# US 10,946,074 B2 · GLP-1 derivatives and uses thereof

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- Number: US 10,946,074 B2
- Document ID: US10946074B2
- Status: Granted
- Kind: B2
- Application number: 16/077,759
- Filed: 2017-03-02
- Published: 2019-02-07
- Granted: 2021-03-16
- Earliest claimed: 2016-03-03
- Assignees: Novo Nordisk A/S
- Applicants: Novo Nordisk A/S
- Inventors: Jacob Kofoed; Janos Tibor Kodra; Lars Linderoth; Patrick William Garibay
- Web page: https://patentgrep.com/patent/US10946074B2

## CPC

- A61K 38/26: Glucagons
- A61K 47/542: {Carboxylic acids, e.g. a fatty acid or an amino acid}
- A61K 47/543: {Lipids, e.g. triglycerides; Polyamines, e.g. spermine or spermidine}
- A61K 47/545: {Heterocyclic compounds (A61K47/558 takes precedence)}
- A61K 47/60: the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
- A61P 1/00: Drugs for disorders of the alimentary tract or the digestive system
- A61P 1/04: for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
- A61P 1/14: Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
- A61P 3/00: Drugs for disorders of the metabolism (of the blood or the extracellular fluid A61P7/00)
- A61P 3/04: Anorexiants; Antiobesity agents
- A61P 3/06: Antihyperlipidemics
- A61P 3/08: for glucose homeostasis (pancreatic hormones A61P5/48)
- A61P 3/10: for hyperglycaemia, e.g. antidiabetics
- A61P 5/50: for increasing or potentiating the activity of insulin
- A61P 9/00: Drugs for disorders of the cardiovascular system
- A61P 9/02: Non-specific cardiovascular stimulants, e.g. drugs for syncope, antihypotensives
- A61P 9/04: Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
- A61P 9/06: Antiarrhythmics
- A61P 9/08: Vasodilators for multiple indications
- A61P 9/10: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
- A61P 9/12: Antihypertensives
- A61P 11/00: Drugs for disorders of the respiratory system
- A61P 11/16: Central respiratory analeptics
- A61P 13/02: of urine or of the urinary tract, e.g. urine acidifiers
- A61P 13/12: of the kidneys
- A61P 15/08: for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
- A61P 17/06: Antipsoriatics
- A61P 19/02: for joint disorders, e.g. arthritis, arthrosis
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 25/02: for peripheral neuropathies
- A61P 25/16: Anti-Parkinson drugs
- A61P 25/28: for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
- A61P 25/30: for treating abuse or dependence
- A61P 25/32: Alcohol-abuse
- A61P 25/36: Opioid-abuse
- A61P 27/02: Ophthalmic agents
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 31/04: Antibacterial agents
- A61P 37/02: Immunomodulators
- C07K 14/605: Glucagons
- A61K 38/00: Medicinal preparations containing peptides (peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00)
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00)

## Abstract

The invention relates to GLP-1 analogues and derivatives having a Trp at a position corresponding to position 8 of GLP-1(7-37), and their pharmaceutical use e.g. in the treatment of type 2 diabetes. These Trp8 compounds are very stable against degradation by DPP-IV, while maintaining the capability to bind to and activate the GLP-1 receptor. The derivatives have one or two substituents (P-L) attached to a Lys residue of the GLP-1 analogue via an optional Branching group (B), wherein P is a Protracting moiety such as a fatty diacid, and L is a linker consisting of one or more linker elements such as, for example, 8-amino-3,6-dioxaoctanoic acid. Examples of compounds of the invention include the 8W variants of liraglutide and dulaglutide. The invention also relates to a method for the fully recombinant preparation of 8W GLP-1 analogues and derivatives which is more simple and thereby cheaper as compared to the preparation of known GLP-1 analogues that have been DPP-IV stabilised by inclusion of one or more non-coded amino acids.

## Claims

### Claim 1

A derivative of formula I:
(P-L)U-B-GLP1,
wherein GLP1 is a GLP-1 analogue having a Trp at a position corresponding to position 8 of GLP-1(7-37) (SEQ ID NO: 1), (P-L) is a substituent attached to a Lys residue of the GLP-1 analogue via an optional Branching group (B) and comprising a Protracting moiety (P) and a Linker (L), U represents the number of substituents (P-L) in the derivative and is 1 or 2, wherein each substituent (P-L) comprises
(i) a Protracting moiety (P) selected from Chem. 10, Chem. 11, Chem. 12, Chem. 13, and Chem. 14:
and
(ii) a Linker (L) comprising at least one linker element selected from Chem. 15, Chem. 16, Chem. 17, and Chem. 18:
wherein
R is —COOH;
each of s, x, y, z, and p independently represents an integer in the range of 8-20;
each of n, m, and q independently represents an integer in the range of 0-4; and
each of k, l, and t independently represents an integer in the range of 1-5; and
(iii) wherein the Branching group (B) if present comprises a Branched linker (BL) selected from Chem. 19 and Chem. 20:
wherein u and v independently represents an integer in the range of 0-5 and each w represents an integer in the range of 0-2, with the provisos that when u is 0 v is an integer in the range of 1-5, and when v is 0 u is an integer in the range of 1-5;
or a pharmaceutically acceptable salt, amide, or ester thereof.

### Claim 2 (depends on 1)

The derivative of claim 1, wherein the GLP-1 analogue comprises a peptide of formula II (SEQ ID NO: 25):
Xaa7-Trp-Glu-Gly-Thr-Xaa12-Thr-Ser-Asp-Xaa16-Ser-Xaa18-Xaa19-Xaa20-Glu-Xaa22-Xaa23-Ala-Xaa25-Xaa26-Xaa27-Phe-Ile-Xaa30-Xaa31-Leu-Xaa33-Xaa34-Xaa35-Xaa36-Xaa37-Xaa38-Xaa39-Xaa40-Xaa41-Xaa42,
wherein
Xaa7 is L-histidine, (S)-2-Hydroxy-3-(1H-imidazol-4-yl)-propionic acid, D-histidine, deamino-histidine, homohistidine, Na-acetyl-histidine, Na-formyl-histidine, Na-methyl-histidine, 3-pyridylalanine, 2-pyridylalanine, or 4-pyridylalanine;
Xaa12 is Phe or Leu;
Xaa16 is Val or Leu;
Xaa18 is Ser, Arg, Val, or Leu;
Xaa19 is Tyr or Gln;
Xaa20 is Leu or Met;
Xaa22 is Gly or Glu;
Xaa23 is Gln, Glu, or Arg;
Xaa25 is Ala or Val;
Xaa26 is Arg or Lys;
Xaa27 is Glu, Lys, or Leu;
Xaa30 is Ala, Glu, or Arg;
Xaa31 is Trp or His;
Xaa33 is Val;
Xaa34 is Arg, His, Asn, or Gln;
Xaa35 is Gly or Ala;
Xaa36 is Arg, Lys, or Gly;
Xaa37 is Gly, Lys, Pro, or absent;
Xaa38 is Ser, Gly, Ala, Glu, Pro, Lys, or absent;
Xaa39 is Ser, Gly, Ala, Glu, Pro, or absent;
Xaa40 is Ser, Gly, Ala, Glu, Pro, or absent;
Xaa41 is Ser, Gly, Ala, Glu, Pro, or absent; and
Xaa42 is Lys or absent;
with the proviso that if one of Xaa37, Xaa38, Xaa39, Xaa40, Xaa41, or Xaa42 is absent then each subsequent amino acid residue is also absent; and
with the proviso that at least one of Xaa26, Xaa27, Xaa36, Xaa37, Xaa38, or Xaa42 is Lys;
or a pharmaceutically acceptable salt, amide, or ester thereof.

### Claim 3 (depends on 1)

The derivative of claim 1, which has formula Ia:
(P-L)-GLP1; Formula Ia:
or a pharmaceutically acceptable salt, amide, or ester thereof.

### Claim 4 (depends on 1)

The derivative of claim 1, which has formula Ib:
(P-L)2-GLP1; Formula Tb:
or a pharmaceutically acceptable salt, amide, or ester thereof.

### Claim 5 (depends on 1)

The derivative of claim 1, which has formula Ic:
(P-L)2>BL-PL-GLP1, Formula Ic:
wherein
(i) >BL is a Branched linker as defined in claim 1, and
(ii) PL is a Pre linker which comprises Chem. 16:
wherein each of k and l independently represents an integer in the range of 1-5;
or a pharmaceutically acceptable salt, amide, or ester thereof.

### Claim 6 (depends on 1)

The derivative of claim 1, which has formula Id:
(P-L)2>BL-GLP1, Formula Id:
wherein >BL is a Branched linker as defined in claim 1;
or a pharmaceutically acceptable salt, amide, or ester thereof.

### Claim 7

A derivative selected from the following:
N{Epsilon-36}-[2-[2-[2-[[2-[2-[2-[[(4S)-4-carboxy-4-[10-(3-carboxyphenoxy)decanoylamino]butanoyl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl],N{Epsilon-37}-[2-[2-[2-[[2-[2-[2-[[(4S)-4-carboxy-4-[10-(3-carboxyphenoxy)decanoylamino]butanoyl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl]-[Trp8,Glu22,Arg26,Arg34,Lys36,Lys37]-GLP-1-(7-37)-peptide,
Chem. 21, derivative of SEQ ID NO: 5:
N{Epsilon-26}-[2-[2-[2-[[2-[2-[2-[[(4S)-4-carboxy-4-(17-carboxyheptadecanoylamino)butanoyl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl]-[Trp8,Arg34]-GLP-1-(7-37)-peptide,
Chem. 22, derivative of SEQ ID NO: 7:
N{Epsilon-27}-[2-[2-[2-[[2-[2-[2-[[(4S)-4-carboxy-4-[10-(4-carboxyphenoxy)decanoylamino]butanoyl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl],N{Epsilon-36}-[2-[2-[2-[[2-[2-[2-[[(4S)-4-carboxy-4-[10-(4-carboxyphenoxy)decanoylamino]butanoyl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl]-[Trp8,Glu22,Arg26,Lys27,Glu30,Arg34,Lys36]-GLP-1-(7-37)-peptidyl-Glu-Gly,
Chem. 23, derivative of SEQ ID NO: 9:
N{Epsilon-26}-[2-[2-[2-[[2-[2-[2-[[(4S)-4-carboxy-4-[10-(4-carboxyphenoxy)decanoylamino]butanoyl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl],N{Epsilon-37}-[2-[2-[2-[[2-[2-[2-[[(4S)-4-carboxy-4-[10-(4-carboxyphenoxy)decanoylamino]butanoyl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl]-[Trp8,Arg34,Lys37]-GLP-1-(7-37)-peptide,
Chem. 24, derivative of SEQ ID NO: 11:
N{Epsilon-26}-[(4S)-4-carboxy-4-(hexadecanoylamino)butanoyl]-[Trp8,Arg34]-GLP-1-(7-37)-peptide,
Chem. 25, derivative of SEQ ID NO: 7:
N{Epsilon-36}-[2-[2-[2-[[2-[2-[2-[[2-[2-[2-[[2-[2-[2-[[(4S)-4-carboxy-4-(13-carboxytridecanoylamino)butanoyl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl],N{Epsilon-37}-[2-[2-[2-[[2-[2-[2-[[2-[2-[2-[[2-[2-[2-[[(4S)-4-carboxy-4-(13-carboxytridecanoylamino)butanoyl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl]-[Trp8,Glu22,Arg26,Arg34,Lys36,Lys37]-GLP-1-(7-37)-peptide,
Chem. 26, derivative of SEQ ID NO: 5:
N{Epsilon-36}-[2-[2-[2-[[2-[2-[2-[[(4S)-4-carboxy-4-[11-(4-carboxyphenoxy)undecanoylamino]butanoyl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl],N{Epsilon-37}-[2-[2-[2-[[2-[2-[2-[[(4S)-4-carboxy-4-[11-(4-carboxyphenoxy)undecanoylamino]butanoyl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl]-[Trp8,Glu22,Arg26,Arg34,Lys36,Lys37]-GLP-1-(7-37)-peptide,
Chem. 27, derivative of SEQ ID NO: 5:
N{Alpha}([Trp8,Glu22,Arg26,Arg34]-GLP-1-(7-37)-peptidyl)-N{Epsilon}[2-[2-[2-[[2-[2-[2-[[(4S)-4-carboxy-4-[[4-[(19-carboxynonadecanoylamino)methyl]cyclohexanecarbonyl]amino]butanoyl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl]Lys-Gly-Gly-Ser-N{Epsilon}[2-[2-[2-[[2-[2-[2-[[(4S)-4-carboxy-4-[[4-[(19-carboxynonadecanoylamino)methyl]cyclohexanecarbonyl]amino]butanoyl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl]Lys,
Chem. 28, derivative of SEQ ID NO: 16:
N{Epsilon-37}-[(2S)-2,6-bis[[2-[2-[2-[[2-[2-[2-[[2-[2-[2-[[2-[2-[2-[[2-[2-[2-[[2-[2-[2-[[(4S)-4-carboxy-4-[[[4-[(19-carboxynonadecanoylamino)methyl]cyclohexanecarbonyl]amino]butanoyl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl]amino]hexanoyl]-[Trp8,Glu22,Arg26,Arg34,Lys37]-GLP-1-(7-37)-peptide,
Chem. 29, derivative of SEQ ID NO: 18:
N{Alpha}([Trp8,Glu22,Arg26,Arg34,Pro37]-GLP-1-(7-37)-peptidyl)-N{Epsilon}[2-[bis[3-[[2-[2-[2-[[2-[2-[2-[[2-[2-[2-[[2-[2-[2-[[2-[2-[2-[[2-[2-[2-[[(4S)-4- carboxy-4-[[4-[(19-carboxynonadecanoylamino)methyl]cyclohexanecarbonyl]amino]butanoyl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl]amino]propyl]amino]acetyl]Lys,
Chem. 30, derivative of SEQ ID NO: 20:
N{Epsilon-37}-[2-[2-[2-[[2-[2-[2-[[(2S)-2,6-bis[[2-[2-[2-[[2-[2-[2-[[2-[2-[2-[[2-[2-[2-[[(4S)-4-carboxy-4-[[4-[(19-carboxynonadecanoylamino)methyl]cyclohexanecarbonyl]amino]butanoyl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl]amino]hexanoyl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl]-[Trp8,Glu22,Arg26,Arg34,Lys37]-GLP-1-(7-37)-peptide,
Chem. 31, derivative of SEQ ID NO: 18:
N{Epsilon-37}-[2-[2-[2-[[2-[2-[2-[[2-[bis[3-[[2-[2-[2-[[2-[2-[2-[[2-[2-[2-[[2-[2-[2-[[(4S)-4-carboxy-4-[[4-[(19-carboxynonadecanoylamino)methyl]cyclohexanecarbonyl]amino]butanoyl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl]amino]propyl]amino]acetyl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl]-[Trp8,Glu22,Arg26,Arg34,Lys37]-GLP-1-(7-37)-peptide, and
Chem. 32, derivative of SEQ ID NO: 18:
or a pharmaceutically acceptable salt, amide, or ester thereof.

### Claim 8

A GLP-1 analogue selected from SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO: 7, SEQ ID NO: 9, SEQ ID NO: 11, SEQ ID NO:15, amino acids 1-275 of SEQ ID NO: 15, SEQ ID NO: 16, SEQ ID NO: 18, and SEQ ID NO:20; or a pharmaceutically acceptable salt, amide, or ester thereof.

### Claim 9 (depends on 1)

A method of preparing a derivative of claim 1, which comprises the step of recombinantly producing a GLP-1 analogue having Trp at a position corresponding to position 8 of GLP-1(7-37) (SEQ ID NO: 1).

### Claim 10 (depends on 9)

The method of claim 9, wherein the GLP-1 analogue has GLP-1 activity and is DPP-IV stabilised.

### Claim 11 (depends on 9)

The method of claim 9, which further comprises the step of purifying the recombinantly produced GLP-1 analogue.

### Claim 12 (depends on 9)

The method of claim 9, which further comprises the step of attaching a substituent to a Lys residue of the GLP-1 analogue and purifying the resulting GLP-1 derivative.

### Claim 13 (depends on 1)

A pharmaceutical composition comprising a derivative according to claim 1, and a pharmaceutically acceptable excipient.

### Claim 14 (depends on 1)

A method comprising:
(i) prevention and/or treatment of all forms of diabetes, and/or for reduction of HbA1C;
(ii) delaying or preventing diabetic disease progression;
(iii) improving β-cell function;
(iv) prevention and/or treatment of cognitive disorders and/or neurodegenerative disorders;
(v) prevention and/or treatment of eating disorders by decreasing food intake, reducing body weight, suppressing appetite, and/or inducing satiety; treating or preventing binge eating disorder, bulimia nervosa, and/or obesity induced by administration of an antipsychotic or a steroid; reduction of gastric motility; delaying gastric emptying; increasing physical mobility; and/or prevention and/or treatment of comorbidities to obesity;
(vi) prevention and/or treatment of diabetic complications;
(vii) improving lipid parameters; increasing HDL; lowering small, dense LDL; lowering VLDL; lowering triglycerides; lowering cholesterol; lowering plasma levels of lipoprotein a (Lp(a)) in a human; and/or inhibiting generation of apolipoprotein a (apo(a)) in vitro and/or in vivo;
(viii) prevention and/or treatment of cardiovascular diseases; and/or reduction of blood pressure;
(ix) prevention and/or treatment of gastrointestinal diseases dyspepsia, and/or gastric ulcers; and/or inflammation, psoriasis, psoriatic arthritis, rheumatoid arthritis, and/or systemic lupus erythematosus;
(x) prevention and/or treatment of critical illness, a critical illness poly-nephropathy (CIPNP) patient, and/or a potential CIPNP patient; prevention of development of critical illness or CIPNP; prevention, treatment and/or cure of systemic inflammatory response syndrome (SIRS) in a patient; prevention or reduction of the likelihood of a patient suffering from bacteraemia, septicaemia, and/or septic shock during hospitalisation; and/or stabilising blood glucose, insulin balance and optionally metabolism in intensive care unit patients with acute illness;
(xi) prevention and/or treatment of polycystic ovary syndrome (PCOS);
(xii) prevention and/or treatment of cerebral disease, cerebral ischemia, cerebral haemorrhage, and/or traumatic brain injury;
(xiii) prevention and/or treatment of sleep apnoea; and/or
(xiv) prevention and/or treatment of alcohol abuse and/or drug abuse, wherein a subject in need of such method is administered a pharmaceutically effective amount of pharmaceutical composition comprising a derivative according to claim 1.

### Claim 15 (depends on 1)

A method comprising: the treatment or prevention of hyperglycemia, type 2 diabetes, impaired glucose tolerance, type 1 diabetes, non-insulin dependent diabetes, MODY (maturity onset diabetes of the young), gestational diabetes, Alzheimer's disease, Parkinson's disease, multiple sclerosis, osteoarthritis, urine incontinence, angiopathy, neuropathy, peripheral neuropathy, nephropathy, retinopathy, dyslipidemia, 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, heart insufficiency, exercise intolerance, acute and/or chronic heart failure, arrhythmia, cardiac dysrhythmia, syncopy, angina pectoris, cardiac bypass and/or stent reocclusion, intermittent A claudication, atherosclerosis obliterans, diastolic dysfunction/and/or systolic dysfunction, reduction of systolic blood pressure, inflammatory bowel disease, short bowel syndrome, Crohn's disease, or colitis;
wherein a subject in need of such method is administered a pharmaceutically effective amount of pharmaceutical composition comprising a derivative according to claim 1.