EP1682540A1 - Azolidinecarbonitriles et leur application comme inhibiteurs de dpp-iv - Google Patents

Azolidinecarbonitriles et leur application comme inhibiteurs de dpp-iv

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EP1682540A1
EP1682540A1 EP03751086A EP03751086A EP1682540A1 EP 1682540 A1 EP1682540 A1 EP 1682540A1 EP 03751086 A EP03751086 A EP 03751086A EP 03751086 A EP03751086 A EP 03751086A EP 1682540 A1 EP1682540 A1 EP 1682540A1
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oxo
ethyl
hydrazino
trifluoroacetate
cyanothiazolidine
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Alangudi Sankaranarayanan
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Definitions

  • the present invention relates to novel heterocyclic compounds useful for normalizing elevated blood glucose levels in diabetics and in treating disorders related to glucose intolerance.
  • These compounds inhibit the enzyme DPP-IV, that degrade the peptide GLP-1, providing for enhanced levels of active GLP-1, a peptide which normalizes elevated blood glucose levels. These compounds are useful to control blood glucose level in diabetic patients and thereby delay the onset of vascular complications in diabetic patients and also transition to type II diabetes in impaired glucose tolerant patients.
  • These compounds are also useful in treating disorders related to glucose intolerance like Cushing's syndrome, hyperthyroidism, obesity, hyperglucagonemia, diseases like ulcers, HIV infection, disorders related to increased gastric emptying, acid secretion and hunger, autoimmune disorders like multiple. sclerosis, rheumatoid arthritis and Grave's disease (Sedo and Kraml, 1994). These compounds also exhibit free radical scavenging activity which is useful in treatment of various disease condition caused by accumulation of free radicals in the body cells. DESCRIPTION OF THERELATED ART
  • Hoist JJ and Deacon CF Inhibition of the activity of Dipeptidyl-peptidase IV as a treatment of type 2 diabetes. Diabetes, 47:1663-1670, 1998.
  • Diabetes mellitus is a clinically and genetically heterogenous group of disorders characterized by abnormally high levels of glucose in the blood.
  • the hyperglycemia is due to deficiency of insulin secretion or to resistance of body cells to the action of insulin, or to a combination of these.
  • Chronic hyperglycemia is a cause of heavy burden of morbidity and premature mortality from diabetic complications. These long-term complications can be delayed by improving glycemic control. None of the currently used medications is capable of reversing an ongoing failure of ⁇ -cell function and reduction in post prandial glucose peak represents an important target for therapeutic strategies.
  • pancreatic insulin secretion is predominantly controlled by blood glucose levels
  • incretins like the peptide GLP-1 derived from enteroinsular axis have an effect on insulin secretion and therefore on the blood glucose level. It is released from the gut in response to ingested nutrients, which acts on the pancreas to potentiate glucose- induced insulin secretion.
  • GLP-1 has beneficial effects in diabetic patients in normalizing elevated blood glucose levels (Hoist J and Deacon C, 1998).
  • GLP-1 has multifaceted actions, which include stimulation of insulin gene expression, trophic effects on ⁇ -cells, inhibition of glucagon secretion, promotion of satiety, and slowing of gastric emptying. Because of glucose dependency of the peptide and glucagonostatic actions, the glucose lowering effect is self-limiting, and the hormone, therefore does not cause hypoglycemia regardless of the dose.
  • the pathogenesis of type-2 diabetes ordinarily involves the development of insulin resistance associated with compensatory hyperinsulinaemia followed by progressive beta-cell impairment that results in decreasing insulin secretion and hyperglycemia.
  • Hyperglycemia itself causes additional inhibition of insulin secretion and more insulin resistance (glucose toxicity), which further accentuates the hyperglycemia.
  • Dipeptidyl Peptidase IV (DPP-IV) inhibitors addresses to a large extent the inadequacies of the presently available therapies. It targets not only the ⁇ -cell dysfunction but also insulin resistance and increased hepatic glucose output by liver. Thus, it has a more holistic approach towards the treatment of type-2 diabetes. Furthermore, by stabilizing / reversing the progressive ⁇ -cell dysfunction, it would prevent the progression of the disease and for the same reason, it has the potential to prevent or delay the occurrence of overt diabetes in subjects with impaired fasting glucose and impaired glucose tolerance. (Pathogenesis of type-2 Diabetes; Harold E Lebovitz, Drug Benefit Trends 12 (supp A):8-16, 2000).
  • the presently used antihyperglycemic drugs target either insulin resistance or ⁇ - cell dysfunction. Hence, there is a need to address both these pathologies together.
  • the homeodomain transcription factor, PDX-1 is essential for the early development of the pancreas and the maintenance of the ⁇ -cell phenotype.
  • PDX-1 is known to regulate insulin, GLUT2 and islet amyloid precursor.
  • GLP-1 induces the differentiation of PDX-1 positive pancreatic epithelial cells into insulin-secreting cells.
  • GLP-1 stimulates the expression of transcription factor PDX-1 while stimulating ⁇ - cell neogenesis and may thereby be an effective treatment for diabetes.
  • GLP-1 and a long acting GLP-1 analogue exendin-4 stimulates both ⁇ -cell replication and neogenesis, resulting in increased ⁇ -cell mass and improved glucose tolerance in partial pancreatectomy rat model of type 2 diabetes (Gang et al, 1999).
  • GLP-1 7-36 is one of the substrate for the circulating exopeptidase dipeptidyl peptidase IV (EC 3.4.14.5), a post proline cleaving enzyme with a specificity for removing Xaa-Pro or Xaa-Ala dipeptides from the N-terminus of polypeptides and proteins.
  • DPP-IV is widely distributed in tissues like kidney, intestine and placenta, hepatocytes, epithelial cells of pancreatic duct, central nervous system, peripheral nervous system, endotheliai cells of blood vessels (Rolf, 1999), and found as soluble enzyme in blood plasma.
  • About 50% of the GLP-l 7-36 amide released from the L cells is inactivated in the capillary bed surrounding these cells by DPP-IV. Furthermore, single pass through the liver inactivates a large fraction of the remaining active GLP -1 (>40%)
  • DPP-IV inhibitor Isoleucine thiazolidide (P-32/98)
  • Isoleucine thiazolidide P-32/98
  • GLP-1 9-36 an antagonist at GLP-1 receptor
  • Inhibition of circulating DPP-IV enhanced insulin secretion and improved glucose tolerance in response to oral glucose challenge in lean and obese fatty (fa/fa) rats.
  • fa/fa lean and obese fatty rats.
  • DPP-IV inhibitor NVP-DPP-728 i.e.
  • Dipeptidyl Peptidase IV (DPP - IV) is a proline specific protease and is involved in breaking peptide bonds before or after a proline residue. It plays an important role in the regulation of the life-time of biological active peptides like growth hormone releasing factor (GRF), Glucagon-like peptide - 1 (GLP-I), Gastric Inhibitory Polypeptide (GIP), Glucagon-like peptide - II (GLP-II), ⁇ -Casomorphin, morphiceptin.
  • GRF growth hormone releasing factor
  • GLP-I Glucagon-like peptide - 1
  • GIP Gastric Inhibitory Polypeptide
  • GLP-II Glucagon-like peptide - II
  • ⁇ -Casomorphin morphiceptin.
  • DPP - IV is present on the surface of a subset of T-cells (lymphocytes) and has been recognized as CD 26 antigen.
  • Dipeptidyl peptidase-IV (DPP-IV) is a serine protease, which cleaves N-terminal dipeptides from a peptide chain containing, preferably, a proline residue in the penultimate position.
  • DPP-IV is responsible for inactivating glucagon-like peptide- 1 (GLP-1). More particularly, DPP-IV cleaves the amino-terminal His-Ala dipeptide of GLP-1, generating a GLP-1 receptor antagonist, and thereby shortens the physiological response to GLP-1.
  • DPP-IV inhibition appears to represent an attractive approach for treating non-insulin-dependent diabetes mellitus (NIDDM).
  • NIDDM non-insulin-dependent diabetes mellitus
  • GLP-1 has multifaceted actions, which include stimulation of insulin gene expression, trophic effects on ⁇ -cells, inhibition of glucagon secretion, promotion of satiety, and slowing of gastric emptying, all of which contribute to normalizing elevated blood glucose levels (Hoist and Deacon, 1998).
  • DPP-IV inhibitors Because of glucose dependency of the peptide and glucagonostatic actions, the glucose lowering effect is self-limiting, and the hormone, therefore does not cause hypoglycemia regardless of the dose.
  • the exact biological functions of DPP - IV / CD 26 are still under investigation, but considerable evidence exists for the therapeutic potential of DPP-IV inhibitors. Although a number of DPP-IV inhibitors have been described, all have limitations relating to potency, stability or toxicity. Accordingly, a great need exists for novel DPP- IV inhibitors, which do not suffer from the above-mentioned limitations.
  • Type - II Diabetes Mellitus - DPP - IV is involved in the degradation of GIP and GLP-I.
  • GIP and GLP-I are considered to be most important, insulin-releasing hormones (incretins) comprising the enteroinsular axis.
  • the term enteroinsular axis refers to the signaling pathways between the gut and pancreatic islets that amplify the insulin response to absorbed nutrients.
  • Inhibition of circulating DPP - IV with orally administered lie-thiazolidine [DPP-IV inhibitor] enhanced insulin secretion and improved glucose tolerance in response to an oral glucose challenge in lean and obese Zucker rats.
  • the enhanced incretin response was greater in obese than in lean animals, with a more profound improvement in glucose tolerance (Pederson R. A, 1998). This was attributed to disruption of DPP - IV inactivation of GIP and GLP-I, resulting in amplification of enteroinsular axis.
  • DPP-IV inhibitors would have very little effect on subjects with normal blood glucose levels regardless of dose because its actions are glucose dependent (Qualmann C et al. 1995).
  • gluconeogenic precursor lactate and glycerol
  • phosphate oxidase increases the capacity for gluconeogenesis from glycerol.
  • hyperthyroidism leads to an increase in futile cycling of glucose, which could contribute to hyperglycemia.
  • Increased activity of several enzymes that could be implicated in the increase in gluconeogenesis have been seen in response to thyroid hormone, including glucokinase, pyruvate carboxylase, phospho-enolpyruvate carboxykinase, and glucose-6-phosphatase.
  • glucokinase pyruvate carboxylase
  • phospho-enolpyruvate carboxykinase phospho-enolpyruvate carboxykinase
  • glucose-6-phosphatase glucose-6-phosphatase.
  • Studies in hyperthyroid patients report impairment in insulin suppression of hepatic glucose production.
  • a recent study has also shown the inability to increase the insulin response appropriately to hyperglycemia and increased proinsulin levels, both fasting and in response to a meal (Michael Berelowitz and Lone A Kourides, 2000).
  • Obesity has been related to insulin resistance and hyperinsulinemia.
  • Visceral obesity is associated with specific changes in skeletal muscle morphology that correlate with insulin resistance and hyperinsulinemia, namely a reduction in capillary density and an increase in the proportion of 'white' or 'glycolytic' fibers which are less insulin sensitive than red (glycolytic) fibers.
  • TNF-alpha is secreted by adipose tissue and its circulating levels parallel total body fat mass. Circulating non-esterified fatty acid (NEFA) levels are raised in obese subjects, especially those with visceral obesity.
  • NEFA non-esterified fatty acid
  • NEFA are oxidised to acetyl CoA, which stimulates pyruvate carboxylase and therefore gluconeogenic production of glucose from pyruvate; hepatic glucose production therefore increases.
  • High NEFA level may also inhibit glucose utilization by skeletal muscle.
  • Increased acetyl CoA levels inhibit pyruvate dehydrogenase, thus decreasing glucose oxidation.
  • the combination of increased hepatic glucose output and reduced peripheral uptake effectively antagonises and would ultimately lead to hyperglycemia (Ronald T Jung, 1997). Glucose intolerance as a result of the above conditions can be managed better by the elevation of GLP-1 levels (as a result of DPP-IV inhibition).
  • Cushing's syndrome represents a distinctive constellation of clinical features associated with prolonged overproduction of impaired glucose tolerance, overt diabetes (in approximately 20%), loss of libido and impotence. Some of these abnormalities such as obesity, deranged glucose metabolism are directly attributable to increased glucocorticoids. These glucocorticoids stimulate gluconeogenesis in diabetes. Also, they increase amino acid uptake by the liver and kidney and increase the activity of enzymes required for gluconeogenesis and may lead to hyperglycemia (Ronald A DeLellius, 1989)
  • Glucose metabolism under the above conditions can be managed better by treatment with DPP-IV inhibitors.
  • DPP-IV inhibitors are reported to inhibit HIV infection such as pyrrolidine-2-nitriles and an irreversible cyclopeptide inhibitor (Nguyen G et al. 1998).
  • DPP-IV has been originally described to be a marker of activated T lymphocytes and lately DPP-IV/CD26 molecular identity has been proven CD26/DPP-IV serves as an essential cofactor for HIV entry into CD 4+ cells and that its enzyme activity is an important condition for this function (Sedo A and Kraml J, 1994). Hence inhibition of DPP-IV could prove useful in the management of HIV infection.
  • Immunosuppressant are reported to inhibit HIV infection such as pyrrolidine-2-nitriles and an irreversible cyclopeptide inhibitor (Nguyen G et al. 1998).
  • DPP-IV has been originally described to be a marker of activated T lymphocytes and lately DPP-IV/CD26 molecular identity has been proven CD26/DPP-IV serves as an essential cofactor for HIV
  • DPP-IV / CD26 plays an important role in the immune system by a number of possible mechanisms. The exact mechanism remains to be elucidated, but a few examples are reported where DPP-IV inhibitors are useful immunosuppressants in vivo. A dipeptide diphenyl phosphonate ester was able to abrogate acute rejection and prolong allograft cardiac survival (Korom S. et al. 1997).
  • DPP-IV inhibitors increase the level of GLP-1.
  • GLP-1 has multifaceted actions, which include stimulation of insulin gene expression, inhibition of glucagon secretion, promotion of satiety, inhibition of food intake and slowing of gastric emptying (Hoist JJ and Deacon CF, 1998).
  • GLP-1 also reduces gastric acid secretion (Michael A Nauck, 1999). Increase in gastric acid secretion is one the main reason for duodenal ulcers. By inhibiting gastric acid secretion, GLP-1 and therefore DPP-IV inhibitors may prove useful for the treatment of ulcers or can be used in combination with other antiulcer agents.
  • DPP-IV is involved in metabolic processing of morphiceptin.
  • Co-administration of a DPP- IV and the opiate peptide morphiceptin could be used in case of diarrhoea, as the experiment with DPP-IV deficient rats showed (Tiruppathi, C, et al, Am. J. Physiol. 1993).
  • Mucosal Regeneration in patient with Intestinal Disease DPP-IV hydrolysis of GLP-2 is responsible for its inactivation.
  • GLP-2 has recently been shown to display intestinal growth factor activity in rodents, raising the possibility that GLP-2 may be therapeutically useful for enhancement of mucosal regeneration in patients with intestinal disease (Drucker, D.J. et al. Diabetes 1998; 47:159).
  • NPY neuropeptide Y
  • NPY activity is prolonged thereby resulting among other things in functionally active NPY YI receptor activity thereby facilitating antidepressive, anxiolytic, analgesic, antihypertension and other neurological effects
  • DPP-IV is able to bind proteins of the extracellular matrix as a cell adhesion molecule. This has been interpreted from the observation that the DPP-IV inhibitors interfere in vitro with the initial spreading of rat hepatocytes on a matrix consisting of fibronectin and collagen. Thus . the DPP-IV inhibitors could also be used for the prevention/treatment of cancer metastasis and tumour colonization (WO 03/002595 dated 09 Jan 2003 by PROBIODRUG AG).
  • Free Radical Scavenging Activity It has been reported that compounds exhibiting free radical scavenging activity are useful in treatment of Neurodegenerative disorders such as Alzheimer's Disease, Parkinson's Disease, Huntington's Disease, Motor Neuron Disease, Prion Disease etc, (b) Diabetes and Diabetic Vascular Complications, (c) Intestinal Diseases such as Intestinal Ischemia, Radiation Enteritis, Inflammatory Bowel Disease, Gastric and Colorectal Cancers etc., (d) Liver Diseases " such as Alcoholic Liver Disease, Chronic Hepatitis C etc., (e) Cancers such as Lung Cancer, Colorectal Cancer, Cervical Cancer, Breast Cancer, Malignant Melanoma etc, (f) Cardiac Diseases such as Atherosclerosis, Myocardial Infarction, Ischemic Stroke, Endotheliai Dysfunction etc., (g) Opthalmic Disorders such as Cataract formation, Macular degeneration etc., (h) HIV Diseases, (i) Respiratory Diseases
  • Oxidative stress induced by ROS damages essential components of the neurons, resulting ultimately in the neuronal death.
  • Oxidative stress is involved in various divergent events leading to neuronal damage, including an increase in membrane rigidity, DNA strand break, and impairment in glucose uptake.
  • oxidative stress in different neurodegenerative disorders have been -well identified (Munch G, et al. 1998).
  • A.D. mitochondrial dysfunction amyloid beta mediated processes; transition metal accumulation and genetic factors are responsible for the redox imbalance (Smith MA, et al. 2000). Point mutations in Superoxide Dismutase enzymes are known in the familial form ofMND.
  • DVCs Diabetes and Diabetic Vascular Complications
  • Oxidative stress in diabetes is not yet fully understood but is thought to be due to mitochondrial dysfunction, direct enzyme inhibition by hyperglycemia, auto- oxidation of glucose, and activation of nicotinamide-adenine dinucleotide phosphate (NADPH)-oxidase.
  • Oxidative stress in diabetes is also increased due to weakened defenses due to reduced endogenous antioxidants.
  • the oxidative stress manifests itself as elevated concentrations of lipid peroxidation products, erythrocyte fragility, and decreases in the antioxidant enzyme systems (CAT, GSH Px, SOD). Recent studies also have shown a positive correlation between blood glucose concentration and oxidant- induced lymphocyte DNA damage (E.J. Harper The 24 th Annual WALTHAM ® /OSU SYMPOSIUM).
  • ROS are generated during glucose oxidation and formation of advanced glycation end products (AGE). Evidence has accumulated indicating that the generation of ROS plays an important role in the development of DVCs. Many biochemical pathways associated with hyperglycemia such as advanced glycosylation, glucose auto oxidation, and polyol pathway can increase the production of free radicals.
  • NO quenching nitric oxide
  • Oxidative stress is an important cause of tissue injury that occurs in inflammation and ischemia. Intestinal ischemia, radiation enteritis, inflammatory bowel disease, and promotion of gastric and colorectal cancers are some of the gastro-intestinal conditions where oxidative stress is implicated in the pathogenesis.
  • liver diseases Alcoholic liver disease- Ethanol induces an increase in lipid peroxidation either by enhancing ROS or decreasing the level of endogenous antioxidants. Ethanol also induces variety of cytochrome P450 enzymes in microsomes and xanthine oxidases in cytosol. The role of these enzymes in the generation of oxidative stress has been well established in various studies (Ishii H, et al. 1997).
  • This fibrogenesis cascade characteristic of severe chronic hepatitis C e.g., oxidative stress, induction of c-myb, activation of stellate cells, and collagen gene expression
  • ROS reactive oxygen species
  • Oxidative damage to DNA is a result of interaction of DNA with ROS, in particular the hydroxyl radical.
  • the hydroxyl radicals produce multiple modifications in DNA.
  • Oxidative attack by OH radical on the deoxyribose moiety leads to the release of free bases from DNA, generating strand breaks with various sugar modifications and simple abasic (AP) sites.
  • ROS also interact with and modify cellular protein, lipid, and DNA, which results in altered target cell function.
  • the accumulation of oxidative damage has been implicated in both acute and chronic cell injury including possible participation in the formation of cancer. Acute oxidative injury may produce selective cell death and a compensatory increase in cell proliferation.
  • ROS therefore, can have multiple effects in the initiation stage of carcinogenesis by mediating carcinogen activation, causing DNA damage, and interfering with the repair of the DNA damage.
  • Oxidative stress in cardiac diseases Lifelong high levels of antioxidant nutrients are supposed to protect against the development of heart disease. High doses of antioxidants in the month following an acute heart attack have been shown to significantly reduce the number of deaths, as well as the extent of cardiac damage in non-fatal cases. It is currently thought that increase in oxidative stress is involved in the pathophysiology of endotheliai dysfunction that accompanies a number of cardiovascular risk factors including hypercholesterolemia, hypertension and cigarette smoking. It also plays a pivotal role in the evolution of clinical conditions such as atherosclerosis and heart failure.
  • Oxidative stress can activate redox-sensitive kinase cascades and transcription factors such as NF R B and AP-1, with resulting increases in the expression of factors associated with an inflammatory response and cellular proliferation.
  • NF R B and AP-1 transcription factors associated with an inflammatory response and cellular proliferation.
  • Atherogenesis is regarded as the outcome of interactions among multiple stimuli.
  • Endotheliai dysfunction plays a key role in the development of atherosclerosis. Elevated homocysteine concentrations are associated with rapid onset endotheliai dysfunction, which is another mechanism by which increased oxidative stress contributes to atherosclerosis.
  • Oxidation of low-density lipoprotein plays an important role at several steps in atherogenesis. Oxidative stress also activates NF R B, which induces expression of genes controlling cytokine expression and leukocyte adhesion to vascular wall. (Maxwell, et al. 1997).
  • HIV disease Perturbation of anti-oxidant defense system has been observed in various tissues in HIV patients. Oxidative stress may contribute to several aspects of HIV disease pathogenesis such as viral replication, inflammatory response, and decreased immune cell proliferation, loss of immune function, apoptosis, chronic weight loss. Antioxidants may offer a promising treatment to HIV patients.
  • COPD Chronic obstructive pulmonary diseases
  • Gamma-GCS gamma- glutamyl cystine synthase
  • Oxidative stress is implicated in the pathogenesis of COPD, since it results in inactivation of anti proteinases, airspace epithelial injury, mucus hypersecretion, increased influx of neutrophils into the lungs, transcription factor activation and gene expression of pro-inflammatory mediators (MacNee W, et al. 2001).
  • Renal Disease ROS have been implicated not only in the genesis of different forms of renal disease, predominantly experimentally induced glomerulonephritis, but also in different forms of acute renal failure. Asthma Although the pathogenesis of asthma is not fully defined, a typical feature is an increase in the number of inflammatory cells in the lung. Such cells generate ROS, which are involved in the pathophysiology of asthma, including airway smooth muscle contraction, increased airway reactivity, and increased vascular permeability.
  • the immune system is particularly sensitive to oxidative stress, primarily because immune cells rely heavily on cell-to-cell communication to work effectively. Peroxidation of cell membranes compromises membrane integrity and disrupts intracellular signaling.
  • Oxidative damage to lens of eye with increase in age has been a major contribution in cataract formation.
  • the following diseases can be treated or controlled :
  • Cardiac Diseases (a) Atherosclerosis (b) Myocardial Infarction (c) Ischemic Stroke (d) Endotheliai dysfunction
  • the first object of the present invention is to provide a new class of compounds which normalize elevated blood glucose levels in diabetic patients thereby delaying diabetic complications and preventing transition to type II diabetes in impaired glucose tolerant patients.
  • DPP-IV inhibitors enhance the level of active GLP-1, which would be advantageous in treating hyperglycemia. Added advantage is that there is no risk of hypoglycemia, since GLP-1 increases glucose mediated insulin secretion. Due to non-peptide nature of the compounds, they can be conveniently administered orally.
  • the increase in GLP-1 level in the active form provides for multifaceted action in respect of increase in insulin level, decrease in glucagon level, neogenesis of pancreatic ⁇ -cell, stimulation of insulin gene expression, and promotion of satiety, all of which contribute to beneficial effects in a diabetic patient.
  • Another object of the invention is to provide a method of treatment of a diabetic patient with glucose intolerance by administration of the compounds of the invention or pharmaceutically acceptable salts thereof either singly or in combination with drugs for anti-diabetic or other therapies for Cushing's syndrome, hyperthyroidism, HIV infection, obesity, ulcers, disorders related to hyperglucagonemia, gastric emptying and hunger in required dosage in admixture with pharmaceutically acceptable diluents, solvents, excepients, carriers or other media as may be appropriate for the purpose.
  • a further object of the invention is to provide a class of compounds having free radical scavenging activity which are useful for treatment of (a) Neurodegenerative disorders such as Alzheimer's Disease, Parkinson's Disease, Huntington's Disease, Motor Neuron Disease, Prion Disease etc, (b) Diabetes and Diabetic Vascular Complications, (c) Intestinal Diseases such as Intestinal Ischemia, Radiation Enteritis, Inflammatory Bowel Disease, Gastric and Colorectal Cancers etc., (d) Liver Diseases such as Alcoholic Liver Disease, Chronic Hepatitis C etc., (e) Cancers such as Lung Cancer, Colorectal Cancer, Cervical Cancer, Breast Cancer, Malignant Melanoma etc., (f) Cardiac Diseases such as Atherosclerosis, Myocardial Infarction, Ischemic Stroke, Endotheliai Dysfunction etc., (g) Opthalmic Disorders such as Cataract formation, Macular degeneration etc., (h)- HIV Diseases, (i) Res
  • Yet another object of the present invention is to provide a method of preparation of these compounds.
  • a still further object of the invention is to provide a pharmaceutical composition
  • a pharmaceutical composition comprising said compound in association with a pharmaceutical acceptable carrier, diluent or excepients.
  • Yet another object of the invention is to provide a method of treatment and/or prophylaxis of mammals including human beings for diseases relating to glucose intolerance and/or disease conditions caused by accumulation of free radicals in the body cells.
  • the present invention provides novel compounds represented by general formula (I) and its pharmaceutically acceptable salts, which is to be understood as also including its derivatives, analogs, tautomeric forms, stereoisomers, polymorphs and their pharmaceutically acceptable solvates, which are useful for one or more of (i) normalizing elevated blood glucose levels in diabetes, (ii) treating disorders related to glucose intolerance and (iii) scavenging free radicals from body cells.
  • X is O, S, SO, S0 2 , NR7 or CHR1 ; n is null or 1; k is null or 1;
  • Z is O, S, and NR7 ;
  • Rl at two positions are independently selected from hydrogen or a substituted or unsubstituted group selected from linear or branched (C ⁇ -C ⁇ 2 )alkyl, (C 2 -C ⁇ 2 )alkenyl, (C 3 - C 7 )cycloalkyl, (C 5 -C 7 )cycloalkenyl, bicycloalkyl, bicycloalkenyl, heterocycloalkyl, aryl, aryloxy, aralkyl, aralkoxy, heteroaryl, heteroaralkyl, heteroaryloxy, heteroaralkoxy, wherein one or more heteroatoms are independently selected from 0, N or S;
  • R2, R3, R4 and R7 are independently selected from hydrogen, perhaloalkyl, - (CO)NR8R9, -(CO)R8,-(CO)OR8, -S02R8, -SOR8, substituted or unsubstituted groups selected from linear or branched (C)-C ⁇ 2 )alkyl, (C 2 -C ⁇ 2 )alkenyl, (C 3 -C 7 )cycloalkyl, (C 5 - C 7 )cycloalkenyl, bicycloalkyl, tricycloalkyl amidino bicycloalkenyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, wherein one or more heteroatoms are independently selected from O, N or S;
  • R5 and R6 are independently selected from by hydrogen or a substituted or unsubstituted group selected from linear or branched (C ⁇ -C ⁇ )alkyl, (C 2 -C ⁇ 2 )alkenyl, (C 3- C 7 )cycloalkyl, (C 5 -C 7 )cycloalkenyl, bicycloalkyl, bicycloalkenyl, heterocycloalkyl, aryl,aralkyl, heteroaryl,heteroaralkyl, wherein one or more heteroatoms are independently selected from O, or S;
  • R8 and R9 are independently selected from hydrogen or a substituted and unsubstituted group selected from linear or branched (C ⁇ -C ⁇ 2 )alkyl, alkoxyaryl, alkoxyalkyl, alkoxycycloalkyl, alkoxyaryl, perhaloalkyl, C 2 -C ⁇ 2 )alkenyl, (C 3 -C 7 ) cycloalkyl, perhalocycloalkyl, haloheterocycloalkyl, cyanoheterocycloalkyl, perhaloheterocycloalkyl, (C 5 -C 7 ) cycloalkenyl, bicycloalkyl, bicycloalkenyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, perhaloaryl, perhaloheteroaryl; wherein in the groups represented by Rl, R2, R3, R4, R5, R6, R7, R8 and R
  • R10 is independently selected from halogens, hydroxy, nitro, cyano, amino, alkoxy carbonyl alkyl, -S02NH alkyl, -S02NH aryl, oxo or oxime, and pharmaceutically usable hydrates and salts thereof ; with the proviso that, if k is null, then R4 and R6 together form an optionally six or seven membered ring, which optionally contains two to three heteroatoms independently selected from O, S and NR7 with Rl as hydrogen, and Ni is attached to hydrogen.
  • aryl and heteroaryl ring includes up to two conjugated or fused ring systems.
  • Pharmaceutically acceptable salts forming part of this invention are intended to include not limited to salts of the carboxylic acid moiety such as alkali metal salts like Li, Na and K salts; alkaline earth metal salts like Ca and Mg salts; salts of organic bases such as lysine, arginine, guanidine, diethanolamine, choline, trimethamine and the like; ammonium or substituted ammonium salts and aluminum salts.
  • alkali metal salts like Li, Na and K salts
  • alkaline earth metal salts like Ca and Mg salts
  • salts of organic bases such as lysine, arginine, guanidine, diethanolamine, choline, trimethamine and the like
  • ammonium or substituted ammonium salts and aluminum salts such as sodium or substituted ammonium salts and aluminum salts.
  • Salts may be acid addition salts which defines but not limited to sulfates, nitrates, phosphates, perchlorates, borates, hydrohalides, acetates, perhaloacetates, tartrates, maleates, citrates, succinates, palmoates, methanesulfonates, benzoates, salicylates, hydroxynaphthoates, benzensulfonates, ascorbates, glycerophosphates, ketoglutarates and the like.
  • the invention also provides a process for preparation of the compounds as defined above.
  • the invention further provides pharmaceutical composition comprising compounds of the invention in association with a pharmaceutically acceptable carrier, diluent or excepient.
  • the invention also provides a method of treatment of mammals including human beings in disease conditions resulting from glucose intolerance and/or accumulation of free radical in the body cells by administering an effective compound of compounds of the invention to the subject in need thereof.
  • the invention further provides use of the compounds of invention in the manufacture of a medicament useful for treatment of diseases conditions resulting from glucose intolerance and/or accumulation free radical in the body cells.
  • Fig. 1 The results of invivo study for compounds 25 and 27 vis-a-vis the vehicle has also been shown in Fig.l of the drawing. DETAILED DESCRIPTION OF THE INVENTION
  • the assay method is a modified method (as described by Welch et al, 1998) based on spectrophotometric determination of the product formed by penultimate proline cleaving activity of the enzyme.
  • Gly-Pro-pNA Glycine-Proline-p-nitroanilide
  • Assay protocol involves incubation of the enzyme dipeptidyl peptidase IV with the test substance at 30° C for 30 min followed by addition of this reaction mixture to the substrate Gly-Pro-pNA that was equilibrated at 30° C for 2 min.
  • the enzyme cleaves the substrate at penultimate proline and releases p-nitroanilide, the optical density of which is measured at 385 nm.
  • the formation of p-nitroanilide will be reduced in the presence of inhibitor.
  • Optical density is measured for 2 hours for every lOmin using a spectrophotometer and N max is calculated to find the activity of new
  • the activity of molecule is expressed in terms of % inhibition. Atleast three different concentrations were tried out for each of the test substances. The percentage inhibitions for each of the concentrations were plotted and an IC5 0 of the test compound was worked out. The enzyme inhibitory activity of different test compounds were compared based on the IC 50 values.
  • the percentage inhibition %I is calculated using the formula:
  • % I [(1-Vj/vo)]* 100 where v; and v 0 are the V max values with and without the test substance, respectively.
  • Enzyme solution Porcine DPP-IV (Sigma-Aldrich Germany) was used throughout the study. 0.4 mU in 80 ⁇ l of Tris. HC1 buffer was prepared. Fresh solutions were prepared everyday for the assays. Inhibitor solution:
  • the compounds of the present invention were dissolved in their respective vehicles.
  • the rate of change in UV absorbance was measured at 385 nm, with respect to wells containing only 0.5 mM substrate in 45 mM phosphate buffer as blank at every 10 min for 2 hours after adding enzyme-inhibitor mixture to wells containing substrate solution.
  • Glucose levels in the body are tightly controlled by insulin. Many factors contribute to insulin release. Administration of glucose by oral route causes an increase in blood glucose levels as it gets absorbed and this increase in the glucose level is brought down by the release of insulin as it increases glucose uptake in skeletal muscles and adipocytes. Glucose stimulated insulin release is impaired in diabetes. By pretreatment with drug that releases or stimulates insulin release before taking food/glucose, glucose levels can be tightly controlled in diabetics too. Oral glucose tolerance test is one of the laboratory markers to test pre-diabetic or diabetic condition and to evaluate insulin secretogogues and/or releasers.
  • Oral Glucose Tolerance Test (OGTT) (Pospisilik et al, 2002) External jugular vein of overnight fasted nOSTZ rats was cannulated using polyethylene cannula with heparinized (100 IU/ml) saline under ether anesthesia and exteriorized at the back of the neck. After the animal was recovered from the anesthesia, blood sample was drawn as marked as '-5 min' sample and drug formulation (in 0.5% sodium caboxymethyl cellulose, Na-CMC) was administered orally at the volume of 1 ml/kg body weight.
  • OGTT Oral Glucose Tolerance Test
  • blood sample was drawn as '0 min' sample and glucose load at the dose of lg/kg body weight was administered orally. Blood samples were drawn subsequently at 5, 10, 15, 20, 30, 45, 60, 75, 90, 120, 180, 240 and 360 min time interval. Blood glucose is measured using glucometer.
  • non-insulin dependent diabetes mellitus type II
  • OGTT oral glucose tolerance test
  • beta cells of pancreas secrete insulin.
  • glucose intolerance the area under the curve for glucose is found to be higher in diabetics as compared to non-diabetics. This is termed as glucose intolerance and attributed to inability of beta cells to respond to the rise in blood glucose levels.
  • Test solution 900 ⁇ l of DPPH radical solution was added to an eppendorf tube. To it was added lOO ⁇ l of various concentrations of drug solutions in methanol.
  • test compounds listed in the Table 3 above exhibit invitro (antioxidant) free radical scavenging activity. Excessive production of free radicals; reactive oxygen species (ROS) results in oxidative stress . Therefore, these molecules would be very effective in reducing oxidative stress by their ability to trap ROS. Antioxidants (free radicals scavengers) are reported to be effective in the management of various diseases linked with oxidative stress.
  • the novel compounds show Free Radical Scavenging Activity which is useful for (a) Neurodegenerative disorders such as Alzheimer's Disease, Parkinson's Disease, Huntington's Disease, Motor Neuron Disease, Prion Disease etc, (b) Diabetes and Diabetic Vascular Complications, (c) Intestinal Diseases such as Intestinal Ischemia, Radiation Enteritis, Inflammatory Bowel Disease, Gastric and Colorectal Cancers etc., (d) Liver Diseases such as Alcoholic Liver Disease, Chronic Hepatitis C etc., (e) Cancers such as Lung Cancer, Colorectal Cancer, Cervical Cancer, Breast Cancer, Malignant Melanoma etc., (f) Cardiac Diseases such as Atherosclerosis, Myocardial Infarction, Ischemic Stroke, Endotheliai Dysfunction etc., (g) Opthalmic Disorders such as Cataract formation, Macular degeneration etc., (h) HIV Diseases, (i) Respiratory Diseases such as Chronic Obstructive Pulmonary
  • Oral glucose tolerance test is one of the methods to test pre-diabetic or diabetic condition and to evaluate insulin secretagogues and/or releasers.
  • Glucose level in the body is mainly controlled by insulin although many other factors contribute to insulin release.
  • Administration of glucose by oral route will increase the glucose level in the blood, which induces the release of insulin. This glucose stimulated insulin release is impaired in diabetes.
  • drugs that releases or stimulates insulin release before taking food/glucose the rise in glucose level can be controlled. Free radicals along with AGE formation contributes to macroangiopathic
  • diabetes cardiovascular disease
  • microangiopathic neuroopathy, retinopathy, nephropathy
  • test compounds listed in Table-3 exhibit in vitro (antioxidant) free radical scavenging activity.
  • novel compounds show free radical scavenging activity, which would be useful for treatment of diabetes and diabetic vascular complications (DVCs).
  • the DPP-IV inhibitors under study are preferably expected to not only control diabetes, but also to prevent diabetic complications by their antioxidant .actions.
  • the compounds of the invention may be prepared by alternative synthetic routes as per Scheme I, 1A, 2 or 3 as described below: SCHEME-I
  • L-prolinamide (1) is then converted to l-chloroacetyl-2- cyanopyrrolidine of formula (3) in two steps which involves chloroacylation of the amide followed by dehydration [Ref. US pat -6124305 dated 26.09.00, WO- 0034241 dated
  • Step-1 involves the reaction of thiazolidine amide of formula (2) with chloroacetylchloride in presence of a base such as potassium carbonate and an inert organic solvent like tetrahydrofuran at a temperature of from 0 °C to 20 °C for 2.5 to 3 hrs.
  • Step 2 involves the dehydration of 3-chloroacetyl-thiazolidine-4-amide prepared in step-1, with 2- equivalents of trifluroacetic anhydride conducted in presence of an inert organic solvent such as tetrahydrofuran at a temperature preferably at 20 °C.
  • the second major component of the present invention i.e. N-2-substituted - tertbutyl carbazates of formulae (18) and (19), is prepared by the conventional manner.
  • the tert-butyl alkylidine carbazates of formula (17) is prepared by refluxing exane or tetrahydrofuran solution of tert-butyl carbazate (15) with appropriate aldehyde or ketone of formula (1 6) in 1 :1 molar ratio for 2-4 hrs.
  • Ghali N.I et al, J.Org.Chem. 46, 1981, 5413-5414 is prepared by the conventional manner.
  • the tert-butyl alkylidine carbazates of formula (17) is prepared by refluxing exane or tetrahydrofuran solution of tert-butyl carbaz
  • the alkylidine carbazates thus formed in the previous step is reduced to N-2 substituted -tert-butyl carbazates of formula (18) using metal hydrides like sodium borohydride or lithium aluminium hydride, preferably sodium borohydride and Sodium cyanoborohydride.
  • metal hydrides like sodium borohydride or lithium aluminium hydride, preferably sodium borohydride and Sodium cyanoborohydride.
  • the solvent used in the reaction is organic solvent like methanol or tetrahydrofuran at a temperature ranging from 25°C to 70°C for 4 to 20 hrs.
  • the Scheme 1A covers the process wherein nitrogen protected cyclic ketone is used as starting material.
  • the protection is by way of for example Fmoc group.
  • Compound of formula 11 or 12 can be prepared as a method depicted in Scheme- 1 A in which refluxing the solution of nitrogen protected ketone with tert-butyl carbazate (15) (as referred earlier) followed by reduction of schiffs base using metal hydrides like sodium cyano borohydride in presence of catalytic amount of titanium tetrachloride.
  • Deprotection of Boc-group by trifluoroacetic acid or by 4 N-HCl-Dioxane provide final compound as triflate or hydrochloride salt respectively.
  • step (c) deprotection of 3 1 obtained in above step (b) is carried out by using base, preferably morpholine at 10- 40°C for 1- 4 hrs. to obtain compound (4 1 )
  • R and R 6 together form optionally six or seven membered ring optionally containing two or three heteroatoms independently selected from O, S and NR 7 , with Ri is hydrogen, and Ni is attached to hydrogen.
  • R and R 6 together form optionally six or seven membered ring optionally containing two or three heteroatoms independently selected from O, S and NR 7 , with Ri is hydrogen, and Ni is attached to hydrogen.
  • compounds may be prepared by the general methods as depicted in Scheme-2.
  • Piperazine-2-carboxylic acid dihydrochloride (20) is first protected by using usual protecting groups like Boc (tert-butyloxycarbonyl) or CBZ (benzyloxycarbonyl).
  • the protected acid (21) is subjected to coupling with L-prolinamide (1) or (R)-(-)-thiazolidine-4- amide (2) to give the coupled products (23) or (24).
  • DCC dicyclohexylcarbodiimide
  • NOSU N- hydroxysuccinimide
  • DIEA diisopropylethyl amine
  • amide derivatives (36,37) can also be obtained by chlorocarbonylation of tert-butyl- carbazates (18) with trichloromethyl chloroformate (33) in presence of Et 3 N at a low temperature(-5° to 0° C), followed by coupling of the amides (1,2) with the chlorocarbonyl derivative of carbazates (38) in presence of Et 3 N / THF at a temperature ranging from 25° to 60°C for 8-12 hrs.
  • Example-1 3-[l-oxo-2-(l-(l-(2-oxo-2-( 4-sulphonylaminophenyl)aminoethyl) piperidine-4- yl))hydrazine] ethyl-4-cyanothiazolidine, dihydrochloride (Compound no. 27)
  • Step-1 To the stirred solution of 4-piperidone monohydrochloride hydrate (30g, 0.2 mol) and sodium carbonate (22g, 0.207 mol) in 300 ml water, added dropwise solution of 9-
  • Fluorenylmethoxysuccinimide (74g, 0.22 mole) in 300 ml dioxane at 0°C over 30 min period. After 7 hrs. of stirring at room temperature, 1000 ml of chilled water was added under continuous stirring. Separated solid was filtered, washed with water (500ml) and dried at 60°C for 6 hrs. to give 60 gm of 9-Fluorenylmethoxy carbonyl-4-piperidone
  • step-1 Product obtained in step-1 (60gm, 0.20 mol) was refluxed with tert-butyl carbazate (27 gm, 0.204 mol) in methanol (300 ml) for 3 hrs. Reaction mixture was evaporated to dryness, treated with 200 ml diethyl ether and filtered to get schiffs base (white solid). To the stirre solution of obtained solid in 500 ml. methanol, added solution of sodium cyanoborohydride (23g, 0.37 mol) in 100 ml. methanol in portion-wise at 0°C, followed by catalytic amount of titanium tetrachloride (4ml) at 0°C.
  • step-2 Crude product obtained in step-2 (20g, 0.045 mol) was refluxed with chloroacetyl-4- cyano thiazolidine (10.4g, 0.052 mole) in dry tetrahydrofuran (300 ml) in presence of potassium cabonate (7.5g, 0.052 mole) and potassium iodide (0.8g, 0.005 mole) for 24 hrs. Reaction mixture was then filtered, distilled off and purified by column chromatography (eluent: 40% ethylacetate - Hexane) to give 8g of required product (yield: 30%).
  • Step-4
  • step-3 Product obtained in step-3 was stirred in 25 ml. morpholine for 1.5 hrs. Reaction mixture was then poured into 100 ml chilled water and filtered. Filtrate was extracted with dichloromethane. Organic layer was dried, distilled to give a solid (3.5 g, yield: 70%).
  • step - 4 Product obtained in step - 4 (6g, 0.016 mole) was dissolved in 100 ml. tetrahydrafuran and added N-[4-sulphonylaminophenyl] chloroacetamide (4.7 g, 0.019 mole), potassium carbonate (2.8g, 0.02 mole). Reaction mixture was then refluxed for 18 hrs., filtered, evaporated and residue was purified by column chromatography (eluent: ethylacetate : hexane, (70 : 30) 1.8g, Yield: 20%).
  • step-5 Product obtained in step-5 (1.2g, 0.002 mole) was stirred in 4-N-dioxane.HCl (8ml) at room temperature for 3 hrs. To the reaction mixture added 20 ml. methanol and 50 ml diethylether. The separated solid was filtered and washed with diethyl ether and suck dried and finally crude product was purified using methanol-diethylether mixture (1:1) to yielded title compound, 3-[l-oxo-2-(l-(l-(2-oxo-2-( 4-sulphonylaminophenyl) aminoethyl) piperidine-4-yl))hydrazine] ethyl-4-cyanothiazolidine, dihydrochloride
  • Example-2 3-[l-oxo-2-(l-(l-(2-oxo-2-(5-chloropyridin-2-yl)aminoethyl) piperidin-4- yl))hydrazino]ethyl(s)-(+)-4-cyanothiazolidine tris-trifluoroacetate (Compound no. 1)
  • the compounds of the invention can also be prepared by the method of Schemes 2 and 3 as described above.
  • compositions may be prepared with a pharmaceutically effective quantity of compounds of general formula I, individually or in combination. It is common practice to administer the compounds in the form of pharmaceutical dosage forms comprising pharmaceutically acceptable excipient(s) and at least one active ingredient. These dosage forms may be administered by a variety of routes including oral, topical, transdermal, subcutaneous, intramuscular, intravenous, intranasal, pulmonary etc. Administration of the agents according to the instant invention may take place over an extended period of time at a dosage level of, for example, up to about 30 mg/kg.
  • the pharmaceutical composition can be in the range of ' 0.5% to 90% by weight of the compound.
  • Oral formulations may be administered as solid dosage forms for example pellets, powders, ' sachets or discreet units such as tablets or capsules and like.
  • Other orally administered pharmaceutical preparations include monophasic and biphasic liquid dosage forms either in ready to use form or forms suitable for reconstitution such as mixtures, syrups, suspensions or emulsions.
  • the preparations in addition may contain diluents, dispersing agents, buffers, stabilizers, solubilizers, surfactants, preservatives, chelating agents and/ or other pharmaceutical additives as are used.
  • Aqueous or non-aqueous vehicle or their combination may be used and if desired may contain suitable sweetener, flavoring agent or similar substances.
  • a suitable thickening agent or suspending agent or emulsifying agent may be present in addition.
  • the compounds may be administered as such in their pure form unassociated with other additives for example as capsules or sachets. It may also be administered with a vehicle.
  • Pharmaceutical preparations can have a slow, delayed or controlled release of active ingredients as is provided by a matrix or diffusion controlled system.
  • excipients include lactose, cellulose and its derivatives such as microcrystalline cellulose, methylcelluloseose, hydroxy propyl methyl cellulose, ethylcellulose, dicalcium phosphate, mannitol, starch, gelatin, polyvinyl pyrolidone, various gums like acacia, tragacanth, xanthan, alginates & its derivatives, sorbitol, dextrose, xylitol, magnesium stearate, talc, colloidal silicon dioxide, mineral oil, glyceryl mono stearate, glyceryl behenate, sodium starch glycolate, Cross Povidone, crosslinked carboxymethylcellulose, various emulsifiers such as polyethylene glycol, sorbitol, fattyacid esters, lactose, cellulose and its derivatives such as microcrystalline cellulose, methylcelluloseose, hydroxy propyl methyl cellulose, ethylcellulose, dicalcium phosphate
  • a typical tablet can have the following compositions:
  • a tablet formulation may be prepared as per the following compositions.
  • Example - 34 Ingredients Qty. (mg / tablet) Active ingredient* 20.0 mg Microcrystalline Cellulose 200.0 mg Starch 50.0 mg Magnesium Stearate 5.0 mg Talc 2.0 mg *Any one or more of compound Nos. 1-32
  • Example - 35 Ingredients Qty. (mg / tablet)
  • Example 36 Ingredients Qty. (mg / tablet) Active ingredient* 5.0 mg Microcrystalline Cellulose 80.5 mg Starch 8.0 mg. Talc 3.3 mg Magnesium Stearate 1.6 mg Colloidal Silicon-dioxide 1.6 mg *Any one or more of compound Nos.1-32
  • Active ingredient, lactose and starch are screened through 40 # sieve and blended.
  • the blend is then granulated with polyvinyl pyrolidone solution. Resultant mass is screened through number 16 sieve.
  • the granules produced are then dried at 50 - 60 °C and passed through 16-mesh sieve.
  • Sodium starch glycolate, magnesium Stearate and colloidal silicon dioxide are sifted through 60-mesh sieve and blended with the granules.
  • the resultant blend is then compressed into tablets.
  • the above ingredients may be blended into tablets by any other conventional materials.
  • the compounds or their salts or suitable complexes thereof may be present in a sterile vehicle which may be an aqueous or non-aqueous vehicle or a combination thereof.
  • a sterile vehicle which may be an aqueous or non-aqueous vehicle or a combination thereof.
  • vehicles are water, ethyl oleate, oils and derivatives of polyols, glycols and their derivatives. It may contain additives common in injectable preparations like stabilizers, solubilizers, pH modifiers, buffers, antioxidants, cosolvents, complexing agents, tonicity modifiers, etc.
  • Some suitable additives are for example tartrate, citrate or similar buffers, alcohol, sodium chloride, dextrose and high molecular weight polymers.
  • Another alternative is sterile powder reconstitution.
  • the compound may be administered in the form of injection for more than once daily administration, or intravenous infusion/ drip or suitable depot preparation.
  • the active ingredient or its salt is dissolved or dispersed in a sterile vehicle.
  • vehicle may be aqueous or non-aqueous and may contain suitable surfactants, solubilizers, buffers, stabilizers, surfactants, antioxidants, cosolvents, chelating agents, tonicity modifiers etc.
  • excipients commonly used include propylene glycol, polythene glycol, mannitol, sodium chloride, ethyloleate, polyethylene glycol fatty acid esters, polyethylene glycol castor oil, polyethylene glycol sarbitan fatty acid esters, sugar esters, various buffers such as phosphate, succinate, citrate, borate, antioxidants such as sodium metabisulphite etc.
  • An injectable formulation containing the following ingredient may be prepared:
  • Example 37 Ingredients Qty.
  • Active ingredient 1 mg Polythylene glycol 0.1 ml Isotonic Saline / WFI to 1 ml Sodium metabisulphite
  • the recommended formulations are gel, ointment, creams, patches, liniment, lotions, oral rinse, gurgles and toothpaste containing appropriate compounds of the compounds of the general formula I.

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  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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  • Diabetes (AREA)
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Abstract

La présente invention se rapporte à de nouveaux composés hétérocycliques répondant à la formule générale (I), leurs stéréoisomères, leurs sels ou solvates pharmaceutiquement acceptables, formule dans laquelle X, n, k, z, R1, R2, R3, R4, R5 et R6 ont les significations définies dans la description, et trouvant application dans (i) la normalisation des taux élevés de glycémie chez les diabétiques, (ii) le traitement des troubles liés à l'intolérance au glucose, et (iii) la phagocytose des radicaux libres chez les mammifères. La présente invention se rapporte également à une composition pharmaceutiquement acceptable renfermant des composés de ce type, à un procédé de préparation des composés définis ci-dessus, et à un procédé de traitement de mammifères et notamment de l'homme par administration d'une quantité efficace desdits composés à un sujet qui en a besoin. Par ailleurs, l'invention se rapporte à l'application desdits composés à la fabrication d'un médicament utilisable dans le traitement de différents états pathologiques, comme précisé ci-dessus.
EP03751086A 2003-10-06 2003-10-06 Azolidinecarbonitriles et leur application comme inhibiteurs de dpp-iv Withdrawn EP1682540A1 (fr)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/IB2003/004377 WO2005033106A1 (fr) 2003-10-06 2003-10-06 Azolidinecarbonitriles et leur application comme inhibiteurs de dpp-iv

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EP1682540A1 true EP1682540A1 (fr) 2006-07-26

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EP (1) EP1682540A1 (fr)
JP (1) JP2007516154A (fr)
CN (1) CN1839131A (fr)
AU (1) AU2003269307A1 (fr)
BR (1) BR0318533A (fr)
CA (1) CA2534634A1 (fr)
PL (1) PL380189A3 (fr)
WO (1) WO2005033106A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012170702A1 (fr) 2011-06-08 2012-12-13 Arena Pharmaceuticals, Inc. Modulateurs du récepteur gpr119 et traitement de troubles associés à celui-ci

Families Citing this family (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008055945A1 (fr) 2006-11-09 2008-05-15 Probiodrug Ag Dérivés 3-hydr0xy-1,5-dihydr0-pyrr0l-2-one utiles en tant qu' inhibiteurs de la glutaminyl-cyclase dans le traitement des ulcères, du cancer et d'autres maladies
WO2008065141A1 (fr) 2006-11-30 2008-06-05 Probiodrug Ag Nouveaux inhibiteurs de glutaminylcyclase
JP5667440B2 (ja) 2007-04-18 2015-02-12 プロビオドルグ エージー グルタミニルシクラーゼ阻害剤としてのチオ尿素誘導体
MX2012002993A (es) 2009-09-11 2012-04-19 Probiodrug Ag Derivados heterociclicos como inhibidores de ciclasa glutaminilo.
JP6026284B2 (ja) 2010-03-03 2016-11-16 プロビオドルグ エージー グルタミニルシクラーゼの阻害剤
MX2012010470A (es) 2010-03-10 2012-10-09 Probiodrug Ag Inhibidores heterociclicos d ciclasa de glutaminilo (qc, ec .3 2. 5).
US8541596B2 (en) 2010-04-21 2013-09-24 Probiodrug Ag Inhibitors
WO2012123563A1 (fr) 2011-03-16 2012-09-20 Probiodrug Ag Dérivés de benzimidazole en tant qu'inhibiteurs de la glutaminyl cyclase
EP3461819B1 (fr) 2017-09-29 2020-05-27 Probiodrug AG Inhibiteurs de la glutaminyl-cyclase

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Publication number Priority date Publication date Assignee Title
IL111785A0 (en) * 1993-12-03 1995-01-24 Ferring Bv Dp-iv inhibitors and pharmaceutical compositions containing them

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO2005033106A1 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012170702A1 (fr) 2011-06-08 2012-12-13 Arena Pharmaceuticals, Inc. Modulateurs du récepteur gpr119 et traitement de troubles associés à celui-ci

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WO2005033106A1 (fr) 2005-04-14
PL380189A3 (pl) 2007-01-08
JP2007516154A (ja) 2007-06-21
CA2534634A1 (fr) 2005-04-14
BR0318533A (pt) 2006-09-12
CN1839131A (zh) 2006-09-27
AU2003269307A1 (en) 2005-04-21

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