The present invention relates to a compound being an (R)-enantiomer of a compound according to the following formula

wherein

Rl or R2 is a group selected from H, -CH3, -CH2CH3, -CH2CH2CH3, and CH2CH2CH2CH3 or can be taken together with another to give a cyclopropyl ring, a cyclobutyl ring, a cyclopentyl ring, or a cyclohexyl ring, R3 is a group selected from -COOH, -COOR6, -CONH2, -CONHR6, -CONR6R7, -CONHS02R6, -COO-(CH2)3-CH20H, -COO- (CH2)4-ON02, -COO-PhOCH3-C2H2-COO-(CH2)4-ON02, tetrazolyl, and a -COOH bioisostere, R4 or R5 is a group selected from -CI, -F, -Br, -I, -CF3, -OCF3, -SCF3, -OCH3, - OCH2CH3, -CN, -CH=CH2, -CH20H, and -N02, R6 or R7 is a group selected from -CH3, - CH2CH3, -CH2CH2CH3, and -CH2CH2CH2CH3, and m or n is an integer selected from 0, 1, 2, and 3, a nitro-variant of said compound, or pharmaceutically acceptable salts of said compound for use in preventing and/or treating diabetes in a subject in need thereof. Moreover, also encompassed by the invention is a composition comprising said compound, nitro-variant, or pharmaceutically acceptable salts and at least one additional therapeutic agent for prevention and/or treatment of diabetes.

Diabetes mellitus, also referred to as diabetes, is a disease of a perturbed metabolism resulting in abnormally high blood sugar levels. Patients with diabetes do not sufficiently produce or respond to the endogenous hormone insulin that is normally produced by the beta cells of the pancreas and is important for controlling glucose levels in the blood. Typical symptoms of diabetes include frequent urination, increased thirst, weight loss, fatigue and blurry vision (Cooke et al. (2008); Type 1 diabetes mellitus in pediatrics. Pediatr Rev 29 (11): 374-84.).

According to the World Health Organisation (WHO), diabetes can be subdivided into four categories:

Type 1 diabetes is considered to be an autoimmune disease and develops due to an absent or reduced production of insulin. Insulin production is low or even absent because the body's immune system attacks the insulin-producing beta cells of the islets of Langerhans in the pancreas. The progressive destruction of beta cells can last months or even years without clinical symptoms until a point is reached where the beta-cell mass is critically low, so that insulin concentrations are no longer adequate to control plasma glucose levels. The type 1 diabetes is sometimes also referred to as "juvenile diabetes" because it mainly develops during childhood; however, it can also develop in adults. Type 1 diabetes is thought to be partly inherited and triggered by environmental factors, i.e. a viral infection, in genetically susceptible people. People with an increased risk of developing type I diabetes often have mutations in multiple genes. Most commonly, those mutations affect the group of human leukocyte antigen (HLA) genes which encode for proteins on the surface of cells that are responsible for regulation of the human immune system.

Type 2 diabetes develops due to a resistance to the effects of insulin. Type 2 diabetes is the most common form of diabetes and is primarily related to lifestyle factors such as obesity, poor diet and lack of physical activity. However, genetic predispositions may also play an important role in the onset of type 2 diabetes, i.e. mutations in the insulin receptor gene (ISNR) decreasing insulin receptor signaling. The insulin receptor is a transmembrane receptor that is activated by the hormone insulin and regulates glucose uptake into the cells. Impaired uptake of glucose into the cells, i.e. by decreased insulin receptor signaling, causes an increase of circulating glucose in the blood (hyperglycemia). Type 3 diabetes, according to the current classification, comprises all other specific types of diabetes characterized by an impaired glucose metabolism resulting in hyperglycaemia. For example, the beta cells may have genetic defects affecting insulin production, insulin resistance may be caused genetically or the pancreas as such may be destroyed or impaired. In addition, hormone deregulation or drugs may also cause type 3 diabetes.

Type 4 diabetes, also known as gestational diabetes, may occur during pregnancy. Gestational diabetes is thought to be linked to pregnancy-related factors such as the presence of human placental lactogen. These factors are likely to interfere with insulin receptor signalling, thus lowering the uptake of glucose into the cells causing elevated blood sugar levels. In addition, several pre-diabetic states are known in the art in which not all of the symptoms required to label a person as diabetic are present, but blood sugar is abnormally high. Pre- diabetic states may include, for example, impaired fasting glycaemia, impaired glucose tolerance, obesity and metabolic syndrome.

Therapy of diabetes is currently based on monitoring the blood sugar levels and reducing an elevated level of blood sugar into a normal level. Under certain conditions, glucose levels in the blood may be regulated by nutritional diets and the exclusion of life-style risk factors, such as smoking, lack of exercise, high cholesterol levels, and increased body weight. Furthermore, sensitization to endogenous insulin can be achieved by administration of insulin-sensitizing drugs such as metformin and thiazolinediones. However, in most cases, administration of exogenous insulin is required. Exogenous insulin is usually administered by multiple injections into the blood or by using an insulin pump. All of the current treatment options have certain limitations or drawbacks, for example insufficient response to the treatment or pain and site reactions caused by multiple injections.

In view of the above, an ongoing demand exists for the development of therapeutic agents for the prevention and/or treatment of diabetes

The technical problem underlying the present invention can be seen as the provision of means and methods for complying with the aforementioned needs. The technical problem is solved by the embodiments characterized in the claims and herein below.

The present invention pertains to a compound being an (R)-enantiomer of a compound according to the following formula (I)

wherein

Ri or R ₂ is a group selected from H, -CH ₃ , -CH ₂ CH ₃ , -CH ₂ CH ₂ CH ₃ , and CH ₂ CH ₂ CH ₂ CH ₃ or can be taken together with another to give a cyclopropyl ring, a cyclobutyl ring, a cyclopentyl ring, or a cyclohexyl ring,

R ₃ is a group selected from -COOH, -COORe, -CONH ₂ , -CONHRg, -CONReRy, - CONHS0 ₂ R ₆ , -COO-(CH ₂ ) ₃ -CH ₂ OH, -COO-(CH ₂ ) ₄ -ON0 ₂ , -COO-PhOCH ₃ -C ₂ H ₂ -COO- (CH ₂ ) ₄ -ON0 ₂ , tetrazolyl, and a -COOH bioisostere,

R ₄ or R ₅ is a group selected from -CI, -F, -Br, -I, -CF ₃ , -OCF ₃ , -SCF ₃ , -OCH ₃ , -OCH ₂ CH ₃ , - CN, -CH=CH ₂ , -CH ₂ OH, and -N0 ₂ , Rs or R ₇ is a group selected from -CH ₃ , -CH ₂ CH ₃ , -CH ₂ CH ₂ CH ₃ , and -CH ₂ CH ₂ CH ₂ CH ₃ , and m or n is an integer selected from 0, 1, 2, and 3, a nitro-variant of said compound, or pharmaceutically acceptable salts of said compound for use in preventing and/or treating diabetes in a subject in need thereof.

Preferably, in accordance with the present invention Rl is hydrogen (H).

Further preferred in accordance with the present invention, the compound for use is selected from the group of consisting of:

(R)-2-(2-fluoro-4-phenylphenyl)propionic acid,

(R)-2-(2-fluoro-biphenyl-4-yl)propionic acid 4-nitrooxybutylester, (R)- 1 , 1 '-biphenyl)-4-acetic acid 2-fluoro-a-methyl-4-hydroxybutylester,

(R)-3-[4-(2-fluoro-a-methyl-[ 1 , 1 '-biphenyl]-4-acetyloxy)-3-methoxyphenyl]-2-propenoic acid 4-nitrooxybutyl ester,

(R)-2-methyl-2(2-fluoro-4'-trifluoromethylbiphen-4-yl)propio nic acid,

(R)-2-methyl-2(2-fluoro-4'cyclohexylbiphen-4-yl)propionic acid,

(R)-2-(2-fluoro-3',5'-bis(chloro)biphen-4-yl) propionic acid amide,

(R)-2-(2-fluoro-4'-trifluoromethylbiphen-4-yl)propionic acid,

(R)-2-(2-fluoro-3'-trifluoromethylbiphen-4-yl) propionic acid,

(R)-2-(2-fluoro-3',5'-bis(trifluoromethyl)biphen-4-yl)pro pionic acid,

(R)-2-(4'-cyclohexyl-2-fluorobiphen-4-yl)propionic acid,

(R)-2-(2-Fluoro-l,l'-biphenyl-4-yl) -2-methylpropanoic acid, and

(R)-5-[l-(2-Fluoro-biphenyl-4-yl)-l-methyl-ethyl]-2H-tetr azole.

Particularly preferred in accordance with the present invention, the compound for use is (R)- Flurbiprofen (Tarenflurbil) or Nitro-(R)-Flurbiprofen.

(R)-Flurbiprofen, the R-enantiomer of racemic Flurbiprofen, belongs to the group of 2-aryl propionic acids (profens) such as Ibuprofen and Naproxen. (R)-Flurbiprofen is a by-product of the marketed racemic Flurbiprofen, the active agent of which is thought to be the (S)- enantiomer. (R)-Flurbiprofen is currently in clinical trials for the treatment of metastatic prostate cancer (NCT00045123: ClinicalTrials.gov Identifier NCT00045123: R-Flurbiprofen in Treating Patients With Localized Prostate Cancer at Risk of Recurrence. https://clinicaltrials.gov/ct2/show/NCT00045123). Furthermore, (R)-Flurbiprofen has been shown to modulate the enzyme gamma-secretase, which cleaves the amyloid precursor protein and is thought to be involved in the development of Alzheimer ^' s disease (Geerts, 2007)). Furthermore, R-Fluriprofen has been suggested to exert an anti-inflammatory effect and has been proposed as novel therapeutic agent for the treatment of multiple sclerosis (MS) (WO 2012/059541) as well as for the treatment of skin diseases (WO 2013/026772 Al). Tarenflurbil, the single enantiomer of the racemate NSAID Flurbiprofen, also designated as Flurizan, (R)-Fluriprofen or (R)-2-(2-fluoro-4-phenylphenyl)propionic acid), was investigated in phase II and phase III clinical trials for Alzheimer ^' s disease. However, the further development for this indication was stopped in 2008 after an insufficient improvement of cognitive functions was found. (Green et al. (2009); Tarenflurbil Phase 3 Study Group. Effect of tarenflurbil on cognitive decline and activities of daily living in patients with mild

Alzheimer disease: a randomized controlled trial. JAMA. 2009;302:2557-64; Geerts (2007);

Drug evaluation: (R)-flurbiprofen-an enantiomer of flurbiprofen for the treatment of

Alzheimer's disease. Drugs. Feb;10(2): 121-33.). Tarenflurbil was also suggested to be beneficial for the treatment of neuropathic pain caused by nerve injury (US 2009-0162421). The compound for use according to the present invention can be provided to the patient in any suitable and effective manner, such as orally, rectally or by injection. Preferably, the compound is administered orally. Furthermore, the compound for use according to the present invention can be provided to the patient in any suitable and effective pharmaceutically acceptable form, such as in the form of a tablet, capsule, dragee, powder, suppository, gel and/or as solution for injection.

The compound for use according to the present invention and, preferably, R-Flurbiprofen or Nitro-R-Flurbiprofen, shall be provided to the patient in an effective dose for the prevention and/or treatment of diabetes. Envisaged is a dosage in the range of about 2 mg/kg of body weight to about 20 mg/kg of body weight per day. Preferably, the compound is provided in a dosage between 5 mg/kg of body weight to 15 mg/kg of body weight per day. Most preferably, the compound is provided in a dosage of about lOmg/kg of body weight per day.

"About" as referred to herein refers to any specific value referred to in this specification, e.g., the indicated dosage, including any variation which is within the range of +/-20%, +/-10%, +/- 5%, +/-4%, +/-3%, +1-2% or +/-!%. Moreover, the compound for use according to the present invention, preferably R- Flurbiprofen or Nitro-R-Flurbiprofen, upon administration shall lower the blood glucose level. Methods to determine the blood glucose level are well known in the art and measurement devices for determining blood glucose levels are commercially available. Preferably, envisaged in accordance wit the present invention is a decrease in blood glucose level which is statistically significant and, more preferably, is a decrease of the blood glucose level by at least about 5%, 10%, 20%, 30%, 40%, 50%, 60% or 70%.

The compound for use according to the present invention shall further inhibit pancreatic autoimmune processes. The term "pancreatic immune processes" as used herein refers to immune system reactions against pancreatic tissue and, in particular, pancreatic islets, and include, for example, induction and propagation of autoimmunity, infiltration of immune cells, release of immunomodulatory cytokines and propagation of beta cell death. Methods to diagnose pancreatic autoimmune processes are known to the skilled artisan and include, for example, determination of autoreactive antibodies or detection of inflammatory cytokines.

The compound for use according to the present invention, and preferably (R)-Flurbiprofen or

Nitro-(R)-Flurbiprofen, can be used alone or in combination with other compounds and treatments that are available for the prevention and/or treatment of diabetes. Use in combination as referred to herein includes a simultaneous or sequential application of the compounds and treatments. For simultaneous application, the compound according to the invention may be manufactures together with further diabetes drugs in a single composition as described elsewhere herein in more detail. Such applications may provide for synergistic effects achieved by the compounds administered in combination in the prevention and/or treatment of diabetes. A further therapeutic agent for prevention and/or treatment of diabetes as envisaged in accordance with the present invention is, preferably, selected from the group consisting of: insulin, glucagon-like peptide-1 (GLP-1) receptor agonists, dipeptidyl peptidase 4 (DPP-4) inhibitors, statins, metformin, dexamethasone, thiazolidinediones, alpha- glucosidase inhibitors, synthetic analogs of human amylin, incretin mimetics, glitazones, sodium-glucose co -transporter 2 (SGLT2) inhibitors, anti-CD3 -antibodies, anti-CD20- antibodies, anti-CD20-antibodies, cyclosporines, azathioprine, antithymocyte globulin and nicotinamide.

The term "diabetes" or "diabetes mellitus" as used herein refers to disease conditions in which the glucose metabolism is impaired. Said impairment results in hyperglycaemia. According to the World Health Organisation (WHO), diabetes can be subdivided into four classes which are all individually encompassed by the term diabetes according to the present invention.

Type 1 diabetes is caused by a lack of insulin. Insulin is produced by pancreatic islet cells, the so called beta cells. Said cells may be destroyed by an autoimmune reaction in Type 1 diabetes (Type la). The progressive destruction of beta cells can last months or even years without clinical symptoms until a point is reached where the beta-cell mass is critically low, so that insulin concentrations are no longer adequate to control plasma glucose levels. The type 1 diabetes is sometimes also referred to as "juvenile diabetes" because it mainly develops during childhood; however, it can also develop in adults. Type 1 diabetes is thought to be partly inherited and triggered by environmental factors, i.e. a viral infection, in genetically susceptible people. People with an increased risk of developing type I diabetes often have mutations in multiple genes. Most commonly, those mutations affect the group of human leukocyte antigen (HLA) genes which encode for proteins on the surface of cells that are responsible for regulation of the human immune system. Moreover, Type 1 diabetes also encompasses an idiopathic variant (Type lb). Idiopathic (Type lb) diabetes usually presents with the typical signs and symptoms of Type la diabetes such as diabetic ketoacidosis, but its subsequent clinical course often resembles Type 2 diabetes. Type 2 diabetes is caused by an insulin resistance. Type 2 diabetes is the most common form of diabetes and is primarily related to lifestyle factors such as obesity, poor diet and lack of physical activity. However, genetic predispositions may also play an important role in the onset of type 2 diabetes, i.e. mutations in the insulin receptor gene (ISNR) decreasing insulin receptor signaling. Type 3 diabetes, according to the current classification, comprises all other specific types of diabetes characterized by an impaired glucose metabolism resulting in hyperglycaemia. For example, the beta cells may have genetic defects affecting insulin production, insulin resistance may be caused genetically or the pancreas as such may be destroyed or impaired. In addition, hormone deregulation or drugs may also cause type 3 diabetes.

Type 4 diabetes, which is also known as gestational diabetes, may occur during pregnancy. Gestational diabetes is thought to be linked to pregnancy-related factors such as the presence of human placental lactogen. These factors are likely to interfere with insulin receptor signalling, thus lowering the uptake of glucose into the cells causing elevated blood sugar levels. It will be understood by those skilled in the art, that diabetes as used herein also includes pre-diabetic states in which not all of the symptoms required to label a person as diabetic are present, but blood sugar is abnormally high. Prediabetic states may include, for example, impaired fasting glycaemia, impaired glucose tolerance, metabolic syndrome and obesity.

Preferably, diabetes as used herein refers to diabetes Type 1.

The diagnosis of diabetes and the distinction between different diabetes types is well known in the art. Diagnostic methods include, for example, blood sugar tests (i.e. fasting blood sugar test or oral glucose tolerance test), determination of autoreactive antibodies (i.e. antibodies to insulin-producing beta-cells) and urine sample tests (i.e. ketone concentration in the urine). Increased fasting blood sugar levels are indicative for diabetes in general, particularly a level larger than 125 mg/dL. Preferably, diabetes as used herein is characterized by a blood glucose level larger than 250mg/dL.

Further symptoms and characteristics of diabetes are well known in the art and are described in the standard text books of medicine, such as Stedman or Pschyrembl. The term "treating" as used herein refers to ameliorating or curing a disease or at least one symptom associated therewith. Thus, if there is amelioration or cure of the disease or at least a symptom associated therewith, the treatment shall be deemed to be effective. It will be understood that treating might not be effective in all subjects. However, according to the present invention it is envisaged that treatment will be effective in at least a statistically significant portion of subjects to be treated. It is well known to the skilled artisan how to determine a statistically significant portion of subjects that can be effectively treated.

Whether a portion of subjects or any other value referred to herein is statistically significant can be determined without further ado by the person skilled in the art using various well known statistic evaluation tools, e.g., determination of confidence intervals, p-value determination, Student ^' s t-test, Mann- Whitney test etc.. Details are found in Dowdy and Wearden, Statistics for Research, John Wiley & Sons, New York 1983. Preferred confidence intervals are at least 90%, at least 95%, at least 97%, at least 98% or at least 99%. The p- values are, preferably, 0.1, 0.05, 0.01, 0.005, or 0.0001.

Preferably, the probability envisaged by the present invention allows that the finding of effective treatment will be correct for at least 60%, at least 70%, at least 80%, or at least 90% of the subjects of a given cohort or population.

Therapeutic efficacy and toxicity of the compound according to the invention as a therapeutic agent can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., ED50 (the dose therapeutically effective in 50% of the population) and LD50 (the dose lethal to 50% of the population). The dose ratio between therapeutic and toxic effects is the therapeutic index, and it can be expressed as the ratio, LD50/ED50. The dosage regimen will be determined by the attending physician and by clinical factors. As is well known in the medical arts, dosages for any one patient depends upon many factors, including the patient's size, age, the particular formulation of the medicament to be administered, sex, time and route of administration, general health, and other drugs being administered concurrently. Progress can be monitored by periodic assessment. Dosage recommendations shall be indicated in the prescribers or users instructions in order to anticipate dose adjustments depending on the considered recipient.

The term "preventing" as used herein refers to avoiding the onset of a disease or at least one symptom thereof. Preferably said disease is diabetes. It will be understood by those skilled in the art, that diabetes as used herein also includes pre-diabetic states in which not all of the symptoms required to label a person as diabetic are present, but blood sugar is abnormally high. Moreover, said pre-diabetic states are also predisposing for the development of diabetes. Pre-diabetic states in accordance with the present invention may include, for example, impaired fasting glycaemia, impaired glucose tolerance, metabolic syndrome and obesity.

The term "hyperglycemia" as used in this context refers to a condition in which an excessive amount of glucose is circulating in the blood. Hyperglycemia is commonly also known as high blood sugar. According to the American Diabetes Association guidelines, a subject with a consistent range of about 5.6 mmol/1 and about 7.0 mmol/1 (100-126 mg/dl) is considered hyperglycemic. Above 7 mmol/1 (126 mg/dl), the subject is recognized as having diabetes. The term "metabolic syndrome" refers to a disease in which at least three of five of the following medical conditions are present: abdominal (central) obesity, elevated blood pressure, elevated fasting plasma glucose, high serum triglycerides, and low high-density lipoprotein (HDL) levels. Methods for the diagnosis of metabolic syndrome and the associated symptoms are known to the skilled artisan. Signs of metabolic syndrome include, for example impaired fasting glucose, insulin resistance high blood pressure, decreased fasting serum HDL cholesterol and elevated fasting serum triglyceride level (VLDL triglyceride). The term "obesity" refers to a medical condition in which the body has acquired excess body fat to the extent that it may have a negative effect on health. Preferably, a subject is considered to have obesity when the body mass index (BMI) is higher than 30. Methods to diagnose obesity including the calculation of the body mass index are known in the art. The prevention as referred to herein can be typically achieved for the period during which a drug, preferably a compound or composition according to the present invention, is administered. If the administration of the drug is stopped, however, the prevention may not persist for an unlimited time but may remain present for a certain preventive time window after application of the drug. It will be understood by those skilled in the art that the predictive time window for prevention of diabetes as used herein may be up to several weeks, months or even years. Typically, the preventive time window in accordance with the present invention may be at least one week, two weeks, three weeks, four weeks, one month, two months, or three months. It will be understood that prevention might not be effective in all subjects. However, according to the present invention it is envisaged that prevention will be effective in at least a statistically significant portion of subjects. It is well known to the skilled artisan how to determine a statistically significant portion of subjects that can be effectively prevented. Whether a portion is statistically significant can be determined without further ado by the person skilled in the art using various well known statistic evaluation tools as discussed above.

The term "subject" as used herein relates to animals, preferably to mammals such as mice, rats, sheep, dogs, cats, horses, monkeys, or cows and, also preferably, to humans. A subject as used herein refers to a subject suspected to suffer from diabetes or to have an increased predisposition of developing diabetes and thus is in need for a therapy for preventing and/or treating diabetes. Preferably, the subject shows symptoms or clinical signs or parameters indicative for diabetes. Preferably, the subject when suffering from diabetes has a blood glucose level larger than 125 mg/dL. More preferably, the subject has a blood glucose level larger than 250mg/dL. However, the term also relates to an apparently healthy subject, i.e. a subject not exhibiting any of the aforementioned symptoms, clinical signs or parameters. Preferably, the apparently healthy subject has an increased predisposition of developing diabetes and may be, therefore, in a pre-diabetic state as referred to elsewhere herein.

The term "predisposition" as used herein means that a subject has not yet developed the disease or any of the aforementioned disease symptoms or other diagnostic criteria but, nevertheless, will develop the disease in the future with a certain likelihood. Said likelihood shall differ significantly from the likelihood of statistical appearance of diabetes mellitus. Preferably, the likelihood for developing diabetes is at least 30%, at least 40%, at least 50%>, at least 60%>, at least 70%>, at least 80%>, at least 90%> or 100% of a predisposition is diagnosed. Diagnosis of a predisposition may sometimes be referred to as prognosis or prediction of the likelihood that a subject will develop the disease. Risk factors that increase the likelihood of developing diabetes may include, for example certain genetic mutations, lifestyle parameters such as smoking or low physical activity, and obesity. More generally, the present invention also contemplates the use of a compound as defined above and, preferably, (R)-Flurbiprofen or Nitro-(R)-Flurbiprofen for the manufacture of a medicament for the prevention and/or treatment of diabetes.

Another general aspect of the present invention relates to a method for prevention and/or treatment of diabetes comprising administering to a patient in need thereof a therapeutically effective amount of a compound according to the present invention, and, preferably, (R)- Flurbiprofen or Nitro-(R)-Flurbiprofen.

Advantageously, it has been found in accordance with the studies underlying the present invention that a compound according to the present invention and, preferably, (R)- Flurbiprofen or Nitro-(R)-Flurbiprofen, is suited for the prevention and/or treatment of diabetes. (R)-Fluriprofen suppresses hyperglycemia, delays diabetic progression and affects the incidence of diabetes. Moreover, administration of (R)-Flurbiprofen was shown to affect different phases of diabetes type I pathology such as induction of autoimmunity, infiltration of immune cells and propagation of beta cell death. Thus, (R)-flurbiprofen or a composition comprising (R)-Fluriprofen, may be especially beneficial for patients with diabetes type I and may help to reduce necessary insulin amount and injections, limiting potential side effects associated therewith. Moreover, in light of the blood glucose level reducing effects elicited by (R)-Flurbiprofen or Nitro-(R)-Flurbiprofen, the compound according to the present invention shall also effect other types of diabetes being accompanied by increased blood glucose levels as well. Moreover, the compound shall have preventive potential as well as it shall be capable of preventing, ameliorating or reversing hyperglycemic states in general. The above explanations and definitions of the terms apply throughout the specification. Moreover, in the following, typical embodiments of the composition according to the present invention are listed. In a preferred embodiment of the compound for use according to the present invention, said compound is (R)-Flurbiprofen (Tarenflurbil) or Nitro-(R)-Flurbiprofen.

In a further preferred embodiment of the compound for use according to the present invention, said diabetes is characterized by a blood glucose level >250mg/dl.

In yet a preferred embodiment of the compound for use according to the present invention, said subject has an increased predisposition of developing diabetes.

In yet a preferred embodiment of the compound for use according to the present invention, said subject is suffering from hyperglycemia, metabolic syndrome and/or obesity.

In yet a preferred embodiment of the compound for use according to the present invention, said diabetes is diabetes mellitus type I, diabetes mellitus type II or gestational diabetes. In yet a preferred embodiment of the compound for use according to the present invention, said compound decreases upon administration the blood glucose level.

In yet a preferred embodiment of the compound for use according to the present invention, said compound inhibits pancreatic autoimmune processes.

The term "pancreatic immune processes" as used herein refers to attacks of the body ^' s immune system against pancreatic tissue and include, for example, induction and propagation of autoimmunity, infiltration of immune cells, release of immunomodulatory cytokines and propagation of beta cell death. Methods to diagnose pancreatic autoimmune processes are known to the skilled artisan and include, for example, determination of autoreactive antibodies or detection of inflammatory cytokines.

In yet a preferred embodiment of the compound for use according to the present invention, said compound is provided in a dosage between 5 mg/kg of body weight to 15 mg/kg of body weight per day.

In yet a preferred embodiment of the compound for use according to the present invention, said compound is administered orally, topically, rectally or by injection. More preferably, the compound is administered orally. In yet a preferred embodiment of the compound for use according to the present invention, said compound is provided in form of a tablet, capsule, dragee, powder, suppository, gel, cream, spray, ointment and/or solution. In yet a preferred embodiment of the compound for use according to the present invention, said compound is provided in combination with at least one additional therapeutic agent for prevention and/or treatment of diabetes.

The term "therapeutic agent" as used herein refers to an agent that prevents, ameliorates or cures the symptoms accompanying a disease or condition referred to in this specification.

More preferably, said at least one additional therapeutic agent is selected from the group consisting of: insulin, glucagon-like peptide-1 (GLP-1) receptor agonists, dipeptidyl peptidase 4 (DPP-4) inhibitors, statins, metformin, dexamethasone, thiazolidinediones, alpha- glucosidase inhibitors, synthetic analogs of human amylin, incretin mimetics, glitazones, sodium-glucose co -transporter 2 (SGLT2) inhibitors, anti-CD3 -antibodies, anti-CD20- antibodies, anti-CD20-antibodies, cyclosporines, azathioprine, antithymocyte globulin and nicotinamide.

It will be understood that the present invention also provides a composition comprising (i) a compound according to the present invention, a nitro-variant of said compound, or pharmaceutically acceptable salts of said compound; and (ii) at least one additional therapeutic agent for prevention and/or treatment of diabetes.

The term "composition" as used herein refers to mixture of the aforementioned compounds according to the invention. Moreover, the composition may comprise further components as well such as further therapeutic or auxiliary ingredients and/or pharmaceutically acceptable carriers and/or diluents. The composition of the present invention is, preferably, a pharmaceutical composition to be used as a medicament. Said medicament is, preferably, applied to treat and/or prevent diabetes as described elsewhere herein in detail.

Preferably, such further ingredients of the composition of the invention can be stabilizing agents, wetting agents, pharmaceutical carriers, additional pharmaceutically active agents, release controlling agents and the like.

Preferred diluents encompass water, alcohols, physiological saline solutions, buffers, such as phosphate buffered saline solutions, syrup, oil, water, emulsions, various types of wetting agents, and the like. A pharmaceutically acceptable diluent according to the invention is selected so as not to affect the biological activity of the combination. Examples of such diluents are distilled water, physiological saline, Ringer's solutions, dextrose solution, and Hank's solution. In addition, the pharmaceutical composition or formulation may also include other carriers, adjuvants, or non-toxic, non-therapeutic, non-immunogenic stabilizers and the like.

A pharmaceutically acceptable carrier according to the invention must be acceptable in the sense of being compatible with the other ingredients of the formulation and being not deleterious to the recipient thereof. The pharmaceutical carrier employed may include a solid, a gel, or a liquid. Exemplary of solid carriers are lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid and the like. Similarly, the carrier or diluent may include time delay material well known to the art, such as glyceryl mono-stearate or glyceryl distearate alone or with a wax. Said suitable carriers comprise those mentioned above and others well known in the art, see, e.g., Remington ^' s Pharmaceutical Sciences, Mack Publishing Company, Easton, Pennsylvania.

The composition shall be adapted for use in treating and/or preventing diabetes. Typically, the desired mode of administration will be systemic administration. Thus, the composition of the invention is, preferably, formulated for a systemic application. Preferably, oral application, e.g. in the form of tablets, solution or drinking ampules, is envisaged or application via injection. However, depending on the nature and the mode of action, the composition may be administered by other routes as well including dermal, intra-muscular, subcutaneous, oral, intravenous or topical administration. The composition can be, preferably, formulated for a bolus administration or can be made for continuous applications as set forth elsewhere herein in detail.

The composition of the invention shall, preferably, comprise the therapeutically active compounds referred to above in a therapeutically effective dose. Therapeutic efficacy and toxicity of the compound can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., ED50 (the dose therapeutically effective in 50% of the population) and LD50 (the dose lethal to 50% of the population) as describe above already.

For formulation as medicament, the composition of the present invention can be prepared in a manner well known in the pharmaceutical art. For example, for manufacturing a medicament, the therapeutically active ingredients will usually be mixed and, preferably, combined with a carrier or the diluent. The resulting formulations are to be adapted to the mode of administration. The procedures for formulating a medicament as referred to herein may involve mixing, granulating, compression or dissolving the ingredients as appropriate to form the desired composition. It will be appreciated that the form and character of the pharmaceutical acceptable carrier or diluent is dictated by the amount of active ingredient with which it is to be combined, the route of administration, and other well-known variables. Dosage recommendations shall be indicated in the prescribers or users instructions in order to anticipate dose adjustments depending on the considered recipient. Finally, it is to be understood that the formulation of a composition according to the invention as a medicament takes place under GMP standardized conditions or the like in order to ensure quality, pharmaceutical security, and effectiveness of the medicament.

In a preferred embodiment of the composition of the present invention, said at least one additional therapeutic agent is selected from the group consisting of: insulin, glucagon-like peptide- 1 (GLP-1) receptor agonists, dipeptidyl peptidase 4 (DPP-4) inhibitors, statins, metformin, dexamethasone, thiazolidinediones, alpha-glucosidase inhibitors, synthetic analogs of human amylin, incretin mimetics, glitazones, sodium-glucose co -transporter 2 (SGLT2) inhibitors. anti-CD3-antibodies, anti-CD20-antibodies, anti-CD20-antibodies, cyclosporines, azathioprine, antithymocyte globulin and nicotinamide.

All references cited in this specification are herewith incorporated by reference with respect to their entire disclosure content and the disclosure content specifically mentioned in this specification.

FIGURES

Figure 1: Chemically induced diabetes by multiple low dose streptozotocin (5 times 40 mg/kg). Figure 1 A: Time course of non-fasted blood glucose concentration following start of streptozotocin application on day 0. Data represents mean S.E.M., n=15, *=p< 0,05 compared to day 0. Figure IB: Relative number of diabetic mice following start of streptozotocin application on day 0. Diabetes was defined as blood glucose > 250 mg/dl. Figure 1C: Area of insulin staining in pancreatic islets using specific anti-insulin antibody. Data represents mean S.E.M., n=3, *=p< 0,05 compared to day 0. Figure ID: Insulin staining in pancreatic islets using specific anti-insulin antibody. Figure 2: Daily application of R-flurbiprofen (10 mg/kg), starting on day 0 together with streptozotocin application. Figure 2A: Suppression of streptozotocin induced hyperglycemia by daily administration of R-flurbiprofen. Administration of R-flurbiprofen started two days before injection of streptozotocin. Data represents mean S.E.M., n=5-8, *=p< 0,05. Figure

2B: Relative number of diabetic mice following administration of R-flurbiprofen. Diabetes was defined as blood glucose > 250 mg/dl. Figure 2C: S-flurbiprofen do not affect streptozotocin induced hyperglycemia. In mice 20% of R-flurbiprofen is metabolized to S- flrubirpofen. Therefore 1/5 of the dosis of R-fluribprofen was administrated. Data represents mean S.E.M., n=5. Figure 2D: Relative number of diabetic mice following administration of S-flurbiprofen. Diabetes was defined as blood glucose > 250 mg/dl.

Figure 3: Application of R-flurbiprofen for different time courses. Figure 3A: Suppression of streptozotocin induced hyperglycemia by short term application of R-flurbiprofen from day -2 to day 4. Data represents mean S.E.M., n=6, *=p< 0,05. Figure 3B: Suppression of streptozotocin induced hyperglycemia by short term application of R-flurbiprofen from day 7 to day 21. Data represents mean S.E.M., n=6, *=p< 0,05. Figure 3C: Suppression of streptozotocin induced hyperglycemia by short term application of R-flurbiprofen from day 14 to day 21. Data represents mean S.E.M., n=6, *=p< 0,05. Figure 4: Summary of administration of R-flurbiprofen for different time courses. Figure 4A: Effect of administration of R- and S-flurbiprofen for different time courses on streptozotocin induced hyperglycemia. Data represents mean S.E.M., n=6, *=p< 0,05 compared to control (white column). Figure 4B: Effect of administration of R- and S-flurbiprofen for different time courses on insulin expression in pancreatic islets. Data represents mean S.E.M., n=3, *=p< 0,05 compared to control (white column).

Figure 5: Model: virus induced RIP-LCMV mouse model. Figure 5A: Suppression of hyperglycemia induced by LCMV infection of transgenic RIP-GP mice. Data represents mean S.E.M., n=10, *=p< 0,05. Figure 5B: Relative number of LCMV induced diabetic mice following administration of R-flurbiprofen. Diabetes was defined as blood glucose > 300 mg/dl

EXAMPLES

The following Examples shall illustrate the invention. By no means, whatsoever, they shall be construed as limiting the scope of the invention.

Example 1 : Induction of diabetes in mice by streptozotocin Male C57BL/6J specific pathogen- free mice, 10-20 weeks old, were bred in the animal facility. Mice were housed at 2-5 mice per cage at constant room temperature (21 +/- 1°C) under a regular light/dark schedule with light from 7:00 a.m. to 7:00 p.m. Food (standard chow) and water (sterile- filtered) were available ad libitum. Experimental autoimmune diabetes was induced by the multiple low dose streptozotocin method (MLD-STZ). Streptozotocin (STZ) was dissolved in 0.1 M citrate buffer (pH 4.5) and injected i.p., within 10 min of preparation, at a dose of 40 mg/kg/day for 5 consecutive days (d0-d4). Plasma glucose was monitored over the following 21 days on days 0, 9, 11, 14 and 21. The blood samples were obtained from the tail vein of non-fasted mice and glucose was measured using a glucometer. Mice were considered diabetic when their non-fasting blood glucose levels were > 250 mg/dl. On day 21 mice were euthanized by injection of ketamine/xylazine followed by cardiac puncture. Plasma was separated by centrifugation of whole blood collected in EDTA tubes and then was snap frozen in liquid nitrogen and stored at -80 °C for further analysis. In order to determine relative amount of viable beta cells pancreas sections were stained for expression of insulin. Entire undamaged pancreata were embedded in optimal cutting temperature (OCT) compound, hardened on solid carbon dioxide and stored at -80 °C. Cryosection of pancreatic tissue was performed on a microtome-cryostat. Sections of 7 μιη thickness were cut and mounted on sialin-coated Superfrost Plus slides, 6 μιη tissue sections were cut. Sections were then fixed with 90% ethanol at -20°C, and, after washing in PBS, an avidin/biotin-blocking step was included. Primary anti-insulin antibodies and biotinylated secondary antibodies were reacted with the sections for 60 min each, and color reaction was obtained by sequential incubation with avidin-peroxidase conjugate and diaminobenzidine-hydrogen peroxide.

STZ induced strong hyperglycemia in mice reaching significant diabetic levels around day 1 1 and highest blood glucose concentration at day 21 to day 40. At day 11 approximately 50% of the STZ-treated mice were diabetic, on day 14 75%>, on day 21 about 90%>, and on day 40 100%, respectively. The increase in blood glucose concentration correlated well with the decrease in viable beta cells. In control mice anti-insulin stained intra-islet area represents about 90% of total islet area. Following STZ anti-insulin stained area was reduced to nearly 60%), and on day 21 a reduction in viable beta cells by about 70%> was observed. These results indicate that multiple applications of low dose of STZ induces hyperglycemia and diabetes, and reduces the ability of beta cells to produce insulin (Figure 1).

Example 2: Effects of R- flurbiprofen and S-flurbiprofen in streptozotocin induced diabetes in mice

R- flurbiprofen was administrated from day -2 to 21 to STZ-treated mice. On day 14 and 21 a significant decrease in blood glucose concentration compared to vehicle administrated STZ- treated mice was detected. Also some extent of hyperglycemia was observed only 25%> of R- flurbiprofen treated mice exhibited diabetes upon STZ application. In a striking contrast, vehicle-treated mice showed about 90%> of diabetes incidence on day 21 following STZ administration. These results indicate that R-fiurbiprofen suppresses STZ-induced diabetes in mice (Figure 2).

In mice, R- flurbiprofen is converted to S-flurbiprofen by about 15-20%. In order to study a possible anti-diabetic action by S-flurbiprofen, S-flurbiprofen was administrated at a dose of 2 mg/kg (representing 20% of R- flurbiprofen dose) from day -2 to 21 to STZ-treated mice. No significant differences were observed in comparison to vehicle-treated mice, neither in blood glucose concentration, nor in diabetic incidence. These results indicate that S-flurbiprofen, formed in vivo by conversion of R- flurbiprofen, did not exert anti-diabetic activity (Figure 2).

Example 3: Effects of R- flurbiprofen on different steps in streptozotocin induced diabetes pathogenesis

In the MLD-STZ diabetes model, three pathological steps are involved: first step, induction of autoimmune reactions during STZ application from day 0 to day 4; second step invasion of immune and autoimmune cells in islets of Langerhans between day 7 and day 14; and third step destruction of beta cells by cytokines or cytotoxic cells, most likely from day 14 on. In order to study the effect of R- flurbiprofen on these different steps, R-flurbiprofen was administrated for different time courses. Short term application of R-flurbiprofen from day -2 to 4 exhibited no effect on STZ-induced hyperglycemia until day 14, however, on day 21 blood glucose concentration was significantly lowered. Administration of R-flurbiprofen from day 7 to 21 caused a significant reduction in blood glucose concentration already on day 14. The reduced blood glucose level remained stable at least until day 21. Administration of R- flurbiprofen at the third step, from day 14 to 21, still caused a significant decrease in blood glucose concentration, albeit to a lower extent (Figure 3). A summary of these observations is given in Figure 4.

Example 4: Effects of R-flurbiprofen on blood glucose levels and diabetes incidence in the RIP-LCMV mouse model

The anti-diabetic action of R-flurbiprofen was studied in the virus induced RIP-LCMV mouse model. The RIP-LCMV model uses the glycoprotein (GP) of LCMV as target antigens expressed by the β-cells. Diabetes is induced by infection with LCMV. For induction in RIP- LCMV-GP, 10 ⁴ plaque forming units LCMV Armstrong clone 53 b were injected intraperitoneally. R-flurbiprofen or vehicle were administrated from day -2 to 21. R- flurbiprofen caused a significant decrease in diabetes induction in the early time course of the model with about 25% diabetic mice on day 10 compared to about 90% in vehicle treated mice. On the long term diabetes incidence increased to about 75%>, however associated with significant lower blood glucose concentrations. On day 21 in the R-flurbiprofen group nearly 70% of the mice were diabetic, in the vehicle group 100%. These results indicate that also in a virus induced diabetes model, R-flurbiprofen is able to suppress incidence of diabetes and to lower blood glucose levels (Figure 5).