventing and/or treating Abuse, such as alcohol abuse and/or drug abuse; a derivative of any one of the specific examples 1 to 208, or an analog of any one of the specific examples 209 to 210, which is administered a pharmaceutically active amount.

The following is another specific example of the present invention:

A derivative of a GLP-1 peptide such as Formula I: Formula I: Xaa ₇ -Xaa ₈ -Glu-Gly-Thr-Xaa ₁₂ -Thr-Ser-Asp-Xaa ₁₆ -Ser- Xaa ₁₈ -Xaa ₁₉ -Xaa ₂₀ -Glu-Xaa ₂₂ -Xaa ₂₃ -Ala-Xaa ₂₅ -Xaa ₂₆ -Xaa ₂₇ -Phe-Ile-Xaa ₃₀ -Xaa ₃₁ -Leu-Xaa ₃₃ -Xaa ₃₄ -Xaa ₃₅ -Xaa ₃₆ -Xaa ₃₇ - Xaa ₃₈ -Xaa ₃₉ -Xaa ₄₀ -Xaa ₄₁ -Xaa ₄₂ , wherein Xaa ₇ is L-histidine acid, (S)-2-hydroxy-3-(1H-imidazol-4-yl)-propionic acid, D- histidine, histidine amino group to the high-histidine, N α ^- acetyl group histidine, N α ^- methyl acyl histidine, N α ^- methyl-histidine, 3-pyridyl-alanine , 2-pyridylamino acid or 4-pyridylalanine; Xaa ₈ is Ala, Gly, Ser, Aib, (1-aminocyclopropyl)carboxylic acid or (1-aminocyclobutyl)carboxylic acid; Xaa ₁₂ is Phe Or Leu; Xaa ₁₆ is Val or Leu; Xaa ₁₈ is Ser, Arg, Lys, Val or Leu; Xaa ₁₉ is Tyr or Gln; Xaa ₂₀ is Leu or Met; Xaa ₂₂ is Gly or Glu; Xaa ₂₃ is Gln, Glu , Lys or Arg; Xaa ₂₅ is Ala or Val; Xaa ₂₆ is Arg or Lys; Xaa ₂₇ is Glu, Lys or Leu; Xaa ₃₀ is Ala, Glu or Arg; Xaa ₃₁ is Trp, Lys or His; Xaa ₃₃ is Val , Lys or Arg; Xaa ₃₄ is Lys, Arg, His, Asn or G Ln; Xaa ₃₅ is Gly or Ala; Xaa ₃₆ is Arg, Lys or Gly; Xaa ₃₇ is Gly or Pro; Xaa ₃₈ is Ser, Gly, Ala, Glu, Pro or Lys; Xaa ₃₉ is Ser, Gly, Ala, Glu Or Pro; Xaa ₄₀ is Ser, Gly, Ala, Glu or Pro; Xaa ₄₁ is Ser, Gly, Ala, Glu or Pro; and Xaa ₄₂ is Lys; the restrictions are Xaa ₁₈ , Xaa ₂₃ , Xaa ₂₇ , Xaa ₃₁ At least one of Xaa ₃₆ or Xaa ₃₈ is Lys; wherein Lys at Xaa ₄₂ is the first K residue, and one of Xaa ₁₈ , Xaa ₂₃ , Xaa ₂₇ , Xaa ₃₁ , Xaa ₃₆ or Xaa ₃₈ Lys is a second K residue; the derivative comprises first and second extensions respectively linked to the first and second K residues, wherein the first and second extensions have the chemical formula 1: chemical formula 1: HOOC-(CH ₂ ) ₁₈ -CO-*; or a pharmaceutically acceptable salt, guanamine or ester thereof.

2. The derivative of embodiment 1, wherein each of the first and second extensions are independently linked to the first and second K residues, respectively, via the first and second linkers, respectively.

3. The derivative of embodiment 2, wherein the first and second linkers each have a *-NH group and a *-CO group.

4. The derivative of any one of embodiments 2 to 3, wherein each of the first and the second linker comprises element 1 of formula 2:

5. The derivative of any of embodiments 1 to 4, wherein Lys at Xaa ₁₈ is the second K residue.

6. The derivative of any of embodiments 1 to 4, wherein Lys at Xaa ₂₃ is the second K residue.

7. The derivative of any one of embodiments 1 to 4, wherein Lys at Xaa ₂₇ is the second K residue.

8. The derivative of any one of embodiments 1 to 4, wherein Lys at Xaa ₃₁ is the second K residue.

9. The derivative of any of embodiments 1 to 4, wherein Lys at Xaa ₃₆ is the second K residue.

10. The derivative of any of embodiments 1 to 4, wherein Lys at Xaa ₃₈ is the second K residue.

A GLP-1 derivative selected from the group consisting of Chemical Formula 21, Chemical Formula 22, Chemical Formula 23, Chemical Formula 24, Chemical Formula 25, Chemical Formula 26, Chemical Formula 27, and Chemical Formula 28; or a pharmaceutically acceptable salt thereof, guanamine Or ester.

12. An intermediate in the form of a GLP-1 analog which, when compared to GLP-1 (7-37) (SEQ ID NO: 1), comprises the following amino acid changes: i) (8Aib, 22E, 26R, 27K, 34R, 38G, 39G, 40G, 41S, 42K); ii) (8Aib, 22E, 26R, 31K, 34R, 38G, 39G, 40G, 41S, 42K); iii) (8Aib, 22E, 26R, 34R, 38K, 39G, 40G, 41S, 42K); iv (8Aib, 22E, 23K, 26R, 34R, 38G, 39G, 40G, 41S, 42K); v) (8Aib, 22E, 26R, 34R, 36K, 38G, 39G, 40G, 41S, 42K); or vi) (8Aib, 18K, 22E, 26R, 34R, 38G, 39G, 40G, 41S, 42K).

13. A pharmaceutical composition comprising a derivative according to any one of embodiments 1 to 11, or an analog of specific example 12, and a pharmaceutically acceptable excipient.

14. The derivative of any of embodiments 1 to 11, or the analog of specific example 12, for use as a medicament.

15. The derivative of any of embodiments 1 to 11, or the analog of specific example 12, for (i) preventing and/or treating all forms of diabetes, such as hyperglycemia, type 2 diabetes, Glucose tolerance abnormalities, type 1 diabetes, non-insulin dependent diabetes, MODY (young adult diabetes), gestational diabetes and/or reduction of HbA1C; (ii) delay or prevention of diabetes progression, such as progression of type 2 diabetes, Delaying the progression of impaired glucose tolerance (IGT) to type 2 diabetes requiring insulin, delaying or preventing insulin resistance and/or delaying the progression of type 2 diabetes requiring insulin to insulin type 2 diabetes; (iii) improving beta- Cellular functions such as reducing β-cell apoptosis, increasing β-cell function and/or β-cell mass and/or restoring glucose sensitivity to β-cells; (iv) preventing and/or treating cognitive impairment and/or neurodegeneration Sexual disorders such as Alzheimer's disease, Parkinson's disease and/or multiple sclerosis; (v) prevention and/or treatment of eating disorders, such as obesity, for example by reducing food Ingestion, weight loss, appetite suppression, and feeling of satiety; treatment or prevention by taking antipsychotics or steroid-induced bulimia, psychogenic eclipse and/or obesity; reducing gastric movement; delaying Emptying of the stomach; increasing body movement; and/or preventing and/or treating comorbidities of obesity, such as osteoarthritis and/or urinary incontinence; (vi) preventing and/or treating diabetic complications, such as vascular disease; neuropathy , including peripheral neuropathy; nephropathy; and/or retinopathy; (vii) improving lipid parameters such as preventing and/or treating dyslipidemia, lowering total serum lipids; increasing HDL; lowering low density LDL; lowering VLDL; lowering triglycerides Lowering cholesterol; lowering the plasma content of lipoprotein a (Lp(a)) in the human body; inhibiting the production of apolipoprotein a (apo(a)) in vitro and/or in vivo; (viii) preventing and/or treating heart Vascular disease, such as syndrome X, atherosclerosis, myocardial infarction, coronary heart disease, reperfusion injury, stroke, cerebral ischemia, early heart or early cardiovascular disease, left ventricular hypertrophy, coronary artery disease, hypertension, primary Hypertension, acute hypertension, cardiomyopathy, cardiac insufficiency, exercise intolerance, acute and/or chronic heart failure, arrhythmia, arrhythmia, syncope, angina pectoris, cardiac bypass and/or stent reocclusion, intermittent Alasoschlerosis oblitterens, diastolic dysfunction and/or systolic dysfunction; and/or lowering blood pressure, such as reducing systolic blood pressure; (ix) preventing and/or treating gastrointestinal disorders such as inflammatory bowel disease, short bowel syndrome or Crowe Crohn's disease or colitis; indigestion and/or gastric ulcer; and/or inflammation, such as psoriasis, psoriatic arthritis, rheumatoid arthritis and/or systemic lupus erythematosus; (x) prevention And/or treatment of critical illness, such as treatment of critically ill patients, critically ill multiple kidney disease (CIPNP) patients and/or potential CIPNP patients; prevention of critical illness or development of CIPNP; prevention, treatment and/or cure of systemic inflammatory response syndrome in patients (SIRS); preventing or reducing the likelihood of bacteremia, sepsis, and/or septic shock during hospitalization; and/or pre-existing blood glucose, insulin balance, and optionally as appropriate in patients with intensive care units with acute disease Metabolic stabilization; (xi) prevention and/or treatment of polycystic ovary syndrome (PCOS); (xii) prevention and/or treatment of brain diseases such as cerebral ischemia, cerebral hemorrhage and/or Traumatic Brain injury; (xiii) prevention and/or treatment of sleep apnea; and/or (xiv) prevention and/or treatment abuse, such as alcohol abuse and/or substance abuse.

Example

This experimental section begins with a list of abbreviations and is followed by a section that includes general methods for synthesizing and characterizing the analogs and derivatives of the invention. Following are a number of examples for the preparation of specific GLP-1 derivatives, and finally including various embodiments relating to the activity and properties of such analogs and derivatives (titled as part of the pharmacological method). The examples are intended to illustrate the invention.

Materials and methods

Abbreviated list

Aib: α-aminoisobutyric acid (2-aminoisobutyric acid)

AcOH: acetic acid

API: Effective pharmaceutical ingredients

AUC: area under the curve

BG: Blood sugar

BHK baby hamster kidney

BW: Weight

Boc: third butoxycarbonyl

Bom: benzyloxymethyl

BSA: Bovine Serum Albumin

Bzl: benzyl

CAS: Chemical Abstracts Service

Clt: 2-chlorotritylmethyl

Collidine: 2,4,6-trimethylpyridine

DCM: dichloromethane

Dde: 1-(4,4-dimethyl-2,6-dioxocyclohexyl)ethyl

DesH: deaminated histidine (imidazopropionic acid or 3-(imidazolium-5-yl)propionic acid), Imp)

DIC: diisopropylcarbodiimide

DIPEA: diisopropylethylamine

DMAP: 4-dimethylaminopyridine

DMEM: Dulbecco's modified Eagle's medium (DMEM)

DooaSuc: 8-amino-3,6-dioxaoctyl succinic acid

EDTA: ethylenediaminetetraacetic acid

EGTA: ethylene glycol tetraacetic acid

FCS: fetal bovine serum

Fmoc: 9-fluorenylmethoxycarbonyl

HATU: (O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyl hexafluorophosphate )

HBTU: (2-(1H-benzotriazol-1-yl-)-1,1,3,3 tetramethyl hexafluorophosphate )

HEPES: 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid

HFIP 1,1,1,3,3,3-hexafluoro-2-propanol or hexafluoroisopropanol

HOAt: 1-hydroxy-7-azabenzotriazole

HOBt: 1-hydroxybenzotriazole

HPLC: high performance liquid chromatography

HSA: human serum albumin

IBMX: 3-isobutyl-1-methylxanthine

Imp: imidazopropionic acid or 3-(imidazolium-5-yl)propionic acid) (also known as deaminoglycolic acid, DesH)

Inp: Isopiperidinecarboxylic acid

I.v. intravenous

ivDde: 1-(4,4-dimethyl-2,6-dioxocyclohexyl)-3-methylbutyl

IVGTT: Intravenous glucose tolerance test

LCMS: liquid chromatography mass spectrometry

LYD: Landrace, Yorkshire, Duroc

MALDI-MS: See MALDI-TOF MS

MALDI-TOF MS: Matrix-assisted laser desorption/ionization time for flight mass spectrometry

MeOH: methanol

Mmt: 4-methoxytritylmethyl

Mtt: 4-methyltrityl

NMP: N-methylpyrrolidone

OBz: benzhydryl ester

OEG: 8-amino-3,6-dioxaoctanoic acid

OPfp: pentafluorophenoxy

OPnp: p-nitrophenoxy

OSu: o-amyl iodide (hydroxy amber ylide)

OtBu: third butyl ester

Oxyma Pure®: Cyano-hydroxyimino-ethyl acetate

Pbf: 2,2,4,6,7-pentamethyldihydrobenzofuran-5-sulfonyl

PBS: phosphate buffered saline

PD: pharmacodynamics

Pen/Strep: penicillin/streptomycin

PK: Pharmacokinetics

RP: reverse phase

RP-HPLC: reverse phase high performance liquid chromatography

RT: room temperature

Rt: residence time

S.c.: under the skin

SD: standard deviation

SEC-HPLC: size exclusion high performance liquid chromatography

SEM: average standard error

SPA: Flashing proximity analysis

SPPS: solid phase peptide synthesis

TBME: third butyl methyl ether

tBu: third butyl

TFA: trifluoroacetic acid

TIS: triisopropyl decane

TLC: thin layer chromatography

Tos: tosylate (or p-toluenesulfonyl)

TotaGlyc: 13-amino-4,7,10-trioxatridecyl diglycolamic acid

Tris: ginseng (hydroxymethyl) aminomethane or 2-amino-2-hydroxymethyl-propane-1,3-diol

Trt: triphenylmethyl/trityl

Trx: Aminocycline

TtdSuc: 13-amino-4,7,10-trioxatridecyl succinic acid

UPLC: Ultra High Performance Liquid Chromatography

special material

Eicosanedioic acid mono-tert-butyl ester

Dodecanoic acid mono-tert-butyl ester

Pentadecanedioic acid, third tert-butyl ester, nonadecanedioic acid

Fmoc-8-amino-3,6-dioxaoctanoic acid

Fmoc-8-amino-3,6-dioxaoctyl succinic acid

Fmoc-13-amino-4,7,10-trioxatridecyl succinic acid

Fmoc-13-amino-4,7,10-trioxatridecyl diglycolamic acid

Fmoc-amine cyclic acid

Fmoc-Lys(Mtt)-OH

Fmoc-Glu-OtBu

Boc-Lys(Fmoc)-OH

4-dimethylaminopyridine (DMAP)

Third butyl methyl ether (TBME)

The preparation of eicosanedioic acid mono-tert-butyl ester, behenedioic acid mono-t-butyl ester and nonadecyldinate mono-tert-butyl ester is described in the following section 2, and the last eleven mentions The materials are commercially available.

chemical method

This section is divided into two parts: Part A relating to the general method of (Preparation (A1); and Detection and Characterization (A2)), and Part B which describes the preparation and characterization of various specific example compounds.

A. General method

A1. Preparation method

This section pertains to methods for solid phase peptide synthesis (SPPS methods, including methods for deprotection of amino acids, methods for recrystallizing peptides from resins and methods for their purification), and for detection And methods for characterizing the obtained peptide (LCMS, MALDI and UPLC methods). By using a group which can be cleaved under acidic conditions, such as, but not limited to, 2-Fmoc-oxy-4-methoxybenzyl or 2,4,6-trimethoxybenzyl The dipeptide peptide protects the dipeptide from the guanamine bond and in some cases improves the solid phase synthesis of the peptide. In the case where serine or threonine is present in the peptide, pseudo-proline dipeptide (available, for example, from Novabiochem, see also WRSampson (1999), J. Pep. Sci. 5, 403) can be used. The Fmoc protected amino acid derivatives used are the recommended standards: Fmoc-Ala-OH, Fmoc-Arg(Pbf)-OH, Fmoc-Asn(Trt)-OH, Fmoc-Asp(OtBu)-OH, Fmoc- Cys(Trt)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Glu(OtBu)-OH, Fmoc-Gly-OH, Fmoc-His(Trt)-OH, Fmoc-Ile-OH, Fmoc-Leu- OH, Fmoc-Lys(Boc)-OH, Fmoc-Met-OH, Fmoc-Phe-OH, Fmoc-Pro-OH, Fmoc-Ser(tBu)-OH, Fmoc-Thr(tBu)-OH, Fmoc-Trp (Boc)-OH, Fmoc-Tyr(tBu)-OH or Fmoc-Val-OH, etc., which are supplied, for example, from Anaspec, Bachem, Iris Biotech or Novabiochem. The natural L-form of the amino acid is used when there is no other designation. The N-terminal amino acid is Boc protected at the alpha amine group (for example, Boc-His(Boc)-OH or Boc-His(Trt)-OH for the peptide, and His is located at the N-terminus). Where a modular albumin binding moiety of SPPS is used, the following suitably protected building blocks are used, such as, but not limited to, Fmoc-8-amino-3,6-dioxaoctanoic acid, Fmoc-amine Bicyclic acid, Fmoc-isopiperidinecarboxylic acid, Fmoc-Glu-OtBu, Fmoc-Lys(Fmoc)-OH, which is supplied, for example, from Anaspec, Bachem, Iris Biotech or Novabiochem. Eicosanedioic acid mono-tert-butyl ester, behenic acid mono-tert-butyl ester, and nonadecyldicarboxylic acid mono-t-butyl ester can be prepared as follows. All the following operations performed in 250 μ mol synthesis scale.

1. Synthetic resin combined with protected peptide backbone

Method: SPPS_P

Loading the resin using an excess of 6 times the amino acid Fmoc- (NMP in the 300mM, 300mM HOAt or accompanied Oxyma Pure®), such as low load Fmoc-Gly-Wang (0.35mmol / g) in 250 μ mol scale SPPS_P was performed on a Prelude Solid Phase Peptide Synthesizer from Protein Technologies (Tucson, AZ 85714 USA). Fmoc deprotection was performed using 20% piperidine in NMP. Coupling was carried out using 3:3:3:4 amino acid/(HOAt or Oxyma Pure®)/DIC/trimethylpyridine in NMP. NMP and DCM top washes (7 ml each, 0.5 min, 2 x 2) were performed between the deprotection and coupling steps. The coupling time is generally 60 minutes. Some amino acids, including but not limited to, Fmoc-Arg(Pbf)-OH, Fmoc-Aib-OH or Boc-His(Trt)-OH, are "double coupled", meaning to be in the first coupling (eg 60 min) Thereafter, the resin is drained and more reagents (amino acid, (HOAt or Oxyma Pure®), DIC and trimethylpyridine) are added, and the mixture is allowed to react again (for example, 60 min).

Method: SPPS_L

Loading the resin using an excess of 6 times the amino acid Fmoc- (NMP in the 300mM, 300mM HOAt or accompanied Oxyma Pure®), such as low load Fmoc-Gly-Wang (0.35mmol / g) in 250 μ mol or SPPS_L performed based on Liberty microwave peptide synthesizer from CEM Corporation (Matthews, NC 28106, USA) at 100 μ mol scale. Fmoc deprotection was carried out using 5% piperidine in NMP at 75 ° C for 30 seconds, after the resin was drained and washed with NMP, and Fmoc deprotection was repeated at 75 ° C (this time lasted 2 minutes). Coupling was carried out using 1:1:1 amino acid/(HOAt or Oxyma Pure®)/DIC in NMP. The coupling time and temperature are generally up to 5 minutes at 75 °C. Longer coupling times are used for larger scale reactions, such as 10 min. If the previous amino acid is sterically hindered (e.g., Aib), the histamine amino acid is double coupled or quadruple coupled at 50 °C. The arginine amino acid was coupled at room temperature for 25 minutes and then heated to 75 ° C for 5 min. Some amino acids, such as, but not limited to, Aib undergo "double coupling", meaning that after the first coupling (eg, 5 min at 75 ° C), the resin is drained and more reagents are added (amino acid, (HOAt) Or Oxyma Pure®) and DIC) and reheat the mixture (eg 5 min at 75 ° C). NMP washing (5 x 10 ml) was performed between the deprotection and coupling steps.

2. Synthetic albumin binding agent

It is known in the art to prepare eicosane mono-t-butyl ester, for example as described in WO 2010102886 A1.

The dodecanedioic acid mono-t-butyl ester can be prepared as described below: under argon at 0 ° C to eicosanedioic acid mono-t-butyl ester (25.0 g, 62.7 mmol) in anhydrous tetrahydrofuran (140 mL) A 1 M solution of borane-tetrahydrofuran complex in tetrahydrofuran (94.1 mL, 94.1 mmol) was added dropwise. The resulting solution was stirred at 0 °C for 2 hours, then the cooling bath was removed and the mixture was stirred overnight at room temperature. A saturated aqueous solution of sodium hydrogencarbonate (300 mL) and water (100 mL) were added and the mixture was extracted with dichloromethane (250 mL, 2×100 mL). The combined organic extracts were dried over anhydrous sodium sulfate and evaporated to dry. The residue was purified by column chromatography on silica gel (eluent: dichloromethane / methanol 99:1). Evaporation is pure The product was eluted and the residue was chromatographed again (eluent: dichloromethane / methanol 99:1). The product was combined and dried in vacuo to give the 20-hydroxy-eicosanoic acid tert-butyl ester as a white solid.

Yield: 16.50 g (68%).

¹ H NMR spectrum _{(300MHz, CDCl 3, δ H} ): 3.64 (t, J = 6.6Hz, 2 H), 2.20 (t, J = 7.5Hz, 2 H); 1.65-1.51 (m, 4 H); 1.45 (s, 9 H); 1.36-1.21 (m, 30 H).

The alcohol prepared above (16.5 g, 42.9 mmol) was dissolved in anhydrous dichloromethane (90 mL). Triethylamine (9.00 mL, 64.4 mmol) was added and the reaction mixture was cooled to EtOAc. After 1 hour, the reaction mixture was allowed to warm to rt and stirred overnight. Water (1.5 mL) was added and the mixture was stirred for 30 minutes. The solvent was evaporated, ethyl acetate (200 mL) was added and mixture was extracted with 1M hydrochloric acid (2×100 mL), 5% sodium carbonate solution (2×100 mL) and water (100 mL). After dehydration by anhydrous sodium sulfate, filtration and evaporation of the solvent, 20-methanesulfonyloxy-eicosanoic acid tert-butyl ester was obtained as a white solid.

Yield: 19.80 g (100%).

¹ H NMR spectrum (300 MHz, CDCl ₃ , δ _H ): 4.22 (t, J = 6.6 Hz, 2 H); 3.01 (s, 3 H); 2.20 (t, J = 7.5 Hz, 2 H); 1.68 (m, 2 H); 1.63-1.51 (m, 2 H); 1.44 (s, 9 H); 1.34-1.22 (m, 30 H).

The mesylate (17.8 g, 38.5 mmol) prepared above was dissolved in acetone (250 mL) and lithium bromide (6.69 g, 77.0 mmol) was added and the reaction mixture was refluxed overnight. After cooling the solvent was evaporated, ethyl acetate (300 mL) was added and the mixture was extracted with 5% sodium hydrogen carbonate solution (3×170 mL). The combined organic extracts were dried over anhydrous sodium sulfate and evaporated. The product was dried in vacuo to yield 20-bromo-eicosanoic acid tert-butyl ester as a white solid.

Yield: 17.10 g (99%).

¹ H NMR spectrum (300 MHz, CDCl ₃ , δ _H ): 3.41 (t, J = 6.9 Hz, 2 H); 2.20 (t, J = 7.4 Hz, 2 H); 1.90-1.77 (m, 2 H); 1.64-1.50 (m, 2 H); 1.43 (s, 9 H); 1.34-1.13 (m, 30 H).

Sodium hydride (60% dispersion in mineral oil, 3.96 g, 99.0 mmol) was dissolved in N,N -dimethylformamide (100 mL) under nitrogen . Dimethyl malonate (22.6 mL, 198 mmol) was added and the reaction mixture was briefly heated at 100 ° C, then cooled to room temperature and the third butyl bromo-eicosanoate (14.8 g, 33.0) prepared above was added. Methyl) a solution in N,N-dimethylformamide (150 mL). The reaction mixture was heated at 100 ° C for 4 hours. After cooling to room temperature, ethyl acetate (150 mL) was evaporated andEtOAc evaporated. The residue was purified by column chromatography eluting EtOAc EtOAc (EtOAc:EtOAc:EtOAc: Acid 22-tert-butyl ester 1-methyl ester.

Yield: 16.10 g (97%).

¹ H NMR spectrum (300 MHz, CDCl ₃ , δ _H ): 3.74 (s, 6 H); 3.36 (t, J = 7.5 Hz, 1 H); 2.20 (t, J = 7.5 Hz, 2 H); 1.84 (m, 2 H); 1.64-1.51 (m, 2 H); 1.44 (s, 9 H); 1.34-1.21 (m, 32 H).

The above-prepared 2-methoxycarbonyl-behenedioic acid 22-tert-butyl ester 1-methyl ester (16.1 g, 32.3 mmol) was dissolved in tetrahydrofuran (85 mL) and lithium hydroxide monohydrate (4.07) was added. g, 96.9 mmol) in water (75 mL). The reaction mixture was stirred at rt EtOAc then EtOAc (EtOAc) The organic extracts were combined, dried over anhydrous sodium sulfate and evaporated. The product was dried in vacuo to yield 2-carboxy-behenedioic acid 22-t-butyl ester as a white solid.

Yield: 14.50 g (95%).

¹ H NMR spectrum (300 MHz, CDCl ₃ , δ _H ): 3.44 (t, J = 7.4 Hz, 1 H); 2.22 (t, J = 7.5 Hz, 2 H); 2.00-1.89 (m, 2 H); 1.63-1.52 (m, 2 H); 1.45 (s, 9 H); 1.37-1.20 (m, 32 H).

2-Carboxylic acid-22-tert-butyl ester (14.5 g, 30.8 mmol) was dissolved in toluene (170 mL) and refluxed at 110 ° C for 48 hours. The solvent was evaporated, the residue was purifiedjjjjjjjjjjjjjj

Yield: 5.25 g (40%).

Total yield: 5.25g (25%)

1H NMR spectrum _{(300MHz, CDCl 3, δ H} ): 2.35 (t, J = 7.5Hz, 2 H); 2.21 (t, J = 7.5Hz, 2 H); 1.68-1.53 (m, 4 H); 1.45 (s, 9 H); 1.35-1.22 (m, 32 H).

The pentadecanedioic acid single tert-butyl ester can be prepared as follows: the nonadecanedioic acid (26.1 g, 79.5 mmol) in toluene (140 mL) and the third butanol (32 mL, 334.8 mmol, 4.4 equivalents) The suspension in the mixture was heated to reflux temperature (97 ° C). The mixture turned into a clear yellow solution. DMAP (1.9 g, 15.2 mmol, 0.2 eq.) was added, followed by dropwise addition of Boc ₂ O in toluene (75 mL) over 90 min. A large amount of CO _{2 was} observed to precipitate. The mixture was stirred at reflux temperature overnight and concentrated to a white powder. Cold toluene (200 mL) was added and the solid was removed via filtration, washed with toluene and dried in vacuo (45[deg.] C) (6.2 g, starting material). The filtrate was concentrated (45 ° C) and heptane (350 mL) was added to oily residue. The white suspension was stirred at 0 °C for 1 hour and the solid was separated by filtration. The buttery filter residue was dissolved in TBME and rinsed through a filter. The heptane filtrate and the TBME filtrate were separately concentrated. The heptane residue (10 g) mainly contained the diester (about 80%) and the TBME residue (13.3 g) mainly contained the monoester (about 80%). The TBME residue was purified by flash chromatography (ceria: 500 g, eluent: CH ₂ Cl ₂ /IPA 98:2 to 97:3). The title compound was obtained as a white solid (10.3 g, 33%).

1H NMR spectrum _{(300MHz, CDCl 3, δ H} ): 2.35 (t, J = 7.6Hz, 2 H); 2.20 (t, J = 7.6Hz, 2 H); 1.68-1.53 (m, 4 H); 1.43 (s, 9 H); 1.39-1.22 (m, 26 H).

3. The side chain is linked to the resin binding protected peptide backbone

When deuteration is present on the side chain of the amine acid, the epsilon amine group of the acid to be deuterated is protected by Mtt, Mmt, Dde, ivDde or Boc depending on the route connecting the extension moiety and the linker. Dde- or ivDde-deprotection was carried out with 2% hydrazine in NMP (2 x 20 mL each 10 min) followed by NMP wash (4 x 20 mL). 2% TFA and 2%-3% TIS in DCM (5 x 20 mL each 10 min) followed by 10% MeOH and 5% DIPEA in DCM (2 x 20 mL), DCM (2 x 20 mL) NMP (4 x 20 mL) wash solution, or Mtt- or Mmt-by treatment with hexafluoroisopropanol/DCM (75:25, 5 x 20 mL, 10 min each) followed by a wash solution as described above protection. In some cases, the Mtt group is removed by an automated step on the Liberty peptide synthesizer. It was washed with hexafluoroisopropanol or hexafluoroisopropanol/DCM (75:25) at room temperature for 30 min, followed by washing with DCM (7 ml x 5) followed by washing with NMP (7 ml x 5). Mtt goes to protect. The extension and/or linker can be linked to the peptide by deuteration of the resin-binding peptide or by deuteration in a solution of the unprotected peptide. In the case where the extension and/or linker are attached to a protected peptidyl resin, the connection can be modularized using SPPS and suitably protected building blocks.

Method: SC_P

Removal of the N-[epsilon]- lysine protecting group as described above and using an appropriately protected building block as described above is carried out by one or more automated steps on the Prelude peptide synthesizer. Chemical modification. Double coupling was performed with 3 hours/coupling as described in SPPS_P.

Method: SC_L

Removal of the N-[epsilon]- lysine protecting group as described above and using an appropriately protected building block as described above is carried out by one or more automated steps on the Liberty peptide synthesizer. Chemical modification. Double coupling is performed as described in SPPS_L.

4. Cleavage and purification of resin-bound peptides with or without linked side chains

Method: CP_M1

After the synthesis, the resin was washed with DCM and the peptide was cleaved from the resin by treatment with TFA/TIS/water (95/2.5/2.5 or 92.5/5/2.5) for 2-3 hours, followed by precipitation with diethyl ether. The peptide is dissolved in a suitable solvent (such as 30% acetic acid) and purified by standard RP-HPLC on a C18, 5 [mu]m column using acetonitrile/water/TFA. The extracts were analyzed by a combination of UPLC, MALDI and LCMS methods and the appropriate fractions were collected and lyophilized.

If necessary, the peptide relative ions can be exchanged for sodium using methods known in the art. As an example, about 2 g of the peptide is dissolved in 250 ml of acetonitrile/water (50/50) and loaded into the preparative form. Waters X-Bridge C8 on a RP-HPLC system, 5 [mu]M, 50 x 250 mm column. After loading, the column was washed with water at a flow rate of 60 ml/min for 8 min and washed with 0.01 N NaOH (pH 11) at a flow rate of 60 ml/min for 2 x 8 min. The sodium salt of the peptide was washed with an equal concentration of water at 60 ml/min for 10 min, followed by elution with a linear gradient of 5% to 85% acetonitrile over 30 min.

Method: CP_M2

After the synthesis, the resin was washed with DCM and the peptide was cleaved from the resin by treatment with TFA/TIS/water (95/2.5/2.5 or 92.5/5/2.5) for 2-3 hours, followed by precipitation with diethyl ether. The peptide is dissolved in a suitable solvent (such as 30% acetic acid) and purified by standard RP-HPLC on a Kinetex C18, 5 μm column by 0.09 M in water/acetonitrile (90:10, pH 3.0). A binary mixture of diammonium phosphate and acetonitrile/2-propanol/water (60:20:20) was eluted. The peptide was then further purified by standard RP-HPLC on a C18, 5 [mu]m column using acetonitrile/water/TFA. The extracts were analyzed by a combination of UPLC, MALDI and LCMS methods and the appropriate fractions were collected and lyophilized.

If necessary, the peptide relative ions can be exchanged for sodium using methods known in the art. As an example, about 2 g of the peptide was dissolved in 250 ml of acetonitrile/water (50/50) and loaded onto a Waters X-Bridge C8, 5 μM, 50 x 250 mm column on a preparative RP-HPLC system. After loading, the column was washed with water at a flow rate of 60 ml/min for 8 min and washed with 0.01 N NaOH (pH 11) at a flow rate of 60 ml/min for 2 x 8 min. The sodium salt of the peptide was washed with an equal concentration of water at 60 ml/min for 10 min, followed by elution with a linear gradient of 5% to 85% acetonitrile over 30 min.

A2. General methods for detection and characterization

1. LC-MS method

Method: LCMS01

LCMS01v1 was performed on a device consisting of a Waters Acquity UPLC system from Micromass and an LCT Premier XE mass spectrometer. Eluent: A: 0.1% formic acid in water; B: 0.1% formic acid in acetonitrile. The analysis is carried out at room temperature by injecting a suitable volume of sample (preferably 2-10 μl) onto the column eluted with a gradient of A and B. UPLC condition, detector settings and mass spectrometer Set to: Column: Waters Acquity UPLC BEH, C-18, 1.7 μm, 2.1 mm x 50 mm. Gradient: Linear 5%-95% acetonitrile at 0.4 ml/min during 4.0 min (or 8.0 min). Detection: 214 nm (analog output from TUV (tunable UV detector)) MS ionization mode: API-ES. Scan: 100-2000 amu (or 500-2000 amu) with a step size of 0.1 amu.

2.UPLC method

Method: UPLC02

RP analysis was performed using a Waters UPLC system equipped with a dual band detector. UV detection at 214 nm and 254 nm was collected at 40 ° C using an ACQUITY UPLC BEH130, C18, 130 Å, 1.7 um, 2.1 mm x 150 mm column. The UPLC system was connected to two eluent reservoirs containing A: 99.95% H ₂ O, 0.05% TFA; B: 99.95% CH ₃ CN, 0.05% TFA. The following linear gradient was used: 95% A, 5% B to 95% A, 5% B over 16 minutes at a flow rate of 0.40 ml/min.

3.MALDI-MS method

Method: MALDI01v01

Molecular weight was determined using matrix-assisted laser desorption and ionization time-of-flight mass spectrometry and recorded on Microflex or Autoflex (Bruker). A matrix of α-cyano-4-hydroxycinnamic acid was used.

B. Preparation of Example Compounds

Example 1

N{ε-27}-[2-[2-[2-[[(4S)-4-carboxy-4-[[4-[(19-carboxy]] Amino)methyl]cyclohexylmethylhydrazinyl]amino]butanyl]amino]ethoxy]ethoxy]ethinyl]amino]ethoxy]ethoxy]ethinyl]-[ Aib8, Glu22, Arg26, Lys27, Arg34]-GLP-1-(7-37)-peptidyl-Gly-Gly-Gly-Ser-N{ε}[2-[2-[2-[[2-[ 2-[2-[[(4S)-4-carboxy-4-[[4-[(19-carboxynonylamino)methyl]cyclohexylmethyl)]amino]butanyl]amino] Ethoxy]ethoxy]ethinyl]amino]ethoxy]ethoxy]ethinyl]Lys

Chemical formula 21:

The peptide is SEQ ID NO: 2.

Synthesis method: SPPS_P; SC_P; CP_M1

UPLC02: Rt = 10.6min

MALDI01v01: calculated value m/z = 5649; experimental value m/z = 5648

Example 2

N[ε-31}-[2-[2-[2-[[(4S)-4-carboxy4-[[4-[(19-carboxy]- 19-yl) Amino)methyl]cyclohexylmethylindenyl]amino]butanyl]amino]ethoxy]ethoxy]ethinyl]amino]ethoxy]ethoxy]ethinyl]-[Aib8 , Glu22, Arg26, Lys31, Arg34]-GLP-1-(7-37)-peptidyl-Gly-Gly-Gly-Ser-N{ε}[2-[2-[2-[[2-[2 -[2-[[(4S)-4-carboxy-4-[[4-[(19-carboxynonylamino))methyl]cyclohexylmethyl)]amino]butanyl]amino] Ethoxy]ethoxy]ethinyl]amino]ethoxy]ethoxy]ethinyl]Lys

Chemical formula 22:

The peptide is SEQ ID NO: 3.

Synthesis method: SPPS_P; SC_P; CP_M1

UPLC02: Rt = 10.6min

MALDI01v01: calculated value m/z = 5593; experimental value m/z = 5590

Example 3

N{α}([Aib8, Glu22, Arg26, Arg34]-GLP-1-(7-37)-peptidyl)-N{ε}[2-[2-[2-[[2-[2-[ 2-[[(4S)-4-carboxy-4-[[4-[(19-carboxynonylamino)methyl]cyclohexylmethyl)]amino]butanyl]amino]ethoxy Ethoxy]ethinyl]amino]ethoxy]ethoxy]ethinyl]Lys-Gly-Gly-Ser-N{ε}[2-[2-[2-[[2-[ 2-[2-[[(4S)-4-carboxy-4-[[4-[(19-carboxynonylamino))methyl]cyclohexylmethyl)]amino]butanyl]amino Ethoxy]ethoxy]ethoxy]amino]ethoxy]ethoxy]ethinyl]Lys

Chemical formula 23:

The peptide is SEQ ID NO: 4.

Synthesis method: SPPS_P; SC_P; CP_M1

UPLC02: Rt = 10.8min

MALDI01v01: calculated value m / z = 5722; experimental value m / z = 5720

Example 4

N{ε-23}-[2-[2-[2-[[(4S)-4-carboxy-4-[[4-[(19-carboxy]] Amino)methyl]cyclohexylmethylhydrazinyl]amino]butanyl]amino]ethoxy]ethoxy]ethinyl]amino]ethoxy]ethoxy]ethinyl]-[ Aib8, Glu22, Lys23, Arg26, Arg34]-GLP-1-(7-37)-peptidyl-Gly-Gly-Gly-Ser-N{ε}[2-[2-[2-[[2-[ 2-[2-[[(4S)-4-carboxy-4-[[4-[(19-carboxynonylamino)methyl]cyclohexylmethyl)]amino]butanyl]amino] Ethoxy]ethoxy]ethinyl]amino]ethoxy]ethoxy]ethinyl]Lys

Chemical Formula 24:

The peptide is SEQ ID NO: 5.

Synthesis method: SPPS_P; SC_P; CP_M1

UPLC02: Rt = 10.6min

MALDI01v01: calculated value m/z = 5651; experimental value m/z = 5649

Example 5

N{ε-36}-[2-[2-[2-[[(4S)-4-carboxy-4-[[4-[(19-carboxy]] Amino)methyl]cyclohexylmethylhydrazinyl]amino]butanyl]amino]ethoxy]ethoxy]ethinyl]amino]ethoxy]ethoxy]ethinyl]-[ Aib8, Glu22, Arg26, Arg34, Lys36]-GLP-1-(7-37)-peptidyl-Gly-Gly-Gly-Ser-N{ε}[2-[2-[2-[[2-[ 2-[2-[[(4S)-4-carboxy-4-[[4-[(19-carboxynonylamino)methyl]cyclohexylmethyl)]amino]butanyl]amino] Ethoxy]ethoxy]ethinyl]amino]ethoxy]ethoxy]ethinyl]Lys

Chemical formula 25:

The peptide is SEQ ID NO: 6.

Synthesis method: SPPS_P; SC_P; CP_M1

UPLC02: Rt=11.3min

MALDI01v01: calculated value m/z = 5623; experimental value m/z = 5621

Example 6

N{ε-18}-[2-[2-[2-[[(4S)-4-carboxy-4-[[4-[(19-carboxy]] Amino)methyl]cyclohexylmethylhydrazinyl]amino]butanyl]amino]ethoxy]ethoxy]ethinyl]amino]ethoxy]ethoxy]ethinyl]-[ Aib8, Lys18, Glu22, Arg26, Arg34]-GLP-1-(7-37)-peptidyl-Gly-Gly-Gly-Ser-N{ε}[2-[2-[2-[[2-[ 2-[2-[[(4S)-4-carboxy-4-[[4-[(19-carboxynonylamino)methyl]cyclohexylmethyl)]amino]butanyl]amino] Ethoxy]ethoxy]ethinyl]amino]ethoxy]ethoxy]ethinyl]Lys

Chemical formula 26:

The peptide is SEQ ID NO: 7.

Synthesis method: SPPS_P; SC_P; CP_M1

UPLC02: Rt = 10.8min

LCMS01: Rt = 2.6 min, m / 3 = 1898; m / 4 = 1424; m / 3 = 1139

Example 7

N{α}([Aib8, Glu22, Arg26, Arg34]-GLP-1-(7-37)-peptidyl)-N{ε}[(2S)-2-amino-6-[[(2S) 2-amino-6-[[(4S)-4-carboxy-4-[[4-[(19-carboxynonylamino)methyl]cyclohexylmethyl)]amino]butanyl] Amino]hexyldecyl]amino]hexyl]Lys-Gly-Gly-Ser-N{ε}[(2S)-2-amino-6-[[(2S)-2-amino-6 -[[(4S)-4-carboxy-4-[[4-[(19-carboxynonylamino)methyl]cyclohexylmethyl)]amino]butanyl]amino]hexyl] Amino] hexyl] Lys

The peptide is SEQ ID NO: 4.

Synthesis method: SPPS_P; SC_P; CP_M1

UPLC02: Rt = 9.8min

LCMS01: Rt = 2.3 min, m / 3 = 1885; m / 4 = 1 415;

Example 8

N{ε-27}-[(2S)-2-Amino-6-[[(2S)-2-amino-6-[[(4S)-4-carboxy-4-(19-carboxy-19) Hydrylamino)butanyl]amino]hexyl]amino]hexyl]-[Aib8, Glu22, Arg26, Lys27, Arg34]-GLP-1-(7-37)-peptidyl-Gly-Gly -Gly-Ser-N{ε}[(2S)-2-amino-6-[[(2S)-2-amino-6-[[(4S)-4-carboxy-4-(19-carboxyl) 19-nonylamino)butanyl]amino]hexyl]amino]hexyl]Lys

The peptide is SEQ ID NO: 2.

Synthesis method: SPPS_P; SC_P; CP_M1

UPLC02: Rt = 8.9min

MALDI01: calculated value m/z = 5303; experimental value m/z = 5302

Example 9

N{α}([Aib8, Glu22, Arg26, Arg34]-GLP-1-(7-37)-peptide Base)-N{ε}[2-[2-[2-[[(4S)-4-carboxy-4-[[4-[(21-carboxy- 21) Mercaptoamino)methyl]cyclohexylmethylhydrazinyl]amino]butanyl]amino]ethoxy]ethoxy]ethinyl]amino]ethoxy]ethoxy]ethinyl]Lys -Gly-Gly-Ser-N{ε}[2-[2-[2-[[2-[2-[2-[2-[[(4S)-4-carboxy-4-[[4-[(21- Carboxyyl decylamino)methyl]cyclohexylmethyl hydrazide]amino]butanyl]amino]ethoxy]ethoxy]ethinyl]amino]ethoxy]ethoxy]醯基]Lys

The peptide is SEQ ID NO: 4.

Synthesis method: SPPS_P; SC_P; CP_M1

UPLC02: Rt = 12.3min

LCMS01: Rt=2.7; m/3=1927; m/4=1444; m/5=1156

Example 10

N{α}([Aib8, Glu22, Arg26, Arg34]-GLP-1-(7-37)-peptidyl)-N{ε}3-[2-[2-[2-[2-[[( 4S)-4-carboxy-4-[[4-[(19-carboxyundecylamino)methyl]cyclohexylmethylindolyl]amino]butanyl]amino]ethoxy]ethoxy] Ethoxy]ethoxy]propanyl Lys-Gly-Gly-Ser-N{ε}3-[2-[2-[2-[2-[[(4S)-4-carboxy-4-[ [4-[(19-Carbonylnonylamino)methyl]cyclohexylmethyl)]amino]butanyl]amino]ethoxy]ethoxy]ethoxy]ethoxy]propyl 醯基 Lys

The peptide is SEQ ID NO: 4.

Synthesis method: SPPS_P; SC_P; CP_M2

UPLC02: Rt=11.2min

LCMS01: Rt = 2.7; m / 3 = 1880; m / 4 = 1 410;

Example 11

N{α}([Aib8, Glu22, Arg26, Arg34]-GLP-1-(7-37)-peptidyl)-N{ε}[2-[2-[2-[[2-[2-[ 2-[[(4S)-4-carboxy-4-[[4-[(19-carboxynonylamino)methyl]cyclohexylmethyl)]amino]butanyl]amino]ethoxy Ethoxy]ethinyl]amino]ethoxy]ethoxy]ethinyl]Lys-Ser-Pro-Glu-N{ε}[2-[2-[2-[[2-[ 2-[2-[[(4S)-4-carboxy-4-[[4-[(19-carboxynonylamino)methyl]cyclohexylmethyl)]amino]butanyl]amino] Ethoxy]ethoxy]ethinyl]amino]ethoxy]ethoxy]ethinyl]Lys

Chemical formula 31:

The peptide is SEQ ID NO: 14.

Synthesis method: SPPS_P; SC_P; CP_M1

UPLC02: Rt = 11.7min

LCMS01: Rt = 2.7 min; m / 3 = 1945; m / 4 = 1460;

Example 12

N{α}([Aib8, Glu22, Arg26, Arg34]-GLP-1-(7-37)-peptidyl)-N{ε}[2-[2-[2-[[2-[2-[ 2-[[(4S)-4-carboxy-4-[[4-[(19-carboxynonylamino)methyl]cyclohexylmethyl)]amino]butanyl]amino]ethoxy Ethoxy]ethinyl]amino]ethoxy]ethoxy]ethinyl]Lys-Pro-Glu-Gly-N{ε}[2-[2-[2-[[2-[ 2-[2-[[(4S)-4-carboxy-4-[[4-[(19-carboxynonylamino)methyl]cyclohexylmethyl)]amino]butanyl]amino] Ethoxy]ethoxy]ethinyl]amino]ethoxy]ethoxy]ethinyl]Lys

Chemical formula 32:

The peptide is SEQ ID NO: 12.

Synthesis method: SPPS_P; SC_P; CP_M1

UPLC02: Rt=11.8min

LCMS01: Rt = 2.7 min; m / 3 = 1935 m / 4 = 1452;

Example 13

N{α}([Aib8, Glu22, Arg26, Arg34]-GLP-1-(7-37)-peptidyl)-N{ε}[2-[2-[2-[[2-[2-[ 2-[[(4S)-4-carboxy-4-[[4-[(19-carboxynonylamino)methyl]cyclohexylmethyl)]amino]butanyl]amino]ethoxy Ethoxy]ethinyl]amino]ethoxy]ethoxy]ethinyl]Lys-Ser-Ala-Glu-N{ε}[2-[2-[2-[[2-[ 2-[2-[[(4S)-4-carboxy-4-[[4-[(19-carboxynonylamino)methyl]cyclohexylmethyl)]amino]butanyl]amino] Ethoxy]ethoxy]ethinyl]amino]ethoxy]ethoxy]ethinyl]Lys

Chemical Formula 33:

The peptide is SEQ ID NO: 13.

Synthesis method: SPPS_P; SC_P; CP_M1

UPLC02: Rt = 11.7min

LCMS01: Rt = 2.7 min; m / 3 = 1937; m / 4 = 1453;

Example 14

N{ε-36}-[2-[2-[2-[[(4S)-4-carboxy-4-[[4-[(19-carboxy]] Amino)methyl]cyclohexylmethylhydrazinyl]amino]butanyl]amino]ethoxy]ethoxy]ethinyl]amino]ethoxy]ethoxy]ethinyl]-[ Aib8, Glu22, Arg26, Arg34, Lys36]-GLP-1-(7-37)-peptidyl-Ala-Glu-Ser-Pro-N{ε}[2-[2-[2-[[2-[ 2-[2-[[(4S)-4-carboxy-4-[[4-[(19-carboxynonylamino)methyl]cyclohexylmethyl)]amino]butanyl]amino] Ethoxy]ethoxy]ethinyl]amino]ethoxy]ethoxy]ethinyl]Lys

The peptide is SEQ ID NO: 9.

Synthesis method: SPPS_P; SC_P; CP_M1

UPLC02: Rt = 12min

LCMS01: Rt = 2.8 min; m / 3 = 1917; m / 4 = 1438;

Example 15

N{ε-36}-[2-[2-[2-[[(4S)-4-carboxy-4-[[4-[(19-carboxy]] Amino)methyl]cyclohexylmethylhydrazinyl]amino]butanyl]amino]ethoxy]ethoxy]ethinyl]amino]ethoxy]ethoxy]ethinyl]-[ Aib8, Glu22, Arg26, Arg34, Lys36]-GLP-1-(7-37)-peptidyl-Pro-Ala-Ser-Glu-N{ε}[2-[2-[2-[[2-[ 2-[2-[[(4S)-4-carboxy-4-[[4-[(19-carboxynonylamino)methyl]cyclohexylmethyl)]amino]butanyl]amino] Ethoxy]ethoxy]ethinyl]amino]ethoxy]ethoxy]ethinyl]Lys

The peptide is SEQ ID NO:11.

Synthesis method: SPPS_P; SC_P; CP_M1

UPLC02: Rt = 12min

LCMS01: Rt = 2.8 min; m / 3 = 1917; m / 4 = 1438;

Example 16

N{ε-36}-[2-[2-[2-[[(4S)-4-carboxy-4-[[4-[(19-carboxy]] Amino group Cyclohexylmethylmercapto]amino]butanyl]amino]ethoxy]ethoxy]ethinyl]amino]ethoxy]ethoxy]ethinyl]-[Aib8, Glu22, Arg26 ,Arg34,Lys36]-GLP-1-(7-37)-Peptidyl-Glu-Gly-Pro-Ala-N{ε}[2-[2-[2-[[2-[2-[2-[2- [[(4S)-4-carboxy-4-[[4-[(19-carboxynonylamino)methyl]cyclohexylmethyl)]amino]butanyl]amino]ethoxy]B Oxy]ethinyl]amino]ethoxy]ethoxy]ethinyl]Lys

The peptide is SEQ ID NO: 10.

Synthesis method: SPPS_P; SC_P; CP_M1

UPLC02: Rt = 12min

LCMS01: Rt = 2.8 min; m / 3 = 1907; m / 4 = 1431;

Example 17

N{α}([Aib8, Glu22, Arg26, Arg34]-GLP-1-(7-37)-peptidyl)-N{ε}[2-[2-[2-[[2-[2-[ 2-[[2-[2-[2-[[2-[2-[2-[[(4S)-4-carboxy-4-[[4-[(19-carboxy-n-decylamino)) Methyl]cyclohexylmethyl indenyl]amino]butanyl]amino]ethoxy]ethoxy]ethinyl]amino]ethoxy]ethoxy]ethinyl]amino]ethoxy Ethoxy]ethinyl]amino]ethoxy]ethoxy]ethinyl]Lys-Gly-Gly-Ser-N{ε}[2-[2-[2-[[2-[ 2-[2-[[2-[2-[2-[[(4S)-4-carboxy-4-[[4-[(19-carboxy- 19-yl) Amino)methyl]cyclohexylmethylindenyl]amino]butanyl]amino]ethoxy Ethyl]ethoxy]amino]ethoxy]ethoxy]ethoxy]amino]ethoxy]ethoxy]ethinyl]amino]ethoxy]ethoxy ]Ethyl]Lys

The peptide is SEQ ID NO: 4.

Synthesis method: SPPS_P; SC_P; CP_M1

UPLC02: Rt=11.3min

LCMS01: Rt = 2.7 min; m / 4 = 1577; m/5 = 1262

Example 18

N{α}([Imp7, Aib8, Glu22, Arg26, Arg34]-GLP-1-(7-37)-peptidyl)-N{ε}[2-[2-[2-[[2-[2 -[2-[[2-[2-[2-[[(4S)-4-carboxy-4-[[4-[(19-carboxy-n-decylamine) Methyl]cyclohexylmethyl fluorenyl]amino]butanyl]amino]ethoxy]ethoxy]ethinyl]amino]ethoxy]ethoxy]ethinyl]amino] Oxy]ethoxy]ethinyl]amino]ethoxy]ethoxy]ethinyl]Lys-Gly-Gly-Ser-N{ε}[2-[2-[2-[[2 -[2-[2-[[2-[2-[2-[[(4S)-4-carboxy-4-[[4-[(19-carboxy-19) Mercaptoamino)methyl]cyclohexylmethylhydrazinyl]amino]butanyl]amino]ethoxy]ethoxy]ethinyl]amino]ethoxy]ethoxy]ethinyl]amine Ethyl]ethoxy]ethoxy 1 ethoxy]amino]ethoxy]ethoxy]ethinyl]Lys

Chemical formula 38:

The peptide is SEQ ID NO: 8.

Synthesis method: SPPS_P; SC_P; CP_M1

UPLC02: Rt = 11.5min

LCMS01: Rt = 2.7 min; m / 4 = 1572; m / 5 = 1258

Example 19

N{α}([Aib8, Glu22, Arg26, Arg34]-GLP-1-(7-37)-peptidyl)-N{ε}[2-[2-[2-[[2-[2-[ 2-[[2-[2-[2-[[(4S)-4-carboxy-4-(19-carboxyl-nonylamino)butanyl]amino] Ethoxy]ethoxy]ethinyl]amino]ethoxy]ethoxy]ethinyl]amino]ethoxy]ethoxy]ethinyl]amino]ethoxy]B Oxy]ethinyl]Lys-Gly-Gly-Ser- N{ε}[2-[2-[2-[[2-[2-[2-[[2-[2-[2-[2-[[ -carboxy-4-(19-carboxynonylnonylamino)butanyl]amino]ethoxy]ethoxy]ethinyl]amino]ethoxy]ethoxy]ethinyl]amino Ethoxy]ethoxy]ethoxy]amino]ethoxy]ethoxy]ethinyl]Lys

The peptide is SEQ ID NO: 4.

Synthesis method: SPPS_P; SC_P; CP_M1

UPLC02: Rt = 10.7min

LCMS01: Rt = 2.6 min; m / 4 = 1507; m / 5 = 1206

Example 20

N{α}([Imp7, Aib8, Glu22, Arg26, Arg34]-GLP-1-(7-37)-peptidyl)-N{ε}[2-[2-[2-[[2-[2 -[2-[[2-[2-[2-[[2-[2-[2-[2-[[(4S)-4-carboxy-4-(19-carboxy- 19-yl) Amino)butanyl]amino]ethoxy]ethoxy]ethinyl]amino]ethoxy]ethoxy]ethinyl]amino]ethoxy]ethoxy]ethenyl] Amino]ethoxy]ethoxy]ethinyl]Lys-Gly-Gly-Ser-N{ε}[2-[2-[2-[[2-[2-[2-[[2- [2-[2-[[2-[2-[2-[[(4S)-4-carboxy-4-(19-carboxynonylamino)butanyl]amino]ethoxy]ethoxy Ethyl]amino]ethoxy]ethoxy]ethoxy]amino]ethoxy]ethoxy]ethinyl]amino]ethoxy]ethoxy]ethenyl ]Lys

The peptide is SEQ ID NO: 8.

Synthesis method: SPPS_P; SC_P; CP_M1

UPLC02: Rt = 10.9min

LCMS01: Rt=2.6 min; m/4=1503; m/5=1203

Example 21

N{α}([Aib8, Glu22, Arg26, Arg34]-GLP-1-(7-37)-peptidyl)-N{ε}[4-[3-[2-[2-[3-[[ (4S)-4-carboxy-4-[[1-(19-carboxynonyl)piperidin-4-carbonyl]amino]butanyl]amino]propoxy]ethoxy]ethoxy] Alanamine]-4-oxobutanyl]Lys-Gly-Gly-Ser-N{ε}[4-[3-[2-[2-[3-[[(4S)-4-carboxy-4-[ [1-(19-carboxynonylidene)piperidin-4-carbonyl]amino]butanyl]amino]propoxy]ethoxy]ethoxy]propylamino]-4-oxobutanyl]Lys

The peptide is SEQ ID NO: 4.

Synthesis method: SPPS_P; SC_P; CP_M1

UPLC02: Rt=11.1min

LCMS01: Rt = 2.7 min; m / 3 = 1897; m / 4 = 1423;

Example 22

N{α}([Aib8, Glu22, Arg26, Arg34]-GLP-1-(7-37)-peptidyl)-N{ε}[2-[2-[3-[2-[2-[3 -[[(4S)-4-carboxy-4-(19-carboxyundecylamino)butanyl]amino]propoxy]ethoxy]ethoxy]propylamino]-2-yloxy Ethoxy]ethinyl]Lys-Gly-Gly-Ser-N{ε}[2-[2-[3-[2-[2-[3-[[(4S)-4-carboxy-4-] (19-carboxynonylnonylamino)butanyl]amino]propoxy]ethoxy]ethoxy]propylamino]-2-oxoethoxyethoxy]ethinyl]Lys

The peptide is SEQ ID NO: 4.

Synthesis method: SPPS_P; SC_P; CP_M1

UPLC02: Rt = 10.7min

LCMS01: Rt = 2.6 min; m / 3 = 1834; m / 4 = 1376;

Example 23

N{α}([Aib8, Glu22, Arg26, Arg34]-GLP-1-(7-37)-peptidyl)-N{ε}[4-[2-[2-[2-[[(4S)) 4-carboxy-4-[[4-[(19-carboxynonylamino)methyl]cyclohexylmethyl)]amino]butanyl]amino]ethoxy]ethoxy]ethylamine ]]-4-oxobutanyl]Lys-Gly-Gly-Ser-N{ε}[4-[2-[2-[2-[[(4S)-4-carboxy-4-[[4-[ (19-carboxynonylnonylamino)methyl]cyclohexylcarbenyl]amino]butanyl]amino]ethoxy]ethoxy]ethylamino]-4-oxobutyl 醯基]Lys

The peptide is SEQ ID NO: 4.

Synthesis method: SPPS_P; SC_P; CP_M1

UPLC02: Rt=11.1min

LCMS01: Rt = 2.7 min; m / 4 = 1401.3;

Example 24

N{α}([Aib8, Glu22, Arg26, Arg34]-GLP-1-(7-37)-peptidyl)-N{ε}[2-[2-[2-[[2-[2-[ 2-[[2-[2-[2-[[2-[2-[2-[[2-[2-[2-[[ Carboxy-4-[[4-[(19-carboxyundecylamino)methyl]cyclohexylmethyl)]amino]butanyl]amino]ethoxy]ethoxy]ethinyl]amine Ethoxy]ethoxy]ethoxy]ethyl]amino]ethoxy]ethoxy]ethinyl]amino]ethoxy]ethoxy]ethinyl]amino]ethoxy Ethoxy]ethinyl]amino]ethoxy]ethoxy]ethinyl]Lys-Gly-Gly-Ser-N{ε}[2-[2-[2-[[2-[ 2-[2-[[2-[2-[2-[[2-[2-[2-[2-[[2-[2-[2-[[ -4-carboxy-4-[[4-[(19-carboxyundecylamino)methyl]cyclohexylmethyl)]amino]butanyl]amino]ethoxy]ethoxy]acetamidine Amino]ethoxy]ethoxy]ethoxy]amino]ethoxy]ethoxy]ethinyl]amino]ethoxy]ethoxy]ethinyl]amino] Ethoxy]ethoxy]ethinyl]amino]ethoxy]ethoxy]ethinyl]Lys

Chemical formula 44:

The peptide is SEQ ID NO: 4.

Synthesis method: SPPS_P; SC_P; CP_M1

UPLC02: Rt = 10.7min

LCMS01: Rt = 2.6 min; m / 4 = 1721; m/5 = 1377

Example 25

N{α}([Aib8, Glu22, Arg26, Arg34]-GLP-1-(7-37)-peptidyl)-N{ε}[2-[2-[2-[[2-[2-[ 2-[[2-[2-[2-[[2-(2-[2-[2-[[(2S)-2-amino]-6-[[(2S)-2-amino-6-(19 -carboxyl 19 decylamino)hexanyl]amino]hexyl]amino]ethoxy]ethoxy]ethinyl]amino]ethoxy]ethoxy]ethenyl] Amino]ethoxy]ethoxy]ethinyl]amino]ethoxy]ethoxy]ethinyl]Lys-Gly-Gly-Ser-N{ε}[2-[2-[2 -[[2-[2-[2-[[2-[2-[2-[[(2S)-2-amino-6-[[(2S)) 2-Amino-6-(19-carboxyundecylamino)hexyl]amino]hexyl]amino]ethoxy]ethoxy]ethinyl]amino]ethoxy Ethoxy]ethinyl]amino]ethoxy]ethoxy]acetamidine Amino]ethoxy]ethoxy]ethinyl]Lys

The peptide is SEQ ID NO: 4.

Synthesis method: SPPS_L; SC_L; CP_M1

UPLC02: Rt = 9.0min

LCMS01: Rt = 2.2 min, m / 4 = 1570; m / 5 = 1257

Example 26

N{α}([Aib8, Glu22, Arg26, Arg34]-GLP-1-(7-37)-peptidyl)-N{ε}[2-[2-[2-[[2-[2-[ 2-[[(4S)-4-carboxy-4-[[4-[(18-carboxyoctadecylamino)methyl]cyclohexylmethyl)]amino]butanyl]amino]ethoxy Ethoxy]ethinyl]amino]ethoxy]ethoxy]ethinyl]Lys-Gly-Gly-Ser-N{ε}[2-[2-[2-[[2-[ 2-[2-[[(4S)-4-carboxy-4-[[4-[(18-carboxyoctadecylamino)methyl]cyclohexylmethyl)]amino]butanyl]amino] Ethoxy]ethoxy]ethinyl]amino]ethoxy]ethoxy]ethinyl]Lys

Chemical formula 46:

The peptide is SEQ ID NO: 4.

Synthesis method: SPPS_P; SC_P; CP_M1

UPLC02: Rt=10.5min

LCMS01: Rt = 2.7 min; m / 4 = 1425; m / 5 = 1140

Example 27

N{α}([Aib8, Glu22, Arg26, Arg34]-GLP-1-(7-37)-peptidyl)-N{ε}[2-[2-[2-[[2-[2-[ 2-[[2-[2-[2-[[2-[2-[2-[[2-(2-[2-[2-(2-)] 2-amino-6-(19-carboxyundecylamino)hexyl]amino]hexyl]amino]ethoxy]ethoxy]ethinyl]amino]ethoxy Ethyl]ethoxy]amino]ethoxy]ethoxy]ethoxy]amino]ethoxy]ethoxy]ethinyl]amino]ethoxy]ethoxy ]Ethyl]Lys-Gly-Gly-Ser-N{ε}[2-[2-[2-[[2-[2-[2-[[2-[2-[2-[2-[[2- [2-[2-[[2-[2-[2-[[(2S))-2-amino-6-[[(2S)-2-amino-6-(19-carboxy- 19-yl) Amino)hexyl]amino]hexyl]amino]ethoxy]ethoxy]ethinyl]amino]ethoxy]ethoxy]ethinyl]amino]ethoxy Ethoxy]ethinyl]amino]ethoxy]ethoxy]ethinyl]amino]ethoxy]ethoxy]ethinyl]Lys

Chemical formula 47:

The peptide is SEQ ID NO: 4.

Synthesis method: SPPS_P; SC_L; CP_M2

UPLC02: Rt = 8.8min

LCMS01: Rt = 2.2 min; m / 4 = 1643; m/5 = 1315

Example 28

N{α}([Aib8, Glu22, Arg26, Arg34]-GLP-1-(7-37)-peptidyl)-N{ε}[2-[2-[2-[[2-[2-[ 2-[[2-[2-[2-[[2-[2-[2-[[2-[2-[2-[[2] Amino-6-[[(2S)-2-amino-6-(19-carboxynonylnonylamino)hexyl]amino]hexyl]amino]ethoxy]ethoxy Ethyl]amino]ethoxy]ethoxy]ethinyl]amino]ethoxy]ethoxy]ethinyl]amino]ethoxy]ethoxy]ethenyl] Amino]ethoxy]ethoxy]ethinyl]amino]ethoxy]ethoxy]ethinyl]Lys-Gly-Gly-Ser-N{ε}[2-[2-[2 -[[2-[2-[2-[[2-[2-[2-[[2-[2-[2-[[2-[2-[2-[2-[[2-[2-[2-[2-[[ -[[(2S)-2-amino-6-[[(2S)-2-amino-6-(19-carboxynonylamino)hexyl]] yl] hexyl] amide Ethoxy]ethoxy]ethoxy]ethyl]amino]ethoxy]ethoxy]ethinyl]amino]ethoxy]ethoxy]ethinyl]amino]ethoxy Ethoxy]ethinyl]amino]ethoxy]ethoxy]ethinyl]amino]ethoxy]ethoxy]ethinyl]Lys

Chemical formula 48:

The peptide is SEQ ID NO: 4.

Synthesis method: SPPS_P; SC_L; CP_M2

UPLC02: Rt = 8.6min

LCMS01: Rt = 2.2 min; m / 4 = 1716;

Pharmacological method

Example 29: In vitro efficiency

The purpose of this example was to test the in vitro activity or potency of GLP-1 derivatives. In vitro efficiency is a measure of human GLP-1 receptor activation in whole cell analysis.

The potency of the GLP-1 derivatives of Examples 1-28 was determined as described below. Smerupeptide was included for comparison.

principle

In vitro efficacy was determined by measuring the response of the human GLP-1 receptor in a genetic assay. Analysis was performed in a stably transfected BHK cell line expressing the human GLP-1 receptor and containing the DNA of the cAMP response element (CRE) coupled to the promoter and the firefly luciferase (CRE luciferase) gene. When the human GLP-1 receptor is activated, it causes the production of cAMP, which in turn causes the luciferase protein to be expressed. When the analytical incubation is completed, a luciferase receptor (luciferin) is added and the enzyme converts the luciferin to oxyluciferin to produce bioluminescence. The luminescence is measured according to the number of readings in the analysis.

Cell culture and preparation

The cells used in this assay (pure line FCW467-12A/KZ10-1) were BHK cells with BHKTS13 as the parental cell line. These cells are derived from a pure line (FCW 467-12A) that expresses the human GLP-1 receptor and are established by further transfection with CRE luciferase to obtain the current pure line.

The cells were cultured in a cell culture medium under 5% CO ₂ . It was aliquoted and stored in liquid nitrogen. Prior to each analysis, an aliquot was taken and washed twice in PBS and subsequently suspended in the assay specific buffer at the desired concentration. For 96 well plates, the suspension was prepared to give a final concentration of 5 x 10 ³ cells/well.

material

The following chemicals were used in the analysis: Pluronic F-68 (10%) (Gibco 2404), human serum albumin (HSA) (Sigma A9511), ovalbumin (Sigma A5503), DMEM (without phenol red) (Gibco 11880) -028), 1M Hepes (Gibco 15630), Glutamax 100× (Gibco 35050) and steadylite plus (PerkinElmer 6016757).

Buffer

Cell culture medium consisting of 10% FBS (fetal calf serum; Invitrogen 16140-071), 1 mg/mL G418 (Invitrogen 15140-122), 240 nM MTX (methylamine oxime; Sigma M9929) and 1% pen/strep (penicillin/chain Composition of DMEM medium of Invitrogen 15140-122).

The assay medium consisted of DMEM (without phenol red), 10 mM Hepes and 1 x Glutamax. The assay buffer consisted of 2% ovalbumin in the assay medium and 0.2% Pluronic F-68.

program

1) Thaw the cell stock solution in a 37 ° C water bath.

2) The cells were washed three times in PBS.

3) The cells were counted and adjusted to 5 × 10 ³ cells / 50 μl (1 × 10 ⁵ cells / ml) in the assay medium. An aliquot of 50 [mu]l of cells was transferred to each well in the assay plate.

4) The stock solution of the test compound and the reference compound was diluted to a concentration of 0.2 μM in the assay buffer. The compound was diluted 10-fold to obtain the following concentrations: 2 × 10 ^-7 M, 2 × 10 ^-8 M, 2 × 10 ^-9 M, 2 × 10 ^-10 M, 2 × 10 ^-11 M, 2 × 10 ^-12 M, 2 × 10 ^-13 M and 2 × 10 ^-14 M.

5) Transfer a 50 μl aliquot of the compound or blank from the dilution dish to the assay plate. The compounds were tested at the following final concentrations: 1 x 10 ^-7 M, 1 x 10 ^-8 M, 1 x 10 ^-9 M, 1 x 10 ^-10 M, 1 x 10 ^-11 M, 1 x 10 ^-12 M, 1 × 10 ^-13 M and 1 × 10 ^-14 M.

6) The assay plates were incubated for 3 h in a 5% CO ₂ incubator at 37 °C.

7) The assay tray was removed from the incubator and allowed to stand at room temperature for 15 min.

8) Add a 100 μl aliquot of the steadylite plus reagent to each well of the assay plate (the reagent is light sensitive).

9) Cover each analysis disk with aluminum foil to protect it from light and shake at room temperature for 30 min.

10) Read each analysis disk in a Packard TopCount NXT instrument.

Calculation and results

Transfer data from the TopCount instrument to the GraphPad Prism software. The software performs a nonlinear regression (logarithmic (agonist) versus reaction). Calculated by the software and displayed in the reported values of ₅₀ pM EC units in Table 1 below.

The minimum of two replicates was measured for each sample. The reported value is the average of the duplicates.

All compounds have potency data demonstrating their availability as GLP-1 receptor agonists.

Example 30: GLP-1 receptor binding

The purpose of this example was to test in vitro receptor binding of GLP-1 derivatives. Receptor binding is a measure of the affinity of a derivative of the human GLP-1 receptor.

principle

The binding of the GLP-1 derivative of Examples 1-28 to the receptor of the human GLP-1 receptor was measured by competitive binding assay. In this type of assay, the labeled ligand ( ¹²⁵ I-GLP-1 in this case) binds to the receptor. Each derivative was added to a separation membrane containing a human GLP-1 receptor at a range of concentrations and the substitution of the labeled ligand was monitored. Receptor binding is reported as the concentration autoreceptors substituted half-tagged ligand, IC ₅₀ values. Smerupeptide was included as a comparative compound. To test the binding of the derivative to albumin, the assay was performed at low concentrations of serum albumin (maximum 0.001% final assay concentration) and in the presence of significantly higher concentrations of serum albumin (2.0% final assay concentration). In increasing IC ₅₀ values indicative of the presence of serum albumin in the serum albumin affinity and represents a method to extend the pharmacokinetic profile of the test substance of an animal model of prediction.

material

The following chemicals were used in the analysis: human serum albumin (HSA) (Sigma A1653), DMEM (without phenol red) (Gibco 11880-028), Pen/strep (Invitrogen 15140-122), G418 (Invitrogen 10131-027) ), 1M Hepes (Gibco 15630), EDTA (Invitrogen 15575-038), PBS (Invitrogen 14190-094), fetal bovine serum (Invitrogen 16140-071), EGTA, MgCl ₂ (Merck 1.05832.1000), Tween 20 (Amresco) 0850C335), SPA particles (wheat germ agglutinin (WGA) SPA beads, Perkin Elmer RPNQ0001), [ ¹²⁵ I]-GLP-1]-(7-36)NH ₂ (internal production), OptiPlate ^TM -96 (Packard 6005290).

Buffer 1 consisted of 20 mM Na-HEPES plus 10 mM EDTA and the pH was adjusted to 7.4. Buffer 2 consisted of 20 mM Na-HEPES plus 0.1 mM EDTA and the pH was adjusted to 7.4. The assay buffer consisted of 50 mM HEPES supplemented with 5 mM EGTA, 5 mM MgCl ₂ , 0.005% Tween 20 and the pH was adjusted to 7.4. The 8% albumin stock was dissolved in the assay buffer at 8% (w/v). HSA composition. The 0.02% albumin stock consisted of HSA dissolved in 0.02% (w/v) in assay buffer.

Cell culture and membrane preparation

The cells used in this assay (pure line FCW467-12A) were BHK cells with BHKTS13 as the parental cell line. The cells express the human GLP-1 receptor.

The cells were grown in DMEM, 10% fetal calf serum, 1% Pen/Strep (penicillin/streptomycin) and 1.0 mg/mL of the selection marker G418 under 5% CO ₂ .

To make a film formulation, the cells were grown to approximately 80% confluence. The cells were washed twice in phosphate buffered saline and collected. The cells were granulated using brief centrifugation and the cell pellets were kept on ice. 1 in a suitable amount of a buffering agent (e.g., 10 mL) in 20-30 seconds by ULTRA-THURRAX ^TM instrument homogenized dispersion of the cell pellet. The homogenate was centrifuged for 15 minutes. The pellet was resuspended (homogenized) in 10 ml buffer 2 and centrifuged. Repeat this step again. The resulting pellet was resuspended in Buffer 2 and the protein concentration was determined. The membrane was aliquoted and stored at minus 80 °C.

program

1. For receptor binding assays in the presence of low HSA (0.005%), 50 [mu]l of assay buffer was added to each well of the assay plate. Continue with the analysis in step 3.

2. For receptor binding assays in the presence of high HSA (2%), 50 [mu]l of 8% albumin stock was added to each well of the assay plate. Continue with the analysis in step 3.

3. Serially dilute the test compound to obtain the following concentrations: 8 x 10 ^-7 M, 8 x 10 ^-8 M, 8 x 10 ^-9 M, 8 x 10 ^-10 M, 8 x 10 ^-11 M, 8 x 10 ^{- 12} M and 8 x 10 ^-13 M. Add 25 μl to the appropriate wells in the assay plate.

4. Thaw the cell membrane aliquot and dilute to its working concentration. 50 μl was added to each well in the assay disk.

5. WGA SPA beads were suspended in assay buffer at 20 mg/mL. The suspension was diluted to 10 mg/mL in assay buffer and immediately added to the assay plate. 50 μl was added to each well in the assay disk.

6. Incubation was started by adding 25 μl of a 480 pM solution of [ ¹²⁵ I]-GLP-1]-(7-36)NH ₂ to each well of the assay disk. A 25 [mu]l aliquot was reserved for measurement of total counts/well.

7. Incubate the assay plate for 2 h at 30 °C.

8. Centrifuge the assay plate for 10 min.

9. Read the analysis disk in the Packard TopCount NXT instrument.

Calculation

Transfer data from the TopCount instrument to the GraphPad Prism software. The software averages the values of the replicas and performs nonlinear regression. The IC ₅₀ value is calculated by software and reported in units of nM.

result

Get the following results:

All compounds showed excellent binding to the GLP-1 receptor in the absence of albumin, and most of the compounds also showed excellent binding in the presence of albumin. have Two compounds of the IC ₅₀ values more than 1000 detection limit of the analysis.

Example 31: Pharmacokinetic Study in Miniature Pigs

The purpose of this study was to determine the in vivo prolongation of the derivatives after intravenous administration of the GLP-1 derivative to mini-pigs, i.e., their time in the body and thereby extending the duration of action. This was done in a pharmacokinetic (PK) study in which the terminal half-life of the derivative was determined. The terminal half-life means the time taken to halve a certain plasma concentration in the terminal elimination phase.

The derivatives of Examples 1-5 were dosed at 2 nmol/kg, the derivatives of Example 6 were dosed at 5 nmol/kg, and the derivatives of Examples 7-9 were dosed at 15 nmol/kg. Smeglutide was included for comparison (1.5 nmol/kg).

Smaller from Ellegaard Göttingen, roughly 7-14 months old and weighed roughly 16-35kg Male Göttingen minipigs from pigs (Dalmose, Denmark) were used for the study. Miniature pigs were housed individually (pores with permanent catheters) or once or twice in the group and daily restricted to the SDS minipigs diet (Special Diets Services, Essex, UK).

After at least 2 weeks of acclimatization, two permanent central venous catheters were implanted into the caudal vena cava or cranial vena cava of each animal. Animals were allowed to recover for 1 week after surgery and subsequently used for repeated pharmacokinetic studies by a suitable elution period between continuous GLP-1 derivative administrations.

The GLP-1 derivative was dissolved in 50 mM sodium phosphate, 70-145 mM sodium chloride, 0.05% tween 80, pH 7.4, to a concentration of usually 20-60 nmol/ml.

An intravenous injection of the compound is given via a catheter or via a venflon cannula (volume corresponds to, for example, 0.050-0.125 ml/kg), and blood is sampled at a predefined time point until 25 days after administration (preferably via other catheters) Or by venipuncture). Blood samples (eg, 0.8 mL) were collected in EDTA buffer (8 mM) and then centrifuged at 4 ° C and 1942 G for 10 minutes.

Plasma was pipetted into the microtubes on dry ice and kept at -20 °C until the plasma concentrations of the individual GLP-1 compounds were analyzed using LOCI. Individual plasma concentration-time characteristics were analyzed by non-compartmental pharmacokinetic methods in Phoenix version 6.2 (Pharsight, Inc., Mountain View, CA, USA) or other related software for PK analysis, and the resulting terminal half-life (harmonic mean) was determined ).

result

The test derivatives of the invention have an extremely long terminal half-life (at least twice the terminal half-life of semaglutide).

Example 32: Pharmacodynamic study in db/db mice

The purpose of this study was to verify the acute effects of GLP-1 derivatives on blood glucose (BG) and body weight (BW) in diabetes settings.

The GLP-1 derivatives of Examples 1-8 and 10 were tested in a single dose study in an obese, diabetic mouse model (db/db mice) as described below. The derivatives were tested at a dose of 10 nmol/kg (Example 10) or 30 nmol/kg (Examples 1-8).

Register 6 db/db mice/compounds (from Taconic, Denmark) to be fed, starting from birth with a diet NIH31 (NIH 31M Rodent Diet, available from Taconic Farms, US, see www.taconic.com), It was used for research at approximately 10 weeks of age. Mice were allowed free access to standard foods (eg, Altromin 1324, Brogaarden, Gentofte, Denmark) and tap water and maintained at 24 °C. After 1-2 weeks of domestication, the basal blood glucose was evaluated twice on two consecutive days (i.e., at 9 am). Mice were assigned to treatment groups based on matching blood glucose levels and body weight. Mice were used in the experiment for a duration of 120 hours and used up to 2 more times. After the last experiment, the mice were euthanized.

Animals were grouped to receive the following treatment: vehicle, subcutaneous or GLP-1 derivative, subcutaneous, wherein the vehicle was 50 mM sodium phosphate, 70 mM sodium chloride, 0.05% polysorbate 80, pH 7.4 (Examples 1, 2) , 7 and 10); or 50 mM sodium phosphate, 145 mM sodium chloride, 0.05% (w/v) tween 80, pH 7.4 (Examples 3-6 and 8).

The GLP-1 derivative is dissolved in the vehicle up to a dose concentration of 1.7-17 nmol/ml (depending on the respective dose). Animals were administered subcutaneously at a dose-volume of 6 ml/kg (i.e., 300 μl/50 g mouse) at the beginning of the experiment.

On the day of dosing, blood glucose was assessed at time -1⁄2 h (8.30 am), after which the mice were weighed. The GLP-1 derivative was dosed at approximately 9 am (time 0). On the day of administration, after administration Blood glucose was assessed at 1, 2, 4, and 8 h (10 am, 11 am, 1 pm, and 5 pm).

Blood glucose was assessed at 24 h, 48 h, 72 h, and 96 h over the next few days. The mice were weighed daily, followed by blood glucose sampling.

Mice were individually weighed on a digital scale.

A sample for measuring blood glucose was obtained from the tip capillary of a self-conscious mouse. 10 μl of blood was collected into heparinized capillaries and transferred to 500 μl of glucose buffer (EKF system solution, Eppendorf, Germany). The glucose concentration was measured using the glucose oxidase method (glucose analyzer Biosen 5040, EKF Diagnostic Co., Ltd., Barleben, Germany). The samples were kept at room temperature for up to 1 h until analysis. If the analysis must be postponed, the sample is kept at 4 ° C for up to 24 h.

Data were presented as % change in blood glucose or body weight measured at 48 h and 96 h time points. For example, the % change in blood glucose content of each individual at 48h is calculated as follows: [[((glycemic content at 48h)-(basal blood glucose level)] / (basal blood glucose level)] x 100%], where basal blood glucose Content refers to the amount before any treatment is applied - and the change in body weight and vice versa. Negative values refer to % reduction.

The following results were obtained (corresponding to the average of all individual measurements for each treatment):

All test derivatives showed a reduction in in vivo effects of BG and BW after 48 h and after 96 h.

Example 33: Pharmacodynamic study in LYD pigs

The purpose of this experiment was to investigate the effect of GLP-1 derivatives on food intake in pigs. This experiment was performed in a pharmacodynamic (PD) study as described below, wherein food intake was measured 1 to 4 days after administration of a single dose of GLP-1 derivative compared to the vehicle-treated control group.

Female Landrace Yorkshire Duroc (LYD) pigs weighing approximately 30-35 kg (n=3-4/group) weighing approximately 3 months old were used. Animals were housed in the group for approximately one week while gradually adapting to the animal facility. Animals were placed in individual pens during the experimental period, at least 2 days prior to dosing and during the complete experiment in which individual food intake was measured. Animals were arbitrarily fed with pig food (Svinefoder, Danish Top or HRC Sow and Weaner Diet) during domestication and experimental time. Record food weight online or manually monitor food intake every 15 minutes. Food weight (24 h period) was recorded daily for each animal from day 2 to day 6 (120 hours) after administration (including administration).

The GLP-1 derivative is first dissolved in phosphate buffer (50 mM phosphate, 0.05% at the desired concentration (such as 12, 40, 120, 400 or 1200 nmol/ml, corresponding to a dose of 10, 15 or 30 nmol/kg). Tween 80, pH 8; or 50 mM phosphate, 145 mM sodium chloride, 0.05% tween 80, pH 7.4). The phosphate buffer acts as a vehicle. Animals were dosed on day 1 with a single subcutaneous dose of GLP-1 derivative or vehicle (common dose volume 0.025 ml/kg) and food intake was measured 1-4 days after dosing. On the last day of each study, blood samples for measuring plasma exposure of GLP-1 derivatives were obtained from the jugular vein/anterior cavity at 1-4 days after administration. The animals were reused for three experiments. The plasma content of the GLP-1 derivative was analyzed using LOCI.

Food intake was calculated as the average 24 h food intake in the 24 h time interval (0-24h, 24-48h, 48-72h, and 72-96h) and may be indicated, for example, as food intake in the vehicle group in the same time interval. Percentage.

Two-way ANOVA repeat measurement, followed by Bonferroni post-test for food intake in the 24-hour interval relative to the GLP-1 derivative group Statistical comparison.

While the invention has been shown and described with reference to the embodiments Therefore, it is to be understood that the appended claims are intended to cover all such modifications and

<110> Norfolk Dick Co., Ltd.

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Claims (14)

A derivative of a GLP-1 peptide, wherein the GLP-1 peptide comprises a peptide of formula I: Formula I: Xaa ₇ -Xaa ₈ -Glu-Gly-Thr-Xaa ₁₂ -Thr-Ser-Asp- Xaa ₁₆ -Ser-Xaa ₁₈ -Xaa ₁₉ -Xaa ₂₀ -Glu-Xaa ₂₂ -Xaa ₂₃ -Ala-Xaa ₂₅ -Xaa ₂₆ -Xaa ₂₇ -Phe-Ile-Xaa ₃₀ -Xaa ₃₁ -Leu-Xaa ₃₃ -Xaa ₃₄ -Xaa ₃₅ -Xaa ₃₆ -Xaa ₃₇ -Xaa ₃₈ -Xaa ₃₉ -Xaa ₄₀ -Xaa ₄₁ -Xaa ₄₂ , wherein Xaa ₇ is L-histidine acid, (S)-2-hydroxy-3-(1H-imidazole- 4- yl) - propionic acid, D- histidine, histidine amino group to the high histidine (homohistidine), N α ^- acetyl group histidine, N ^[alpha] - methyl acyl histidine, N ^α - methyl-histidine, 3-pyridyl alanine, 2-pyridyl or 4-pyridyl alanine-alanine; Xaa ₈ is Ala, Gly, Ser, Aib, (1- amino-cyclopropyl) carboxylic acid, or (1 -Aminocyclobutyl)carboxylic acid; Xaa ₁₂ is Phe or Leu; Xaa ₁₆ is Val or Leu; Xaa ₁₈ is Ser, Arg, Lys, Val or Leu; Xaa ₁₉ is Tyr or Gln; Xaa ₂₀ is Leu or Met; Xaa ₂₂ is Gly or Glu; Xaa ₂₃ is Gln, Glu, Lys or Arg; Xaa ₂₅ is Ala or Val; Xaa ₂₆ is Arg or Lys; Xaa ₂₇ is Glu, Lys or Leu; Xaa ₃₀ is Ala, Glu or Arg; Xaa ₃₁ is Trp, Lys or His; Xaa ₃₃ is Val , Lys or Arg; Xaa ₃₄ is Lys, Arg, His, Asn, or Gln; Xaa ₃₅ is Gly or Ala; Xaa ₃₆ is Arg, Lys or Gly; Xaa ₃₇ is Gly or Pro; Xaa ₃₈ is Ser, Gly, Ala, Glu, Pro or Lys; Xaa ₃₉ is Ser, Gly, Ala, Glu or Pro; Xaa ₄₀ is Ser, Gly, Ala, Glu or Pro; Xaa ₄₁ is Ser, Gly, Ala, Glu or Pro; and Xaa ₄₂ is Lys The restriction condition is that at least one of Xaa ₁₈ , Xaa ₂₃ , Xaa ₂₇ , Xaa ₃₁ , Xaa ₃₆ or Xaa ₃₈ is Lys; wherein Lys at Xaa ₄₂ is the first K residue, and Xaa ₁₈ , Xaa ₂₃ , wherein one of Xaa ₂₇ , Xaa ₃₁ , Xaa ₃₆ or Xaa ₃₈ is a second K residue; the derivative comprises first and second respectively connected to the first and second K residues An extension, wherein the first and the second extension are selected from the group consisting of Chemical Formula 1, Chemical Formula 1a, and Chemical Formula 1b: Chemical Formula 1: HOOC-(CH ₂ ) ₁₈ -CO-*, Chemical Formula 1a: HOOC-(CH ₂ ) ₁₇ - CO-*, and Chemical Formula 1b: HOOC-(CH ₂ ) ₂₀ -CO-*; or a pharmaceutically acceptable salt, guanamine or ester thereof. A derivative according to claim 1, wherein Xaa ₈ is Aib. A derivative according to any one of claims 1 to 2, wherein Xaa ₂₂ is Glu. A derivative according to any one of claims 1 to 2, wherein Xaa ₂₆ is Arg. A derivative according to any one of claims 1 to 2, wherein Xaa ₃₄ is Arg. A derivative according to any one of claims 1 to 2, wherein in the formula I, Xaa ₇ is L-histamine, (S)-2-hydroxy-3-(1H-imidazole-4 -yl)-propionic acid, D-histidine acid, deaminoglycolic acid, N ^α -ethinyl histidine, N ^α -formyl histidine, N ^α -methylhistamine; Xaa ₈ is Ala, Gly, Ser, Aib, (1-aminocyclopropyl)carboxylic acid or (1-aminocyclobutyl)carboxylic acid; Xaa ₁₂ is Phe; Xaa ₁₆ is Val or Leu; Xaa ₁₈ is Ser, Arg Or Lys; Xaa ₁₉ is Tyr or Gln; Xaa ₂₀ is Leu or Met; Xaa ₂₂ is Gly or Glu; Xaa ₂₃ is Gln, Glu, Lys or Arg; Xaa ₂₅ is Ala or Val; Xaa ₂₆ is Arg or Lys; Xaa ₂₇ is Glu, Lys or Leu; Xaa ₃₀ is Ala or Glu; Xaa ₃₁ is Trp, Lys or His; Xaa ₃₃ is Val, Lys or Arg; Xaa ₃₄ is Lys, Arg or Asn; Xaa ₃₅ is Gly; Xaa ₃₆ is Arg, Lys or Gly; Xaa ₃₇ is Gly or Pro; Xaa ₃₈ is Gly, Ala, Glu, Pro or Lys; Xaa ₃₉ is Ser, Gly, Ala, Glu or Pro; Xaa ₄₀ is Ser, Gly, Ala, Glu or Pro; Xaa ₄₁ is Ser, Gly, Ala, Glu or Pro; and Xaa ₄₂ is Lys. A derivative according to any one of claims 1 to 2, wherein the GLP-1 peptide has up to 12 when compared to GLP-1 (7-37) (SEQ ID NO: 1) The amino acid changes. The derivative of any one of the first to second extensions, wherein each of the first and second extensions are respectively connected to the first and The second K residue. The derivative of claim 8, wherein each of the first and the second linker comprises at least one connecting element selected from the group consisting of: Wherein k is an integer in the range of 1-5, and n is an integer in the range of 1-5; Chemical formula 5: *-NH-(CH ₂ ) _q -CH[(CH ₂ ) _w -NH ₂ ]-CO-*, wherein q is an integer in the range of 0-5, and w is in the range of 0-5 An integer whose constraint is that when w is 0, q is an integer in the range of 1-5, and when q is 0, w is an integer in the range of 1-5; Wherein y is 1 or 2, z is 1 or 2, p is 0 or 1, and X represents a carbon atom or an oxygen atom; A GLP-1 derivative selected from the group consisting of Chemical Formula 21, Chemical Formula 22, Chemical Formula 23, Chemical Formula 24, Chemical Formula 25, Chemical Formula 26, Chemical Formula 27, Chemical Formula 28, Chemical Formula 29, Chemical Formula 30, Chemical Formula 31, Chemical Formula 32, Chemical Formula 33 , Chemical Formula 34, Chemical Formula 35, Chemical Formula 36, Chemical Formula 37, Chemical Formula 38, Chemical Formula 39, Chemical Formula 40, Chemical Formula 41, Chemical Formula 42, Chemical Formula 43, Chemical Formula 44, Chemical Formula 45, Chemical Formula 46, Chemical Formula 47, and Chemical Formula 48; An acceptable salt, guanamine or ester. A pharmaceutical composition comprising a derivative according to any one of claims 1 to 10 and a pharmaceutically acceptable excipient. A derivative for use as a medicament according to any one of claims 1 to 10. A derivative according to any one of claims 1 to 10, (i) for preventing and/or treating all forms of diabetes, such as hyperglycemia, type 2 diabetes, glucose tolerance Sexual abnormalities, type 1 diabetes, non-insulin-dependent diabetes mellitus, MODY (young adult diabetes), gestational diabetes and/or reduction of HbA1C; (ii) delay or prevention of diabetes progression, such as progression of type 2 diabetes, delaying glucose tolerance Progressive abnormalities (IGT) progress to type 2 diabetes requiring insulin, delay or prevent insulin resistance and/or delay progression of type 2 diabetes requiring insulin to insulin type 2 diabetes; (iii) improved beta-cell function, Such as reducing β-cell apoptosis, increasing β-cell function and/or β-cell mass and/or restoring glucose sensitivity to β-cells; (iv) preventing and/or treating cognitive disorders and/or neurodegenerative disorders, Such as Alzheimer's disease, Parkinson's disease and/or multiple sclerosis; (v) prevention and/or treatment of eating disorders, such as obesity, for example by reducing food Involve, reduce body weight, suppress appetite, induce satiety; treat or prevent by taking antipsychotics or steroid-induced bulimia, psychogenic eclipse and/or obesity; reduce gastric motility; delay gastric tract Empty; increase body movement; and/or prevent and/or treat obesity comorbidity, such as osteoarthritis and/or urinary incontinence; (vi) prevent and/or treat diabetic complications, such as vascular disease; Neuropathy, including peripheral neuropathy; nephropathy; and/or retinopathy; (vii) improving lipid parameters such as preventing and/or treating dyslipidemia, lowering total serum lipids; increasing HDL; lowering low density LDL; lowering VLDL; lowering triglyceride Ester; lowering cholesterol; lowering plasma levels of lipoprotein a (Lp(a)) in humans; inhibiting in vitro and/or Production of apolipoprotein a (apo(a)) in vivo; (viii) prevention and/or treatment of cardiovascular diseases such as syndrome X, atherosclerosis, myocardial infarction, coronary heart disease, reperfusion injury, stroke, cerebral ischemia Early heart or early cardiovascular disease, left ventricular hypertrophy, coronary artery disease, hypertension, essential hypertension, acute hypertension, cardiomyopathy, cardiac insufficiency, exercise intolerance, acute and/or chronic heart failure, Arrhythmia, arrhythmia, syncope, angina pectoris, cardiac bypass and/or stent reocclusion, atheroschlerosis oblitterens, diastolic dysfunction and/or systolic dysfunction; and/or lowering blood pressure, such as reducing systolic blood pressure; Ix) prevention and/or treatment of gastrointestinal diseases such as inflammatory bowel disease, short bowel syndrome or Crohn's disease or colitis; dyspepsia and / or gastric ulcer; and / or inflammation, such as psoriasis, psoriasis Arthritis, rheumatoid arthritis and/or systemic lupus erythematosus; (x) prevention and/or treatment of critical illness, such as treatment of critically ill patients, critical illness, multiple kidney disease (critial) Illness poly-nephropathy; CIPNP) patients and/or potential CIPNP patients; prevention of critical illness or development of CIPNP; prevention, treatment and/or cure of systemic inflammatory response syndrome (SIRS) in patients; prevention or reduction of patients during hospitalization The possibility of bacteremia, sepsis and/or septic shock; and/or the stabilization of blood glucose, insulin balance and, where appropriate, the presence of a patient in an intensive care unit with acute disease; (xi) prevention and/or treatment of polycystic Ovarian syndrome (PCOS); (xii) prevention and/or treatment of brain diseases such as cerebral ischemia, cerebral hemorrhage and/or traumatic brain injury; (xiii) prevention and/or treatment of sleep apnea; and/or (xiv Prevent and/or treat abuse, such as alcohol abuse and/or substance abuse. Use of a derivative according to any one of claims 1 to 10 for the manufacture of a medicament for use in the following: (i) Prevention and/or treatment of all forms of diabetes, such as hyperglycemia, type 2 diabetes, impaired glucose tolerance, type 1 diabetes, non-insulin dependent diabetes, MODY (young adult diabetes), gestational diabetes And/or reduce HbA1C; (ii) delay or prevent progression of diabetes, such as progression of type 2 diabetes, delaying progression of glucose tolerance (IGT) to insulin type 2 diabetes, delaying or preventing insulin resistance and/or delaying Type 2 diabetes that does not require insulin progresses to type 2 diabetes requiring insulin; (iii) improves beta-cell function, such as reducing beta-cell apoptosis, increasing beta-cell function and/or beta-cell mass and/or beta - cells restore glucose sensitivity; (iv) prevent and/or treat cognitive disorders and/or neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease and/or multiple Sclerosis; (v) prevention and/or treatment of eating disorders, such as obesity, for example by reducing food intake, reducing body weight, suppressing appetite, inducing satiety; treatment or prevention by administration Psychotropic or steroid-induced bulimia, psychogenic eclipse and/or obesity; reducing gastric motility; delaying gastric emptying; increasing body movement; and/or preventing and/or treating comorbidities of obesity, such as bone Arthritis and/or urinary incontinence; (vi) prevention and/or treatment of diabetic complications, such as vascular disease; neuropathy, including peripheral neuropathy; nephropathy; and/or retinopathy; (vii) improved lipid parameters, such as prevention and/or Treatment of dyslipidemia, reduction of total serum lipids; increase of HDL; reduction of low-density LDL; reduction of VLDL; reduction of triglycerides; lowering of cholesterol; reduction of plasma levels of lipoprotein a (Lp(a)) in humans; inhibition of in vitro / or produce apolipoprotein a (apo(a)) in vivo; (viii) prevent and/or treat cardiovascular diseases such as syndrome X, atherosclerosis, myocardial infarction, coronary heart disease, reperfusion injury, stroke, brain Ischemia, early heart or early blood Tube disease, left ventricular hypertrophy, coronary artery disease, hypertension, essential hypertension, acute hypertension, cardiomyopathy, cardiac insufficiency, exercise intolerance, acute and/or chronic heart failure, arrhythmia, arrhythmia, Syncope, angina pectoris, cardiac bypass and/or stent reocclusion, atheroschlerosis oblitterens, diastolic dysfunction and/or systolic dysfunction; and/or lowering blood pressure, such as reducing systolic blood pressure; (ix) prevention and/or Treatment of gastrointestinal diseases such as inflammatory bowel disease, short bowel syndrome or Crohn's disease or colitis; dyspepsia and/or gastric ulcer; and/or inflammation, such as psoriasis, psoriatic arthritis, rheumatoid Arthritis and/or systemic lupus erythematosus; (x) prevention and/or treatment of critical illness, such as treatment of critically ill patients, critically ill multiple kidney disease (CIPNP) patients and/or potential CIPNP patients; prevention of critical illness or CIPNP Development; prevention, treatment, and/or cure of systemic inflammatory response syndrome (SIRS) in patients; prevention or reduction of bacteremia, sepsis, and/or hospitalization during hospitalization The possibility of septic shock; and/or the stabilization of blood glucose, insulin balance and, where appropriate, the presence of a patient in an intensive care unit with acute disease; (xi) prevention and/or treatment of polycystic ovary syndrome (PCOS); Preventing and/or treating brain diseases such as cerebral ischemia, cerebral hemorrhage and/or traumatic brain injury; (xiii) preventing and/or treating sleep apnea; and/or (xiv) preventing and/or treating abuse, Such as alcohol abuse and / or drug abuse.