MXPA06002950A - Azolidinecarbonitriles and their use as dpp-iv inhibitors - Google Patents
Azolidinecarbonitriles and their use as dpp-iv inhibitorsInfo
- Publication number
- MXPA06002950A MXPA06002950A MXPA/A/2006/002950A MXPA06002950A MXPA06002950A MX PA06002950 A MXPA06002950 A MX PA06002950A MX PA06002950 A MXPA06002950 A MX PA06002950A MX PA06002950 A MXPA06002950 A MX PA06002950A
- Authority
- MX
- Mexico
- Prior art keywords
- oxo
- ethyl
- piperidin
- hydrazino
- aminoethyl
- Prior art date
Links
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Abstract
The invention discloses a novel heterocyclic compounds that falls within f the ambit of general formula (I), its stereoisomers, pharmaceutically acceptable salts or solvates wherein X, n,k,z, R1, R2, R3, R4, R5 and R6 are as defined in the specification that are useful in (i) normalizing elevated blood pglucose levels in diabetes, (ii) treating disorders related to glucose intolerance and (iii) for scavenging free radicals of mammals. The invention also discloses pharmaceutically acceptable composition comprising these compounds, method for preparation of the compounds as defined bove and method of treating mammals including human beings by administering an effective amount of said compounds to a subject in need thereof. The invention further discloses use of these compounds in the manufacture of a medicament useful for treatment of different disease conditions as stated above.
Description
AZOLIDINCARBON1TRILOS AND ITS USE AS INHIBITORS DPP-1V
FIELD OF THE INVENTION
The present invention relates to novel heterocyclic compounds useful for the normalization of elevated blood glucose levels in diabetics and the treatment of disorders related to glucose intolerance. These compounds inhibit the DPP-IV enzyme, which degrades the GLP-1 peptide, providing improved levels of active GLP-1, a peptide that normalizes elevated blood glucose levels. These compounds are useful for controlling the level of glucose in the blood in diabetic patients and therefore delay the onset of vascular complications in diabetic patients and also the transition of type II diabetes in impaired glucose tolerance patients. These compounds are also useful in the treatment of disorders related to glucose intolerance such as Cushing's syndrome, hyperthyroidism, obesity, hyperglucagonemia, ulcer-type diseases, HIV infection, disorders related to increased gastric emptying, acid secretion and hunger, autoimmune disorders of multiple sclerosis type, rheumatoid arthritis, and Grave's disease (Sedo and Kraml, 1994). These compounds also exhibit free radical scavenging activity which is useful in the treatment of various disease conditions caused by the accumulation of free radicals in the cells of the body.
DESCRIPTION OF THE RELATED TECHNIQUE
References in the Literature Augustyns K. and others. The unique propertiesof Dipeptidyl-peptidase IV (DPP-IV / CD26) a nd t he t herapeutic p otential or D PP-IV i nhibitors. C urrent M edical C hemistry
1999; 6: 311-327 Bork Balkan and Sue Li: Portal GLP-1 administration rats augments the insulin response to glucose vianeuronal mechanisms. Am J Physiol regulatory Comp
Physiol 279: R1449-R1454, 2000. Balkan B, KwasnikL, Miserendino Rep, Hoist JJ, LiX: Inhibition of dipeptidyl peptidase IV with NVP-DPP728 plasma plasma increases GLP- (7-36 amide) and oral glucose tolerance in obese zucker rats Diabetology 42: 1324-1331, 1999. Brubaker P. L. et al., Am. J. Physio. 1997; 272: E1050. Browne SE and others. Brain Pathology (1999) 9; 147-163 Carolyn F D, Thomas EH, Jens JH: Dipeptidyl peptidase IV inhibition potentiates the insulinotropic effect of glucagon-like peptide in the anaesthetized pig. Diabetes
47: 764-769, 1998. Doyle ME and Egan JM: Glucagon-like peptide-1. Glucagon-like peptide 1. Recent Prog Horm Res 56: 377-399, 2001. Drucker, D. J. et al. Diabetes 1998; 47: 159. Ganget. and others, Diabetes, Vol. 48, December, 1999; 2270-2276 Harold E Lebovitz, Pathogenesis of type-2 Diabetes; Drug Benefit Trends 12 (supp A): 8-16, 2000 Harper E.J. The 24th Annual WALTHAM (r) / OSU SYMPOSIUM. 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.
Ishii et al. Journal of Gastroenterology and Hepatology (1997) 12 (Suppl.), S272- S282. Korom S. and others. Transplantation 1997; 63: 1495. MacNee W, Rahman I, Trends Mol Med 2001 Feb; 7 (2): 55-62 Marks V, Dawson A. Rapid stick method for determining blood glucose concentration. Br Med J 1: 293, 1965. Maxwellet. Al, Br J Clin Pharmacol 1997; 44: 307-317. Michael A Nauck: Is glucagons-like peptide 1 anincretin hormone. Diabetologia, 42: 373-379, 1999. MichaelBerelowitz and lone A Kourides: Diabetes mellitus secondary to other endocrine disorders. In: Diabetes Mellitus: A fundamental and clinical text ,. Second edition: Lippincott Williams & Wiikins, pg. 592-593, 2000. Munch G et al., J Neural Transm (1998) 105: 439-461 Nguyen C et al. J Med Chem 1998; 41: 2100 Pederson R. A, et al., Diabetes 1998; 47: 1253. Porta B, Giroix MH, Serrated P, Movassat J, Bailbe D, Kergoat M. The neonatally streptozotocin-induced (n-STZ) diabetic rats, a family of N1 DDM models. In: Animal Models of Diabetes, a Primer. Eds: Sima AAF, Shafrir E. Harwood Academic Publishers, Amesterdam, The Netherlands, 247-272, 2001. Pospisilik JA, Stafford SO, Demuth HU, Brownsey R, Parldlouse W, Finegood DT,
Mclntosh CHS, Pederson RA. Long-term treatment with the dipeptidyl peptidase IV inhibitor P32 / 98 with constant improvements in glucose tolerance, insulin sensitivity, hyperinsulinemia, and (3-cell glucose responsiveness in VDF (alpha) Zucker rats, Diabetes 51: 943-950, 2002.
Qualmann C and others Insulinotropic actions of intravenous glucagon-like peptide-1 in the fasting state in healthy volunteers. Acta Diabetologica 1995; 32: 13-16. Raymond AP, Heather AW, Dagmar S, Robert PP, Christopher HSM, Hans-UIrich D: Improved glucose tolerance in zucker fatty rats by oral administration of the dipeptidyl peptidase-IV inhibitor Isoleucine thiazolidide. Diabetes 47: 1253-1258, 1998. Robert PP, Hans-UIrich D, Fred Rep, Jorn S, Heather AW, Francis L, Christopher HSM, Raymond AP: Improved glucose tolerance in rats treated with dipeptidyl peptidase- IV (CD26) inhibitorlIe -Thiazolidide. Metabolism 48: 385-389, 1999. Ronald A DeLellis: The Endocrine system. In: Robbins pathologic basis of disease, fourth edition, W. B. Saunders international edition, pg. 1254-1255, 1989. Ronald T Jung: Obesity and nutritional factors in the pathogenesis of non-insulin dependent diabetes mellitus. In: Textbook of diabetes, second edition: Blackweil science, pg. 19. 13-19. 14, 1997. Rosenfeld ME et al., Arterioscler Thromb Vasc Biol 1998 Sep, 18 (9): 1506-13. Sedo A and Kraml J: Dipeptidylpeptidase IV in cell proliferation and differentiation. Shorn lek, 95 (4): 285-288, 1994. Siegel EG, Scharf, Gallwitz B, Mentlein Rep, Morys-Wortmann C, Folsch UR, Schmidt WE: Comparison of the effect of n ative glucagon-like peptide 1 and dipeptidyl peptidase IV-resistant analogues on insulin relay from rat pancreatic islets. Eur J Clin Invest 29 (7): 610-614, 1999. Smith MA, Biochim Biophys Acta 2000 July 26; 1502 (1): 139-144. Tina Vilsboll, Thure Krarup, Carolyn F Deacon, Sten Madsbad, Jens J Hoist: Reduced postprandial concentrations of intact biologically active glucagon-like peptide 1 in type 2 diabetic patients. Diabetes 50: 609: 13, 2001.
Tiruppathi.O, and others., Am.J. Physio. 1993; 265: G81-89. ZallDa G. et al., J physiol Biochem, 56 (1) 2000; 57-64. Diabetes mellitus is a group of clinically and genetically heterogeneous disorders characterized by abnormally high levels of glucose in the blood. Hyperglycemia is due to the deficiency of insulin secretion or the resistance of the cells of the body to the action of insulin, or to the combination of these. Chronic hyperglycemia is a cause of a heavy burden of late payment and premature mortality of diabetic complications. These long-term complications can be delayed through improved glycemic control. None of the medications currently used is capable of reversing the failure of the ß cell function and the reduction in glucose peak after meals represents an important objective for therapeutic strategies. Although pancreatic insulin secretion is predominantly controlled by blood glucose levels, incretins, GLP-1 peptide-type derived from the enteroinsular axis has an effect on insulin secretion and consequently on the level of glucose in the blood . It is released from the intestines in response to ingested nutrients, which act on the pancreas to enhance insulin secretion induced by glucose. GLP-1 has beneficial effects in diabetic patients in the normalization of blood glucose levels (Hoist J and Deacon C, 1998). GLP-1 has multifaceted actions, which include the expression of the insulin gene, trophic effects on β-cells, inhibition of glucagon secretion, promotion of satiety, and deceleration of gastric emptying. Due to the glucose dependence of the peptide and the glucogonostatic actions, the effect of decreasing glucose 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 hyperinsulinemia followed by progressive beta cell deterioration resulting in decreased insulin secretion and hyperglycemia. Hyperglycemia itself causes an additional inhibition of insulin secretion and more insulin resistance (glucose toxicity), which also accentuates hyperglycemia (Augustyns K. et al., The unique properties of Dipeptidyl peptidase I V (DPP-IV / CD26) and the therapeutic potential of DPP-IV inhibitors.; 6: 311-327) Most of the therapies used in the end finally fail to control the blood sugar level after 3-5 years. This is due to progressive β-cell failure in the course of the disease and insulin is eventually required in most type 2 diabetic patients. The detrimental glucose tolerance and the detrimental fasting glucose are present in a great population. These abnormalities progress to a large extent of apparent diabetics. No therapy has been approved for the prevention or delay of type 2 diabetes in these patients. Inhibitors of dipeptidyl peptidase IV (DPP-IV) are directed towards a large extent of inadequacy of currently available therapies. These activate not only ß cell dysfunction but also insulin resistance and increased hepatic glucose output through the liver. In this way, he has a more holistic approach towards the treatment of type II diabetes. In addition, through the stabilization / reversal of progressive β cell dysfunction, it could prevent the progression of the disease or delay the occurrence of apparent 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 anti-hyperglycemic drugs currently used activate either insulin resistance or ß cell dysfunction. Therefore, there is a need to conduct both pathologies together. The transcription factor of the central dom PDX-1, is essential for the early development of the pancreas and the menance of the β cell phenotype. It is known that PDX-1 regulates insulin, GLUT2 and the islet amyloid precursor. Under conditions of sustd hyperglycemia, such as in a diabetic state, there is down-regulation of PDX-1 expression and an increase in insulin secretion (Doyle and Egan, 2001). GLP-1 induces the differentiation of positive pancreatic epithelial cells within cells that secrete insulin. GLP-1 stimulates the expression of the transcription factor PDX-1 while stimulating the β cell neogenesis and therefore can be an effective treatment for diabetes. GLP-1 and a long-acting GLP-1 analogue, exendin-4, both stimulate β cell replication and neogenesis, resulting in an increase in β-cell mass and improved glucose tolerance in the cell. rat model of partial pancreatectomy of type 2 diabetes (Gang et al. 1999). GLP-17-36 is one of the substrates for circulation of dipeptidyl peptidase IV exopeptidase (EC 3.4.14.5), a post-proline cleavage enzyme with specificity to remove Xaa-Pro or Xaa-Ala dipeptides from the N-terminus of the polypeptides and proteins. DPP-IV is widely distributed in liver, intestine, and placental tissues, hepatocytes, pitelial d cells, pancreatic duct, central nervous system, peripheral nervous system, blood vessel endothelial cells (Rolf, 1999), and is found as a soluble enzyme in blood plasma. About 50% of the GLP-1736 amide released from L s cells is active in the capillary bed surrounding these cells by DPP-IV. In addition, a single pass through the liver inactivates the large fraction of the remng active GLP-1 (> 40%) (Bork and Xue, 2000). In this way two processes together with inactivation in the circulatory system and in other organs can be expected to inactivate or remove most of the GLP-1 released from the duodenum and intestine before the peptide can reach the pancreas in an active form. Active hydrolysis of GLP-1736 through DPP-IV produces the truncated oligopeptide GLP-1936 and the dipeptide His-Ala. This N-terminally truncated form is not insulinotropic and acts as an antagonist at the GLP-1 receptor. GLP-1 is rapidly degraded in the circulation, which results in elimination that exceeds cardiac output and an apparent half-life of 1-1.5 minutes. The truncated metabolite is removed more slowly, with half lives of 4-5 minutes for GLP-19-36. It has been speculated that DPP-IV-mediated hydrolysis is the main mechanism for the inactivation of this hormone in vivo (Tina et al., 2001). Due to the rapid degradation, the effects of individual injections of GLP-1 are of short duration and for a complete demonstration of their anti-diabetogenic effects, continuous intravenous infusion is required. Accordingly, it is proposed that the inhibition of DPP-IV, which elevates the levels of active GLP-1 and reduces the level of the antagonistic metabolite, may be useful for treating impaired glucose tolerance and perhaps the transition to type 2 diabetes. (Siegel et al. (1999) reported that GLP-1 analogs resistant to degradation through DPP-IV could help to realize the potential of GLP-1 in diabetes therapy.The DPP-IV inhibitor, thiazolide isoleucine (P-32/98), completely inhibits the formation of GLP-19-36, an antagonist in the GLP-1 receptor, when incubated with 30 mM / L of G LP-1g-36 and serum for 21 hours. inhibition of improved insulin secretion with circulating DPP-IV and improved glucose tolerance in response to the challenge of oral glucose in obese and thin fat rats (fa / fa) (Raymond et al., 1998). improved glucose tolerance in zucker fatty rats (Robert et al., 1999) It is reported that an NVP-DPP-728 DPP-IV inhibitor, i.e. 1 - [- 2-. { (5- cyanopyridin-2-yl) amino} ethylamino] acetyl-2-cyano- (S) -pyrrolidine inhibits DPP-IV activity and glucose tolerance, through the increased effects of endogenous GLP-1. The improvement in food homeostasis during the inhibition of DPP-IV through this molecule suggests that the inhibition of this enzyme is a promising target to treat type 2 diabetes (Balkan et al., 2000). This molecule also showed an enhancement of the insulinotropic effects of GLP-1 in an anesthetized pig (Carolyn et al., 1998). These data support a therapeutic method for the manipulation of plasma incretin activity drugs through the decrease of glucose levels in
NIDDM and other disorders involving glucose intolerance. Dipeptidyl Peptidase IV (DPP-IV) is a proline-specific protease and is involved in the cleavage of peptide bonds before or after a proline residue. This plays an important role in regulating the lifespan of active biological peptides such as growth hormone releasing factor (GRF), peptide I type
Glucagon (GLP-I), Gastric Inhibitor Polypeptide (GIP), Glucagon type II peptide (GLP-II), β-Casomorphin, morficeptin, human Neuropeptide Y. DPP-IV of Human YY Peptide (Augustyns K. et al., 1999) is present on the surface of a subset of T cells (lymphocytes) and has been recognized as CD26 antigen. Dipeptidyl peptidase-IV (DPP-IV) is a serine protease, which divides N-terminal dipeptides from a peptide chain preferably containing a proline residue in the penultimate position. DPP-IV is responsible for the activation of Glucagon-like peptide-1 (GLP-1). More particularly, DPP-IV divides the amino-terminal dipeptide of Amino-terminal GLP-1, generating a GLP-1 receptor antagonist, and therefore shortens the physiological response to GLP-1. Since the half-life for the division of DPP-IV is much shorter than the half-life for the removal of GLP-1 from the circulation, a significant increase in the bioactivity of GLP-1 is anticipated (from 5 to 10 times) from the inhibition of DPP-IV. Since GLP-1 is a major stimulator of pancreatic insulin secretion and has direct beneficial effects on glucose elimination, inhibition of DPP-IV appears to be an attractive method to treat non-insulin dependent diabetes mellitus (NIDDM). GLP-1 has multifaceted actions, which include the stimulation of g expression in nsulin, trophic effects on cells, inhibition of glucagon secretion, promotion of satiety, and deceleration of gastric emptying, all of which contribute to the normalization of elevated blood glucose levels (Hoist and Deacon, 1998). Because of the glucose dependency of the peptide and glucagonostatic actions, the effect of the glucose decrease is self-limiting, and the hormone, therefore, does not cause hypoglycemia regardless of the dose. The exact biological functions of DPP-IV / CD26 are still under investigation, but there is considerable evidence of the therapeutic potential of DPP-IV inhibitors. Although a number of DPP-IV inhibitors have been described, they all have limitations related to potency, stability, or toxicity. Accordingly, there is a great need for novel DPP-IV inhibitors, which do not suffer from the aforementioned limitations.
Type II Diabetes Mellitus: DPP-IV is involved in the degradation of GIP and GLP-11. GIP and GLP-1 are considered to be the most important insulin release hormones (incretins) that comprise the enteroinsular axis. The term "enteroinsular" refers to the signaling pathways between the intestines and the pancreatic islets that amplify the insulin response to absorbed nutrients. Inhibition of circulating DPP-IV with improved insulin secretion of orally linked thiazolidine administered [DPP-IV inhibitor] and improved glucose tolerance in response to an oral glucose challenge in obese and fatty Zucker rats. The improved incretin response was higher in obese than in fatty animals, with a more profound improvement in glucose tolerance (Pederson R.A, 1998). This was attributed to the interruption of the DPP-IV inactivation of GIP and GLP-I, resulting in the amplification of the enteroinsular axis. DPP-IV inhibitors would have very little effect on subjects with normal blood glucose levels regardless of dose, because their actions are glucose dependent (Qualmann C et al., 1995).
Hyperthyroidism and glucose intolerance In patients with pre-existing type I or type II diabetes mellitus, the presence of hyperthyroidism makes the administration of glucose in the blood more difficult. The influences of the thyroid hormone on insulin secretion and cell metabolism have been implicated on the basis of in vitro and animal studies. In rats, the treatment of thyroxine and triodothyronine inhibits delayed phase of glucose-mediated secretion of insulin-triodothyronine being five times more potent than thyroxine. In the hyperthyroid states, the gluconeogenic precursor (lactate and glycerol) are present in an increased concentration in plasma. In rats, the increased activity of mitochondrial glycerol, phosphate oxidase increases the capacity of gluconeogenesis of glycerol. It has also been shown in rats and pigs that hyperthyroidism leads to an increase in the useless glucose cycle, which could contribute to hyperglycemia. The increased activity of several enzymes that could be involved in the increase in glucocogenesis has been seen in response to the thyroid hormone, including glucokinase, pyruvate carboxylase, carboxyphangase phospho-enolpyruvate, and glucose-6-phosphatase. Studies in hyperthyroid patients reported an obstacle in insulin suppression of hepatic glucose production. A recent study has also demonstrated the inability to increase the insulin response appropriately to hyperglycemia and increased proinsulin levels, both in fasting and is replenished at a meal (Michael Berelowitz and Lone A Kourides, 2000). Glucose intolerance as a result of hyperthyroidism can be better managed by improving the levels of GLP-1, a glucose-dependent insulinotrophic agent.
Obesity and glucose intolerance Obesity has been related to insulin resistance and hyperinsulinemia. Visceral obesity is associated with specific changes in the skeletal muscle morphology that correlates with insulin resistance and hyperinsulinemia, mainly a reduction in capillary density and an increase in the proportion of "white" or "glycolytic" fibers that are on less sensitive to insulin than red fibers (glycolytic). TNF-alpha is secreted through adipose tissue and its circulation levels are parallel to the total body fat mass. The levels of non-esterified fatty acids in circulation (NEFA) are increased in obese subjects, especially those with visceral obesity. In the liver, NEFA is oxidized to CoA acetyl, which stimulates the pyruvate carboxylase and consequently the gluconeogenic glucose production of pyruvate; the production of hepatic glucose consequently increases. The high level of NEFA can also inhibit glucose utilization by skeletal muscle. Increased acetyl CoA levels inhibit pyruvate dehydrogenase, thereby decreasing glucose oxidation. The combination of increased hepatic glucose output and reduced peripheral absorption effectively antagonizes and eventually leads to hyperglycemia (Ronald T Jung, 1997). Glucose intolerance as a result of the above conditions can be better managed through the elevation of GLP-1 levels (as a result of inhibition of DPP-IV).
Cushing's Syndrome and Glucose Level Cushing's syndrome represents a different constellation of clinical features associated with prolonged overproduction of impaired glucose tolerance, visible diabetes (by approximately 20%), loss of libido and impotence.
Some of these abnormalities, such as obesity, that disrupt glucose metabolism are directly attributable to the increase in glucocorticoids. These glucocorticoids stimulate luconeogenesis in patients with diabetes. Also, the increase in the use of amino acid by the liver and kidney and the increase in the activity of the enzymes required for gluconeogenesis and can lead to hyperglycemia (Ronald A DeLellius,
1989). The metabolism of glucose under the above conditions can be better managed through treatment with DPP-IV inhibitors.
The role of DPP-IV in HIV infection Prevention and Treatment of HIV infection The role of CD26 in HIV infections is not yet complete, but it seems to be important. It is reported that some DPP-IV inhibitors inhibit HIV infection such as pyrrolidin-2-nitriles and an irreversible cyclopeptide inhibitor (Nguyen G et al., 1998). DPP-IV has been originally described as being a marker of activated T lymphocytes and lately the molecular identity of DPP-IV / CD26 has proven that CD26 / DPP-IV serves as an essential cofactor for the entry of HIV into CD cells and that its Enzyme activity is an important condition for this function (Sedo A and Kraml J, 1994). Therefore inhibition of DPP-IV would prove to be useful in the administration of HIV infection.
Immunosuppressant It has been shown that DPP-IV / CD26 plays an important role in the immune system through a number of possible mechanisms. The exact mechanism is still explained, but some examples were reported where DPP-IV inhibitors are useful immunosuppressants in vivo. A diphenyl dipeptide phosphonate ester was able to abrogate acute rejection and prolonged allograft cardiac survival (Korom S. et al., 1997).
Role of DPP-IV inhibitors in ulcers, hyperglucanomia, gastric emptying and hunger. DPP-IV inhibitors increase the level of GLP-1. GLP-1 has mutifacetic actions, which include the stimulation of insulin gene expression, the inhibition of glucagon secretion, the promotion of satiety, the inhibition of food consumption and deceleration of gastric emptying (Hoist JJ and Deacon CF, 1998).
GLP-1 also reduces the secretion of gastric acid (Michael A Nauck, 1999). The increase in the secretion of gastric acid is one of the main reasons for duodenal ulcers. By inhibiting the secretion of gastric acid, GLP-1 and consequently DPP-IV inhibitors can prove that they are useful for the treatment of ulcers or can be used in combination with other anti-ulcer agents.
Diarrhea DPP-IV is involved in the metabolic processing of morphineceptin. Coadministration of a DPP-IV and the morphiceptine peptide opiate could be used in the case of diarrhea, such as the experiment with DPP-IV-deficient rats shown (Tiruppathi, C, et al., Am. J. Physio, 1993).
Regeneration of the mucosa in a patient with Intestinal Disease The hydrolysis of DPP-IV of GLP-2 is responsible for its inactivation. GLP-2 has recently shown that it displays the activity of intestinal growth factor in rodents, increasing the possibility that GLP-2 may be therapeutically useful for the improvement of mucosal regeneration in patients with intestinal disease (Drucker, DJ and others , Diabetes 1998; 47: 159). The use of [Gly2] GLP-2, resistant to the hydrolysis of DPP-IV, increases the weight of the small intestine in mice, predominantly due to a significant increase in hair height (Brubaker PL et al., Am. J. Physio 1997).
Growth Hormone Deficiency Since GRF is also degraded by DPP-IV, the use of a DPP-IV inhibitor along with GRF may be useful in treating children with growth hormone deficiency (Augustyns K. et al., 1999) .
Neurological and Neurophysiological Disorders The administration of a suitable DPP-IV inhibitor leads as a casual consequence to a reduced degradation of neuropeptide Y (NPY) in the brain of mammals. Said treatment will result in a reduction or delay in the reduction of the NPY neuron concentration (1-36) functionally active, the NPY activity is prolonged therefore results among other things in the activity of the functionally active NPY Yl receptor, therefore facilitating the antidepressant, anxiolytic, analgesic, antihypertensive and other neurological effects (WO 02/34243 dated May 2, 2002 through PROBIODRUG AG).
Cancers and Tumors DPP-IV is able to bind extracellular matrix proteins as a cell adhesion molecule. This has been interpreted from the observation that DPP-IV inhibitors interfere in vitro with the initial distribution of rat hepatocytes over a matrix consisting of fibronectin and collagen. In this way the inhibitors
DPP-IV could also be useful for the prevention / treatment of cancer metastasis and tumor colonization (WO 03/002595 dated January 9, 2003 through PROBIODRUG AG).
Free Radical Cleansing Activity It has been reported that compounds exhibiting free radical cleansing activity are useful in the treatment of Neurodegenerative disorders such as
Alzheimer's disease, Parkinson's disease, Huntington's disease,
Motor Neuron Disease, Prion Disease, etc., (b) Diabetic Diabetes and Complications, (c) Intestinal Diseases such as Intestinal Ischemia, Radiation Enteritis, Inflammatory Spleen Disease, Gastric and Colorectal Cancers, etc., (d) Liver Diseases such as Liver Disease of Alcoholic, Chronic Hepatitis C, (e) Cancers such as Colorectal Cancer, Cervical Cancer, Breast Cancer, Malignant Melanoma, etc., (f) Cardiac Diseases, such as Atherosclerosis , Myocardial Infarction, Ischemic Shock, Endothelial Dysfunction,
(g) Ophthalmic Disorders such as Cataract formation, Macular degeneration, (h) HIV Diseases, (i) Respiratory Diseases, such as Chronic Obstructive Pulmonary Diseases, Asthma, etc., (j) Kidney Diseases such as Glomerulonephritis, Acute Renal Failure, etc. Neurodegenerative disorders such as Alzheimer's disease (A.D.), Parkinson's disease (P.D.), Huntington's disease (H.D.), motor neuron disease (M.N.D), Prion disease. When people age, their antioxidant levels decrease and these low levels are directly linked to the many diseases associated with aging, such as Alzheimer's and Parkinson's. One of the main hypotheses is that ROS-induced oxidative stress damages the essential components of neurons, ultimately resulting in neuronal death. Oxidation stress is involved in several divergent events that lead to neuronal damage, including an increase in membrane stiffness, breakdown in DNA structure, and deterioration in glucose activity. Several potential sources of severe stress oxidation in different neurodegenerative disorders have been well identified (Munch G, et al., 1998). In mitochondrial dysfunction A.D., processes mediated by amyloid beta; Transition metal accumulation and genetic factors are responsible for redox imbalance (oxidation-reduction) (Smith MA, et al., 2000).
Point mutations in Superoxide Dismutase enzymes are known - in the familiar form of MND. Alterations in the metabolism of neuronal energy have been implicated as a pathogenic mechanism for H.D. (Browne SE, and others, 1999).
Diabetes and Diabetic Vascular Complications (DVCs) The cause of oxidative stress in diabetes is still not well understood but is thought to be due to mitochondrial dysfunction, inhibition of the direct enzyme, through hyperglycemia, glucose auto-oxidation, and activation of the phosphate (NADPH) -oxidase of the nicotinamide adenine dinucleotide. Stress by oxidation in diabetes is also increased due to weakened defenses due to reduced endogenous antioxidants. The oxidation stress is self-evident as the high concentrations of lipid peroxidation products, erythrocyte fragility, and decreases in the antioxidant enzyme systems (CAT, G SH Px, SOD). Recent studies have also shown a positive correlation between blood glucose concentration and lymphocyte DNA damage induced by oxidants (E.J. Harper The
24th Annual WALTHAM® / OSU SYMPOSIUM). ROS is generated during the oxidation of glucose and the formation of advanced glycation end products (AGE). Evidence has accumulated indicating that ROS generation plays an important role in the development of DVCsI. Many biochemical trajectories associated with hyperglycemia such as glycosylation, auto oxidation of glucose, and the trajectory of the polyol can increase the production of free radicals. Hyperglycemia in diabetic patients leads to an excess of auto oxidation of glucose, therefore, molecular oxygen and the performance of oxidation intermediates are reduced such as peroxide ions (O2"), hydroxyl radicals (" OH) , and hydrogen peroxide (H2O2). Free radicals accelerate the formation of advanced glycosylation end products (AGE), due to fragmentation and changes in conformation that occur during glycosylation and glucose oxidation have been demonstrating that they are dependent on free radicals. AGEs in turn supply more free radicals; this process is referred to as glycosylation of oxidation or glycooxidation. These free radicals damage vascular relaxation through the inactivation or extinction of nitric oxide (NO) and also adversely affect the function of the endothelium. The evidence also suggests that the Maillard reaction acts as an amplifier of oxidative damage in aging and diabetes.
Intestinal Diseases Oxidation stress is a major cause of tissue damage that occurs in inflammation and ischemia. Intestinal ischemia, radiation enteritis, inflammatory spleen disease, and promotion of gastric and colorectal cancers are some of the gastrointestinal conditions where oxidative stress is involved in the pathogenesis.
Liver diseases
Alcoholic Liver Disease. Ethanol induces an increase in lipid peroxidation either through ROS enhancement or by decreasing the level of endogenous antioxidants. Ethanol also induces a 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 several studies (Ishii H, et al., 1997).
Chronic Hepatitis C C-enhanced oxidation stress initiates a cascade of fibrogenesis in the liver of patients with chronic hepatitis C. Evidence becomes important when the support of a stress path by oxidation (for example, stress by oxidation, induction of c-myb, activation of skeletal cells, and expression of the collagen gene) is stimulated through ROS.
Cancers Damage due to DNA oxidation is a result of the interaction of DNA with ROS, in particular the hydroxyl radical. Hydroxyl radicals produce multiple modifications in DNA. The attack of oxidation through the OH radical in the deoxyribose portion leads to the release of free bases of DNA, which generates breaks in the chain structure with several sugar modifications and simple abasic sites (AP). ROS also interacts with and modifies cellular protein, lipid and DNA, which results in a function of the altered target cell. Accumulation of damage by oxidation has been implicated in both acute and chronic cell damage including possible involvement in the formation of cancer. The damage by acute oxidation can produce the death of the selective cell and a compensatory increase in the proliferation of the cell. This stimulus may result in the formation of freshly initiated pre-neoplastic cells and / or improve the selective clonal expansion of latent initiated pre-neoplastic cells. Similarly, damage by acute sublethal oxidation can cause damaging DNA damage and result in the formation of new mutations and, potentially, new cells initiated. ROS, therefore, can have multiple effects in the stage of initiation of carcinogenesis through the mediation of the activation of the carcinogen, which causes DNA damage, and interferes with the repair of DNA damage.
The benefits of various antioxidants in the prevention or treatment of the following cancers have been extensively studied. 1) Lung cancer 2) Colorectal cancer 3) Cervical cancer 4) Breast cancer 5) Malignant melanoma.
Oxidation Stress in Heart Disease High lifetime levels of antioxidant nutrients are supposed to protect against the development of heart disease. The high doses of antioxidants in the month following the acute heart attack have shown that they significantly reduce the number of deaths, as well as the extent of the cardiac year in non-fatal cases. It is currently believed that the increase in oxidative stress is involved in the pathophysiology of endothelial dysfunction that accompanies a number of cardiovascular risk factors including hypercholesterolemia, hypertension and cigarette smoking. It also plays a fundamental role in the evolution of clinical conditions such as atherosclerosis and heart failure. Oxidative stress can activate cascades of activated redox-sensitive kinase and transcription factors such as NFKB and AP-1, with resultant increases in the expression of factors associated with an inflammatory response and cell proliferation. There are three enzyme systems that produce reactive oxygen species in the vascular wall: NADH / NADPH oxidase, xanthine oxidoreductase, and endothelial nitric oxide synthase (Zalba G. et al., 2000, Rosenfeld ME, 1998).
Atherogenesis is related to the result of the interactions between the multiple stimuli. Endothelial dysfunction plays a key role in the development of atherosclerosis. Elevated homocysteine concentrations are associated with the rapid onset of endothelial dysfunction, which is another mechanism through which increased oxidative stress contributes to atherosclerosis. The oxidation of low density lipoprotein plays an important role in several steps in atherogenesis. Oxidation stress also activates NFKB, which induces the expression of genes that control cytokine expression and leukocyte adhesion to the vascular wall (Maxwell, et al., 1997). Studies in animals have provided evidence through the suggestion that free radicals can promote thrombosis, directly damage vascular cells and other tissues, and interfere with vasomotor regulation with the clinical sequelae of myocardial infarction and ischemic shock. In tissues where the oxygen supply is consumed after ischemia, as in myocardial ischemia, the enzyme xanthine oxidase is changed to a form that has the potential to reduce oxygen in superoxides. In the readmission of oxygen, for example, through reperfusion, there is a burst of generation of free radicals. ROS is formed at an accelerated rate in the post-ischemic myocardium. In this way the biochemical damage due to free radicals contributes to the ischemic damage. Stress by oxidation also seems to be one of the mechanisms that can produce defects in the membrane and result in an overload of intracellular calcium, and cardiac contractile dysfunction in the concussed myocardium.
Macular Degeneration and Cataracts Oxidative damage to eye lenses that increases with age has a major contribution to the formation of cataracts. Macular degeneration has also been recognized as a consequence of oxidative damage.
HIV disease The disruption of the antioxidant defense system has been observed in several tissues in patients with HIV. Stress by oxidation may contribute to several aspects of the pathogenesis of HIV disease such as viral replication, the inflammatory response, and decreased proliferation of the immune cell, loss of immune function, apoptosis, chronic weight loss. Antioxidants may offer a promising treatment for patients with HIV.
Chronic Obstructive Pulmonary Diseases (COPD) Alterations in alveolar and glutathione lung metabolism are widely recognized as a central feature of many inflammatory lung diseases including COPD. These changes are a result of the alteration in the expression of the gamma-glutamyl cysteine synthase gene (Gamma-GCS), the enzyme of limited speed in the synthesis of glutathione. Oxidation stress is implicated in the pathogenesis of COPD, as it results in the inactivation of anti-proteinases, air space epithelial damage, mucus hypersecretion, increased influx of neutrophils into the lungs, transcription of the activation factor and expression of the gene of pro-inflammatory mediators (MacNee W, et al., 2001).
Renal Disease ROS has 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 completely defined, a typical feature is an increase in the number of inflammatory cells in the lung.
These cells generate ROS, which is involved in the pathophysiology of asthma, including smooth muscle contraction of the airways, increased reactivity of the airways, and increased vascular permeability.
Effect of antioxidant status on immune function The immune system is particularly sensitive to oxidative stress, mainly because immune cells rely heavily on cell-to-cell communication to work efficiently. Peroxidation of the cell membranes compromises the integrity of the membrane and disrupts intracellular signaling.
Cataract Damage by oxidation to the lenses of the eye with increasing age has been a major contribution in the formation of the cataract. In this way, by cleaning free radicals, the following diseases can be treated or controlled: 1) Neurodegenerative Disorders (a) Alzheimer's Disease (b) Parkinson's Disease (c) Huntington's Disease (d) Disease of the Motor Neuron (e) Prion Disease 2) Diabetes and Diabetic Vascular Complications
3) Intestinal Disease (s) (a) Intestinal Ischemia (b) Radiation Enteritis (c) Inflammatory Spleen Disease (d) Gastric and Colorectal Cancers 4) Liver Disease (s) (a) Alcohol Liver Disease (b) Chronic Hepatitis C 5) Cancers (a) Lung Cancer (b) Colorectal Cancer (c) Cervical Cancer (d) Breast Cancer (e) Malignant Melanoma 6) Cardiac Diseases (a) Atherosclerosis (b) Myocardial Infarction (c) Ischemic Shock (d) Endothelial Dysfunction 7) Ophthalmic Disorders (a) Cataract Formation (b) Macular Degeneration 8) HIV Disease 9) Respiratory Diseases (a) Chronic Obstructive Pulmonary Diseases (COPD) (b) Asthma 10) Kidney Diseases ( a) Glomerulonephritis (b \ Acute Renal Failure
OBJECTS OF THE INVENTION
The first object of the present invention is to provide a new class of compounds that normalize elevated blood glucose levels in diabetic patients, therefore delaying diabetic complications and preventing the transition of type II diabetes in patients tolerant of harmful glucose. . These compounds exhibit an in vitro inhibitory activity of DPP-IV. DPP-IV inhibitors improve the level of active GLP-1, which would be advantageous in the treatment of hyperglycemia. The added advantage is that there is no risk of hypoglycemia, since GLP-1 increases the glucose-mediated secretion of insulin. Due to the non-peptide nature of the compounds, these can conveniently be administered orally. The increase in the level of GLP-1 in the active form provides the multifaceted action with respect to the increase in the level of insulin, the decrease in the level of glucagon, the neogenesis of the pancreatic cell 13, the stimulation of the expression of the insulin gene, and the promotion of satiety, all of which contribute to the 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 through the administration of the compounds of the invention or pharmaceutically acceptable salts thereof, either individually or in combination with anti-aging drugs. diabetics or other therapies for Cushing's syndrome, hypothyroidism, HIV infection, obesity, ulcers, disorders related to hyperglucagonemia, gastric emptying and hunger in a required dose mixed with diluents, solvents, excipients, pharmaceutically acceptable carriers, or other means as appropriate be appropriate for this purpose. A further object of the invention is to provide a class of compounds having the free radical cleansing activity, which is useful for the treatment of Neurodegenerative agents such as Alzheimer's Disease,
Parkinson's Disease, Huntington's Disease, Motor Neuron Disease, Prion Disease, etc., (b) Diabetic Diabetic and Diabetes Complications, (c) Intestinal Diseases such as Bowel Ischemia, Radiation Enteritis, Inflammatory Spleen Disease, Hepatitis G Chronic, (e) Liver Diseases such as Liver Disease of Alcohol, Colorectal Cancer, Cervical Cancer,
Breast Cancer, Malignant Melanoma, etc., (f) Cardiac Diseases, such as Atherosclerosis, Myocardial Infarction, Ischemic Shock, Endothelial Dysfunction, (g) Ophthalmic Disorders such as Cataract formation, Macular degeneration, (h) HIV Diseases , (i) Respiratory Diseases, such as Chronic Obstructive Pulmonary Diseases, Asthma, etc., 0) Kidney Diseases such as
Glomerulonephritis, Acute Renal Failure, etc. Still another object of the present invention is to provide a method for the preparation of these compounds. Still a further object of the invention is to provide a pharmaceutical composition comprising said compound in association with a pharmaceutically acceptable carrier, diluent or excipients. Still another object of the invention is to provide a method for the treatment and / or prophylaxis of mammals including humans for diseases related to glucose intolerance and / or disease conditions caused by the accumulation of free radicals in the cells of the body.
BRIEF DESCRIPTION OF THE INVENTION
The present invention provides novel compounds represented by the general formula (I) and its pharmaceutically acceptable salts, which is also understood to include its pharmaceutically acceptable derivatives, analogs, tautomeric forms, stereoisomers, polymorphs and its solvates, which are useful for one or more than (i) normalizing elevated blood glucose levels in diabetes, (ii) treating disorders related to glucose intolerance, and (ii) cleansing free radicals from body cells.
(i)
wherein X is O, S, SO, S02, NR7 or CHR1; n is null or 1; k is zero or 1;
Z is O, S, and NR7; R1 in two positions is independently selected from hydrogen or a substituted or unsubstituted group selected from linear or branched alkyl of 1 to 12 carbon atoms, alkenyl of 2 to 12 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, cycloalkenyl from 5 to 7 carbon atoms, bicycloalkyl, bicycloalkenyl, heterocycloalkyl, aryl, aryloxy, aralkyl, aralkoxy, heteroaryl, heteroaralkyl, heteroaryloxy, heteroaralkoxy, wherein one or more heterogeneous atoms are independently selected from O, N or S; R2, R3, R4 and R7 are independently selected from hydrogen, perhaloalkyl, - (CO) NR8R9, - (CO) R8, - (CO) OR8, -S02R8, -SORB, substituted or unsubstituted groups selected from alkyl of 1 to 12 carbon atoms, straight or branched alkenyl of 2 to 12 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, cycloalkenyl of 5 to 7 carbon atoms, bicycloalkyl, tricycloalkyl amidino bicycloalkenyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl , wherein one or more heterogeneous atoms are independently selected from O, N or S; R5 and R6 are independently selected from hydrogen or a substituted or unsubstituted groups selected from linear or branched alkyl of 1 to 12 carbon atoms, alkenyl of 2 to 12 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, cycloalkenyl of 5 to 7 carbon atoms, bicycloalkyl, bicycloalkenyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, wherein one or more heterogeneous atoms are independently selected from O, N or S; R8 and R9 are independently selected from hydrogen or a substituted or unsubstituted group selected from linear or branched alkyl atoms of 1 to 12 carbon atoms, alkoxyalkyl, alkoxycycloalkyl, alkoxyaryl, perhaloalkyl, alkenyl of 2 to 12 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, perhalocycloalkyl, haloheterocycloalkyl, cyanoheterocycloalkyl, perhaloheterocycloalkyl, cycloalkenyl
to 7 carbon atoms, bicycloalkyl, bicycloalkenyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, perhaloaryl, perhaloheteroaryl; wherein in the groups represented by R1, R2, R3, R4, R5, R6, R7, R8 and R9 when substituted, the substituents are optionally and independently combined through - (CO) -, - CH2 (CO) - ( CO) 0, - (CO) NH-, -CH2 (CO) NH-, -NH-, -NR8-, -O-, -S-, - (SO) -, - (SO2) -, - (SO2 NH-, -NHCH2 (CO) NH-, -NH (S02) -, -O (CO) - or NH (CO) -; are selected from hydrogen, halogen, hydroxyl, nitro, cyano, amino, oxo, oxime, substituted or unsubstituted by R10 for the groups selected from alkyl of 1 to 8 straight or branched carbon atoms, cycloalkyl of 3 to 7 carbon atoms tricycloalkyl, alkylcycloalkyl, alkoxyalkyl, perhaloalkyl, perhalocycloalkyl, aryl, aralkyl, alkylaryl, alkylheteroaryl, aralkoxyalkyl, perhaloaryl, alkylheterocycloalkyl, heterocicloalqullo, perhaloheterocycloalkyl, heteroaryl, heteroaralkyl, alkylaryl, perhaloheteroaryl, acyl, acyloxy, acylamino, alkylamino, arylamino, aralkoxy, alkoxyalkyl , alkylthio, thioalkyl, arylthio, thioarl, carboxylic acid and its derivatives, or sulphonic acid or its derivatives wherein the groups / substituents present on the same adjacent atoms or atoms such as carbon or nitrogen, optionally together independently can form a ring of five or six or seven members that optionally conti has one or more double bonds and optionally contains one or more heterogeneous atoms selected from O, N or S; and wherein R10 is independently selected from halogens, hydroxy, nitro, cyano, amino, alkoxy, carbonyl alkyl, -S02NH alkyl, -S02NH aryl, oxo or oxime, and hydrates and pharmaceutically usable salts therein; provided that, if k is zero, then R4 and R6 together optionally form a six- or seven-membered ring, which optionally contains two to three heterogeneous atoms independently selected from O, S and NR7 with R1 as hydrogen and N1 binds to hydrogen . As used herein, the aryl and heteroaryl ring includes up to two conjugates or fused ring systems. The pharmaceutically acceptable salts forming part of this invention are intended to include, but not limited to, salts of the carboxylic acid moiety such as alkali metal salts such as Li, Na and K salts; alkaline earth metal salts such as Ca and Mg salts; salts of organic bases such as lysine, arginine, guanidine, diethanolamine, choline, trimethamine and the like; salts of ammonia or substituted ammonia and aluminum salts. The salts may be acid addition salts which define but are not limited to sulfates, nitrates, phosphates, perchlorates, borates, hydrohalides, acetates, perhaloacetates, tartrates, maleates, citrates, succinates, palmoates, methanesulfonates, benzoates, salicylates, hydroxynaphthates, benzenesulfonates , ascorbates, glycerophosphates, ketoglutarates and the like. The invention also provides a process for the preparation of the compounds as defined above. The invention further provides pharmaceutical compositions comprising compounds of the invention in association with a pharmaceutically acceptable carrier, diluent or excipient. The invention also provides a method for the treatment of mammals, including humans under disease conditions resulting from glucose intolerance / or free radical accumulation in the cells of the body through the administration of an effective compound of the compounds of the invention. Nvention to the subject in need thereof. The invention further provides the use of the compounds of the invention in the manufacture of a medicament useful for the treatment of disease conditions resulting from glucose intolerance / or free radical accumulation in body cells.
BRIEF DESCRIPTION OF THE APPENDIX DRAWINGS
Figure 1: The results of the in vivo study for compounds 25 and 27 with respect to the vehicle have also been shown in Figure 1 of the drawing.
DETAILED DESCRIPTION OF THE INVENTION
The representative compounds of the formula (I) as referred to above are listed in the following Table which can be conveniently prepared, by methods as described below. These compounds can exist both as diastereomeric mixtures or as diastereomerically pure or enantiomerically pure compounds.
TABLE 1 Representative Compounds
The representative compounds of the invention listed in Table 1 can be identified by their following chemical names: a) tris-trif luoroacetate (s) - (+) - 4-cyanothiazolidin of 3- [1-oxo-2- ( 1- (1- (2-oxo-2- (5-chloropyridin-2-yl) aminoethyl) piperidin-4-yl)) hydrazino] ethyl (Compound No. 1) b) tris-trifluoroacetate of 3- [1-] oxo-2- (1- (1- (2-oxo-2- (5-bromothiazol-2-yl) aminoethyl) piperidin-4-yl)) hydrazino] etl-4-cyanothiazolidine, (Compound No. 2) ) c) 3- [1-oxo-2- (1- (1- (2-oxo-2-amino) ethyl) piperidn-4-yl) hydrazino-ethyl-4- bis-trifluoroacetate cyanothiazolidine. (Compound No. 3) d) tris-trifluoroacetate of 3- [1-oxo-2- (1- (1- (2-oxo-2- (4,5-dimethylthiazol-2-yl) aminoethyl) piperidin-4 -yl)) hydrazino] ethyl-4-cyanothiazolidine. (Compound No. 4) e) tris-f luoroacetate 3- [1-oxo-2- (1- (1-2-oxo-2 (5-cyanopyridin-2-yl) aminoethyl) piperidin-4-yl) ) hydrazino] ethyl-4-cyanothiazolidine. (Compound No. 5) f) 3- [1-Oxo-2 - (- 1 - (- 1- (2-oxo-2- (2-chloropyridyl-3-l) amynoethyl) tris-fluoroacetate) piperidin-4-yl)) hydrazino] ethyl-4-ciantothiazolidine. (Compound No. 6) g) bis-trifluoroacetate 3- [1-oxo-2- (1- (1- (2-oxo-2- (2-flurobenzyl) aminoethyl) piperidin-4-yl)) hydrazino ] ethyl-cyanothiazolidine, (Compound No. 7) h) bis-trifluoroacetate 3- [1-oxo-2- (1- (1-phenoxyethyl) p-peridin-4-yl) hydrazino] ethyl-4-cyano -thiazolidine. (Compound No. 8) i) 3- [1-Oxo-2- (1- (1- (2-oxo-2- (5-chloropyridin-2-yl) aminoethyl) piperidin-4-yl tris-fluoroacetate )) hydrazino-ethyl-2-cyanopyrrolidine. (Compound No. 9) j) 3- [1-oxo-2- (1- (1- (2-oxo-2-cyclohexyl) aminoethyl) piperidin-4-yl) hydrazino] ethyl- trifluoroacetate 4-cyanothiazoline. (Compound No. 10) k) 3 - [(1-oxo-2- (1- (1- (2-oxo-2- (3-isopropoxy pr-1-yl) amino ethyl) piperidine- bis- trifluoroacetate 4-yl)) hydrazino] ethyl-4-cyanothiazolidine (Compound No. 11) I) 3- [1-oxo-2- (1- (1- (2-oxo-2- (2-bis-trifluoroacetate]] (thiophen-2-yl) ethyl) aminoethyl) piperidin-4-yl)) hydrazino] ethyl-4-cyanothiazolidine. (Compound No. 12) m) 3- [1-oxo-3- (1- (1- (2-oxo-3-chloro-4-fluoro-phenyl) aminoethyl) piperidin-4-yl) bis-trifluoroacetate) ) hydrazino] ethyl-4-ciantothiazolidine. (Compound No. 13) n) 3- [1-Oxo-2- (1- (1- (2-oxo-2- (4-ethoxycarbonyl methyl thiazol-2-yl) aminoethyl) piperidin-4-tris-fluoroacetate -yl)) hydrazino] ethyl-4-ciantothiazolidine. (Compound No. 14) o) 3- [1-oxo-2- (1- (1- (2-oxo-2- (3,4-methylenedioxyphenyl) aminoethyl) piperidin-4-yl) bis-trifluoroacetate) hydanzane] ethyl-4-cyanothiazolidine. (Compound No. 15) p) 3- [1-oxo-2- (1- (1- (2-oxo-2- (4-aminosulfonylphenyl) aminoethyl) piperidin-4-yl) hydrazino] trifluoroacetate] ethyl-4-ciantothiazolidine. (Compound no.
16) q) 3- [1-oxo-2- (1- (1- (3-oxo-3-cyclopropyl) aminopropyl) piperidin-4-yl)) hydrazino] ethyl-4-cyantothiazolidine bis-trifluoroacetate (Compound No. 17) r) 3- [1-Oxo-2- (1- (1- (2-oxo-2- (5-chloropyridin-2-yl) aminoethyl) piperidin-4-yl trichlorohydrate) -2- methoxycarbonyl) hydrazino] ethyl-4-ciantothiazolidine. (Compound No. 18) s) 3- [1-Oxo-2- (1- (1- (2-oxo-2- (thiazol-2-yl) -aminoethyl) piperidin-4-yl tris-fluoroacetate) ) hydrazino] ethyl-4-ciantothiazolidine. Compound no. 19) t) 3- [1-oxo-2- (1- (1- (2-oxo-2- (2-methoxyethyl) aminoethyl) piperidin-4-yl)) hydrazino] ethyl- trifluoroacetate 4-cyanothiazolidine. (Compound No. 20) u) 3- [1-oxo-2- (1- (1- (2-oxo-2- (pyridin-2-yl) aminoethyl) piperidin-4-yl tris-fluoroacetate )) hydrazino] ethyl-4-ciantothiazolidine. Compound no. 21) v) 3- [1-oxo-2- (1- (1- (3-pyridylacetyl) piperidin-4-yl)) hydrazino] ethyl-4-cyanothiazolidine bis-trifluoroacetate. (Compound No. 22) w) 3- [1-Oxo-2- (1- (1- (2-oxo-2- (benzothiazol-2-yl) piperidin-4-yl)) hydrazino tris-fluoroacetate] ethyl-4-cyanothiazolidine. (Compound No. 23) x) 3- [1-Oxo-2- (1- (1- (5-methylpyrazin-2-ylcarbonyl) amino-4-cyclohexyl)) hydrazino] ethyl-4 tris-fluoroacetate -cyntothiazolidine. (Compound No. 24) i) 3- [1-oxo-2- (1- (1- (2-oxo-2- (5-cyano-pyridin-2-yl) aminoethyl) piperidin-4-yl trichlorohydrate) ) hydrazino] ethyl-4-cyanothiazolidine. (Compound No. 25) z) 3- [1-oxo-2- (1- (1- (2-oxo-2- (2-chloro-pyridin-3-yl) aminoethyl) piperidin-4-yl trichlorohydrate) ) hydrazinoethyl-4-cyanothiazolidine. (Compound No. 26) aa) 3- [1-Oxo-2- (1- (1- (2-oxo-2- (4-aminosulfonyl phenyl) aminoethyl) piperidin-4-yl)) hydrazino] ethyl dihydrochloride -4-cyanothiazolidine. (Compound No. 27) bb) 3- [1-Oxo-2- (1- (1- (2-oxo-2- (4-chlorophenyl) aminoethyl) piperidin-4-yl) hydrazino] ethyl-4-dihydrochloride -anthiazolidine (Compound No. 28) ce) 3- [1-oxo-2- (1- (1-2-oxo-2- (benzothiazol-2-yl) aminoethyl) piperidin trichlorohydrate 4-yl)) hydrazine] ethyl-4-ciantothiazolidine. (Compound No. 29) dd) 3- [1-oxo-2- (1- (1- (2- (4) trichlorohydrate, 5-dimethylthiazol-2-yl) aminoethyl) piperidin-4-yl)) hydrazino] ethyl-4-cyanotizolidine. (Compound No. 30) ee) 3- [1-Oxo-2- (1- (1- (2-cyclopropyl-1-yl) aminoethyl) piperidin-4-yl)) hydrazino] ethyl-4-dihydrochloride -annotazolidine (Compound No. 31) ff) 3 - [- oxo-2- (2-tert-butyloxycarbonyl) hydrazino] ethyl-4-cyanooxazolidine. (Compound No. 32)
Testing DPP-IV enzyme inhibitory activity The test method is a modified method (as described by Welch et al., 1998) based on the spectrophotometric determination of the product formed through the division activity of the penultimate proline of the enzyme. The following equation explains the principle of the test method 2
Test + Substrate Gly-Pro + pNa ^
(Dipeptidyl peptidase-IV) (Gly-Pro-pNA)
OD measured at 385 nm
Gly-Pro-pNA: Glycin-Proline-p-nitroanilide was measured at 385 nm. The formation of p-nitroanilide will be reduced in the presence of the inhibitor. The optical density was measured for 2 hours during every 10 minutes using a spectrophotometer and the Vmax was calculated to find the activity of the new chemical entities. The activity of the molecule was expressed in terms of% inhibition. At least three different concentrations were treated for each of the test substances. The percentage inhibitions for each of the concentrations were calculated and a test compound was added. The inhibitory activity of the enzyme of different test compounds was compared based on the values IC5o- The percentage inhibition% l, was calculated using the formula: [(1-v¡ / vo)] * 100 where; v and v0 are the Vmax values with and without the test substance, respectively
Reagents and their preparation: substrate solution: 0.5 mM in 45 mM Phosphate pH regulator Substrate used: Gly-Pro-p-nitroanilide (Source: Sigma-Aldrich Co. Germany) M. Wt de Gly-Pro-p- nitroanilide = 328.8 3,288 mg of substrate were prepared in 1 ml 45 mM phosphate pH buffer as a concentrated solution. 0.25 ml of this concentrated solution was diluted to 5 ml to obtain 0.5 mM of substrate solution (90 μl to be added in each cavity). The concentrated solution of the substrate was used within three days of the preparation. Enzyme Solution: Porcine DPP-IV (Sigma-Aldrich Germany) was used throughout the study. 0.4 mU was prepared in 80 μl of Tris. PH regulator of HCl was prepared. Fresh solutions were prepared every day during the trials. Inhibitor solution: The compounds of the present invention were dissolved in their respective vehicles. Several concentrations of the inhibitor were used: 0.391 μM, 0.781 μM, and 3.125 μM. The inhibitor solutions were prepared and used on the same day.
Experimental Procedure: Different concentrations of the inhibitor vehicle, the substrate and the enzyme were prepared according to standard procedures. 280 μl of enzyme solution (0.4-mU / 801 μl in Tris HCi pH buffer) was added to the eppendorf containing 70 μl of inhibitor or vehicle solution and mixed. This reaction mixture was incubated for 30 minutes at 30 ° C. The 96-well plate containing the substrate solution was thermally equilibrated in the spectrophotometer for 2 minutes at 30 ° C. Then 100 μl of the solution was added in pre-incubation of the enzyme-inhibitor to the respective cavities in a 96-well plate. Each concentration of the inhibitor was tested in triplicate. The degree of change in UV absorbance (in the presence of various concentrations of the inhibitor) was measured at 385 nm, with respect to the cavities containing only 0.5 mM of the substrate in 45 mM phosphate pH regulator as in soft every 10 minutes during 2 hours after adding the enzyme-inhibitor mixture to the cavities containing the substrate solution.
TABLE 2
(The values are the mean ± SD of the three experiments except for compounds Nos. 18 and 24)
Effect of the compound no. 25 and compound no. 27 in neonatal diabetic rats on oral glucose tolerance induced with E streptozotocin (nO STZ)
The glucose levels in the body are strongly controlled by insulin. Many factors contribute to the release of insulin. The administration of glucose through an oral route causes an increase in blood glucose levels as it is absorbed and this increase in glucose level decreases by the release of insulin as the absorption of glucose in the skeletal muscles increases and adipocytes. The release of insulin stimulated by glucose is detrimental in diabetes. Through pretreatment with the drug that releases or stimulates the release of insulin before eating / taking glucose, glucose levels can be strongly controlled also in diabetics. The glucose tolerance test is one of the laboratory markers to test the pre-diabetic or diabetic condition and to evaluate the secretors and / or insulin releasers.
METHODOLOGY
Principle of glucose estimation through the glucometer (One Touch, Lifescan, USA)
Each cm2 of the test strip contains the following reactive ingredients in the approximate concentration listed below:
Oxidated glucose 14 IU Peroxidase 11 IU 3-Methyl-2-benzothiazolinonhydrazone hydrochloride 0.06 mg 3-dimethylaminobenzoic acid 0.12 mg
Glucose and oxygen react in the presence of glucose oxidase which produces gluconic acid and acid peroxide. The acid peroxide subsequently oxidizes the dyes in a peroxidase-mediated reaction which produces a blue-colored form of the dyes (Marks and Damson, 1965). The intensity of the blue color is proportional to the concentration of glucose in the sample.
Animals
Wistar rats were converted to type 2 diabetics by injection of streptozotocin (STZ) at a dose of 90 mg / kg intraperitoneally on the day of birth (nOSTZ) in male offspring (Portha et al., 2001). Animals that showed fasting blood glucose levels between 7-10 mM at the age of 1 0-12 weeks were used for the study. In the experiment, the animals fasted during the night with free access to water.
Oral Glucose Tolerance Test (OGTT) (Pospisilik et al., 2002)
A cannula was inserted into the external jugular vein in nOSTZ rats that fasted overnight using a polyethylene cannula with heparinized saline (100 lU / ml) under ether anesthesia and exteriorized at the back of the neck. After the animal was recovered from the anesthetic, a blood sample was taken as a sample that was marked as a '-5 minute' sample and the drug formulation was administered (in 0.5% sodium carboxymethyl cellulose, Na- CMC) orally at a volume of 1 ml / kg of body weight. Five minutes after the administration of the drug, the blood sample was extracted as a '0 minute' sample and the glucose load was administered at the dose of 1 g / kg of the body orally. The blood samples were subsequently extracted at time intervals of 5.10, 15, 20, 30, 45, 60, 75, 90, 120, 180, 240 and 360 minutes. Blood glucose was measured using a glucometer. The animals were divided into three groups: 1. Treated with vehicle (0.5% Na-CMC), 2. Treated with compound no. 25 (22 mg / kg) and 3. Treated with compound no. 27 (22 mg / kg).
Calculations The change in blood glucose at several points in time was measured as the increase or decrease in the percentage of the basal glucose level. A graph A was plotted using time (minutes) on the X axis and the change in the corresponding percentage of blood glucose on the Y axis as shown in Figure 1 of the drawings. The area under the curve (AUC) for glucose was calculated using WinNonlin software.
CONCLUSION OF THE IN VIVO STUDY The administration of the oral glucose load of 1 g / kg caused an increase in blood glucose in fasted rats during the night with glucose levels reaching the maximum in the 45 minute time interval ( 157.07 + 14.17% of the basal level) in rats treated with the vehicle. In rats treated with compound 25 and compound no. 27, peak glucose levels were significantly lower (99.19 + 17.87% and 87.25 + 15.61%, respectively) as compared to the vehicle-treated group. The area below the glucose curve (AUCg ucose) for rats treated with Compound 25 and Compound 27 (6939.0 + 1632.0 and 7554.0 + 955.3, respectively) was found to be significantly lower compared to rats treated with vehicle (15623.0 ± 1019.0). Among the several laboratory markers analyzed, the most consistent indicator of non-insulin-dependent diabetes mellitus (type U) has been a high concentration of fasting serum insulin, closely followed by high glucose concentration in fasting plasma and glucose in the plasma after an oral glucose test (OGTT). During the OGTT, in response to increased levels of glucose in the blood, the beta cells of the pancreas secrete insulin. When blood glucose levels are plotted against time, the area below the glucose curve is found to be higher in diabetics compared to non-diabetics. This is called glucose intolerance and is attributed to the inability of beta cells to respond to increased levels of glucose in the blood. The results of the present investigation indicate improved glucose tolerance in rats treated with Compound 25 and Compound 26 as AUCg | UC0Sa values for treated animals were significantly lower than in animals treated with the vehicle. Improved glucose tolerance in rats treated with Compound 25 and Compound 27 may be due to the release of insulin stimulated by the increased glucose. From the investigation of the present it is concluded that Compound 25 and Compound 27 may be good candidates for the administration of hyperglycemia in type II diabetes.
Cleaning activity of Free Radical 1. Objective: To determine the in vitro free radical cleaning activity of compounds of the general formula I on the radical 2.2, -diphenyl-1-picrylhydraz (DPPH) (Ref: W. Brand - Williams, ME Cuvelier, C.Berset "Use of a free radical method to evaluate antioxidant activity", Lebensm.-Wiss.u. Technol., 1995, 28, Nr.1: 25-30).
2. Principle involved: To evaluate the cleaning activity of the free radical of the compounds that allow them to react with the stable radical DPPH '. In this radical form, DPPH "is absorbed at the characteristic wavelength of 515 nm, but once the reduction is made through an antioxidant or radical (AH) cleanser, the absorption disappears.
Equation: a. DPPH '+ AH? DPPH-H + A * (free radical) (antioxidant)
3. Reagents and Chemicals DPPH '(SigmaAldrich) Methanol (Merck)
4. Instrument used: Spectrophotometer visible through UV (Jasco) Quartz Microcuvette (capacity of 1 ml)
. Process
Preparation of DPPH 'solution: 10"4 M of DPPH' solution in methanol was prepared.
Preparation of the drug solution: Various concentrations (10 mM, 1 mM, 0.5 mM, 0.25 mM and 0.125 mM) of the drug solutions in methanol were prepared.
Preparation of the control solution: 900 μl of the DPPH 'radical solution was added to an Eppendorf tube. To this was added 100 μl of methanol.
Preparation of the test solution: 900 μl of the DPPH * radical solution was added to the Eppendorf tube. To this was added 100 μl of various concentrations of the drug solutions in methanol.
Measurement of absorbance (O.D.): The absorbance of the test and control samples was recorded after incubation at 30 ° C for 30 minutes, at 515 nm taking the methanol as blank.
6. Calculations The antioxidant activity percentage was calculated according to the formula:% antioxidant activity = 100- [O.D. of the test sample / O. Control D. * 100]
TABLE 3 CLEANING ACTIVITY OF FREE RADICAL IN VITRO OF MOLECULES
USE THE FREE RADICAL DPPH
The test compounds listed in Table 3 above exhibit the activity of clearing the free radical (antioxidant) in vitro. Excessive production of free radicals; reactive oxygen species (ROS) result in stress by oxidation. Therefore, these molecules could be very effective in reducing oxidative stress through their ability to catch ROS. Antioxidants (free radical scavengers) were reported to be effective in the administration of several diseases linked to oxidative stress. Also, the novel compounds show the Free Radical Cleansing 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 Spleen Disease, Gastric and Colorectal Cancers, etc., (d) Liver Diseases such as Liver Disease of Alcohol, 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 Shock, Endothelial Dysfunction, (g) Ophthalmic Disorders such as Cataract formation, Macular degeneration, (h) HIV Diseases, (i) Respiratory Diseases, such as Diseases Chronic Obstructive Pulmonary, Asthma, etc., (j) Kidney Diseases such as Glomerulonephritis, Acute Renal Failure, etc.
Discussion of Test Results: The glucose tolerance test is one of the methods to test the diabetic or prediabetic condition and to evaluate insulin secreting / releasing agents. The level of glucose in the body is mainly controlled through Insulin, although many other factors contribute to the release of insulin. The administration of glucose through the oral route will increase the level of glucose in the blood, which induces the release of insulin. This insulin release stimulated by glucose is detrimental in diabetes. Through pretreatment with drugs that release or stimulate the release of insulin before eating / taking glucose, the increase in glucose level can be controlled. Free radicals together with the AGE formation contribute to the macroangiopathic complication (atherosclerosis, coronary artery disease) and microangiopathic (neuropathy, retinopathy, nephropathy) of diabetes. The test compounds listed in Table 3 exhibit the free radical clearance activity in vitro (antioxidant). The novel compounds show free radical cleansing activity, which may be useful for the treatment of diabetes and diabetic vascular complications (DVCs). The DPP-IV inhibitors under study are preferably expected not only to control diabetes, but also to prevent diabetic complications through other antioxidant actions.
Preparation of the compounds of the invention The compounds of the invention can be prepared through alternative synthetic routes according to Scheme I, 1 A, 2 or 3 described below.
SCHEME -I
'Reagents and conditions for Scheme-1:
[a] (1) Et3N, THF, K2C03, CICH2COCI, 0-20 ° C, 2.5-3.0 hours. (II) (CF3CO) 20 / THF;
[b] K2C03, Kl, THF, Reflux, 6-20 hrs. [c] CF3COOOH, room temperature, 10-20 min. [d] Hexane / Reflux, 2-4 hrs. [e] NaBH 4, MeOH, Reflux, 4-20 hrs. [f] Net, Reflux. [g] (i) Aldehyde / Ketone, MeOH, Reflux, (ii) NaCNBH3, TiCl4, MeOH [h] (i) R8NHCOC1 or R8S02CI or R8COC1, TEA, THF, 0-20 ° C (ii) [c]
Description: The compounds of the present invention can be prepared by general methods as described in Scheme (1). The starting amide compound of the formula (1), ie L-prolinamide is prepared in four steps from L-proline following the same methods as described in the literature for the synthesis of (R) - (-) -thiazolidin-4-amide of the formula and the corresponding acid. Patent Reference of E.U.A. No. 6110949 dated 29.8.00, Doreen M and others, Bio. Org. Med. Chem. Lett. 6 (22), 1996, 2745-48]. L-prolinamide (1) is then converted to 1-chloroacetyl-2-cyanopyrrolidine of the formula (3) in two steps involving the chloroacetylation of the amide followed by dehydration [Ref. patent of E.U.A. 6124305 dated 26.09.00, WO-0034241 dated 15.06.00 and Patent of E.U.A. No. 6011155 dated 01.04.00]. In a similar manner, the other 3-chloroacetyl-4-cyanothiazolidine starting material of the formula (4) is prepared following a sequence of two-step reactions. Step 1 involves the reaction of thiazolidine amide of the formula (2) with chloroacetyl chloride in the presence of a base such as potassium carbonate and an inert organic solvent such as tetrahydrofuran at a temperature of 0 ° C to 20 ° C during 2.5 to 3 hours. Step
2 involves the dehydration of 3-chloroacetyl-thiazolidin-4-amide prepared in step 1, with 2 equivalents of trifluoroacetic anhydride conducted in the presence of an inert organic solvent such as tetrahydrofuran at a temperature preferably of 20 ° C. The second main component of the present invention, ie, N-2-substituted terbutyl carbazones of the formula (18) and (19), are prepared by a conventional manner. The alkyl-tert-butyl carbazates of the formulas (17) are prepared by refluxing a solution of hexane or tetrahydrofuran of the tert-butyl carbazate (15) with the appropriate aldehyde or ketone of the formula (16) in a molar ratio 1: 1 for 2.4 hours. [Reference Dutta Anand S et al., J. Chem. Soc. Perkin I, 1975, 1712-1720. Ghali N.l et al., J. Org. Chem. 46, 1981, 5413-5414]. The alkylidene carbazoates thus formed in the previous step are reduced to N-2-substituted tert-butyl chateats of formula (18) using metal hydrides such as sodium borohydride or lithium aluminum hydride, preferably sodium borohydride. and sodium cyanoborohydride. The solvent used in the reaction is an organic solvent such as methanol or tetrahydrofuran at a temperature in the range of 25 ° C to 70 ° C for 4 to 20 hours. On the other hand, the direct alkylation of tert-butyl carbazate with alkyl or aryl halides preferably with the corresponding chlorines or bromines in a clear reaction condition or in the presence of an inorganic base such as potassium carbonate and a catalyst such as potassium iodide in the presence of THF provides carbazate derivatives of the formula (19). The coupling of the chloroacyl derivatives of the formula (3) or (4) with the tert-butyl carbazate derivatives (18) or (19) in the presence of K2C03 / KI in THF gives rise to hydrazinoacyl derivatives (11). ), (7), (12) or (8) which in deprotection using trifluoroacetic acid provides the final compounds (13), (9a), (14) or (10a) respectively as trifluoroacetate salts and the additional reaction of (to), (14) or 10 (a) with the appropriate aldehyde followed by reduction using metal hydride as sodium borohydride or sodium cyanoborohydride in the presence of the TiCl catalyst compound (titanium tetrachloride) gives rise to compounds 9 (b) or 10 (b). The similar reaction of 9 (a) or 10 (a) with appropriate acid chloride or sulfonyl chloride gives rise to the respective compounds 9 (c) or 0 (c). Alternatively, the hydrazino derivatives (5) or (6) can be prepared from corresponding chloroacyl derivatives (3) or (4) through the reaction with the tert-butyl carbazate itself. The alkylation of (5) or (6) with alkyl halides gives rise to the penultimate intermediaries (7) or (8) respectively. Also, the reaction of the compound (5) or (6) with the carabamoyl chloride, sulfonyl chloride or appropriate acid chloride followed by deprotection with trifluoroacetic acid gives rise to the compound 5 (a) or 6 (a) respectively. The compounds of the present invention can also be synthesized according to Scheme 1A which is given below in another embodiment.
SCHEME-1A
13; X = CH2 14; X = S
Fmoc: 9-fluorenyl methoxy carbonyl Boc: tertiary butoxycarbonyl TFA: trifluoroacetic acid
(a) (i) Methanol, BoCNHNH2, Reflux, 2-3 hours. (ii) Methanol, 0 ° C-room temperature, NaCNBH3, TiCl4 (b) K2C03, Kl, THF, Reflux, 24-40 hours. (c) Morpholine (d) Acid, EDC1, DIEA, THF or Acid Chloride, TEA, THF or Sulfonyl Chloride, THF, TEA or Alkyl Halide, K2C03, THF, N-Substituted Chloroacetamide or Reflux, K2CO3, THF, Reflux . (e) CF3COOH, room temperature, 10-20 minutes. (f) 4N-HCI-dioxane Scheme 1A covers the process wherein the cyclic ketone protected with nitrogen is used as the starting material. The protection is through for example the Fmoc group. The compound of formula 11 or 12 can be prepared as a method described in Scheme ~ 1A wherein the reflux of the nitrogen-protected ketone solution with tert-butyl carbazate (15) (as referred to above) followed by the reduction of base schiffs using metal hydrides such as sodium cyanoborohydride in the presence of a catalytic amount of titanium tetrachloride. The reaction of the N-2-substituted tert-butyl carbazate obtained in the previous step with corresponding chloroacrylic derivatives (3) or (4) in the presence of a base such as potassium carbonate in a suitable solvent such as tetrahydrofuran for use in and I p roducto copied p rotected with nitrogen. The functionalization of said free amino group gives rise to compound no. 11 or 12. The deprotection of the Boc group through trifluoroacetic acid or through 4N-HCI-Dloxane provides the final compound as the triflate or hydrochloride salt respectively. More specifically, the compounds of the formula 11 or 12 11; X-CH2 '12; X = S
wherein R4 and X are as defined above, can be prepared through the following steps of the process: (a) by reacting an N-protected cyclic ketone (11) preferably Fmoc protection with BocNHNH2 in alcoholic solvents under heating during 1- 8 hours, followed by reduction in an alcohol solvent at 0-35 ° C to obtain (21) N-2-substituted tert-butyl carbazate. (b) through the coupling of said carbazate derivative with 3 or 4 in the presence of a base and in an organic solvent under heating of 20-50 hours, optionally in the presence of potassium iodide to obtain the coupled product (3-, )
(c) the deprotection of 31 obtained in the previous step (b) is carried out using a base, preferably morpholine at 10-40 ° C for 1-4 hours, to obtain the compound (41) (d) the functionalization of the unprotected product (41) to obtain the compound of the formula 11 or 12 with the substituent R4 as desired. Scheme 2 below is another route for the synthesis of the compounds of the invention.
SCHEME 2
reagents and conditions for Scheme-2: [a]: (Boc) 20, NaOH, Dioxane, H20, 0-25 ° C, 2-4 hours;
[b]: NOSU, DCC, DCM, THF, 0-15 ° C, 3-5 hours; [c]: HOBT, DCC, DIEA, DCM, -5 ° -25 ° C, 6-16 hours;
[d]: DCM or THF, 5 -25 ° C, 12-22 hours; [e]: (CF3CO) 2O, DCM or THF, room temperature, 1-3 hours; [f]: CF3COOH, CH3CN, room temperature, 3-4 hours; [g): R7Br, Et3N, K2CO3, THF, CH3CN or RBr, Et3N, THF, 0 ° -60 ° C, 1-25 hours. In another embodiment of the present invention wherein the compounds, wherein the value of "k" mentioned in general formula (I) is "null", then R4 and R6 together optionally form a six or seven member ring optionally containing two or three heterogeneous atoms independently selected from O, S and NR7, with R-es is hydrogen, and N-está is linked to hydrogen. As described represented by the formula (II), the compounds can be prepared by general methods as described in Scheme-2.
(II)
The piperazine-2-carboxylic acid dihydrochloride (20) is first protected using customary protecting groups such as Boc (tert-butyloxycarbonyl) or CBZ (benzyloxycarbonyl). The protected acid (21) is subjected to coupling with L-prolinamide (1) or (R) - (-) - thiazolidin-4-amide (2) to give the coupled products (23) or (24). This can be done either by first coupling dicyclohexylcarbodiimide (DCC) -mediated coupling of acid (21) with N-hydroxysuccinimide (NOSU) to form the active ester (22) followed by its reaction with the amides (1 or 2) , or through the direct coupling of the protected acid. SCHEME 3 Bac-NH-NH-CHRR '
(c)
39; X = CH, 41; X = CH, 40; X = S 42; X = S 1. (e) 2. (f)
43; X = CR, 44; X = S Reagents and Scheme Conditions -3:
a) Et3N, THF or DCM, -25 ° to 4 ° C, N2, 10-16 hours. b) EtaN, THF or DCM, Reflux, 6-10 hours. c) (CF3CO) 2O, THF, room temperature 2-4 hours, d) CF3COOH, THF, 5 ° C at room temperature 0.5 a2 hours. e) aqueous NaHC03 f) MeOH. HCl g) EtgN, THF, -5 ° C at 0 ° C, 1-2 hours, N2, h) Et3N, THF, 5 ° C to 60 ° C, 12-18 hours.
In still another embodiment of the present invention wherein the described compounds represented by the formula (III), wherein the value of "n" mentioned in the formula (i) is "null", can be prepared by general methods such as it is described in Scheme-3.
(III)
The N-2-substituted tert-butyl carbazate (18) in the reaction with 2,4,5-trichlorophenyl chloroformate (34), prepared from 2,4,5-trichlorophenol and trimethyl chloroformate (33) through the The method described in the literature, in the presence of trimethylamine as a base, results in the formation of carbazate derivatives (35). [Reference, Konakahara T et al., Synthesis, 1993, 03-106.] The carbazate derivatives (35) in coupling with L-prolinamide (1) or thiazolidin amide (2) in the presence of a tertiary amine as a base, preferably triethylamine in an organic solvent such as THF under reflux for 4-10 hours gives the coupled products (36.37). These amide derivatives (36,37) can also be obtained through the chlorocarbonylation of carbazates (18) with trichloromethyl chloroformate (33) in the presence of Et3N at a low temperature (-5 ° to 100 ° C), followed by the coupling of the amides (1, 2), with the chlorocarbonyl derivative of the carbazones (38) in the presence of Et 3 N / THF at a temperature in the range of 25 ° to 60 ° C for 8-12 hours. Subsequently the usual dehydration of the amide derivatives (36,37) with trifluoroacetic anhydride in THF at the temperature of 5 ° to 30 ° C for 2-4 hours, followed by deprotection of the corresponding cyano derivatives (39.40) with a deprotection agent such as trifluoroacetic acid at the temperature in the range of 5 ° C to 30 ° C for 0.5 to 2 hours, results in the formation of the final compounds (41,42) such as the trifluoroacetate salts. These can optionally be purified by neutralization with aqueous alkali as sodium bicarbonate (aqueous), purifying the free base thus obtained through column chromatography followed by the conversion of the hydrochloride salts (43,44) by treating them with methanolic hydrochloric acid. at 10 ° C to 20 ° C for 1 to 2 hours.
REPRESENTATIVE EXAMPLE OF SCHEME 1A
EXAMPLE 1 3-RI-Oxo-2- (1- (1- (2-oxo-2- (4-sulfonylaminophenyl) aminoetiDpiperidin-4-yl)) h -drazino-1-yl-4-cyanothiazolidine dihydrochloride (Compound No. 27) Step-1 To a stirred solution of 4-piperidone monohydrochloride hydrate (30 g, 0.2 moles) and sodium carbonate (22 g, 0.207 moles) in 300 ml of water, a solution was added dropwise. of 9-fluorenylmethoxysuccinimide (74 g, 0.22 mol) in 300 ml dioxane at 0 ° C for a period of 30 minutes After stirring for 7 hours at room temperature, 1000 ml of ice water was added under continuous stirring. filtered, washed with 500 ml of water and brine and dried at 60 ° C for 6 hours to give 60 gm of 9-fluorenylmethoxycarbonyl-4-piperidone (yield: 93%).
Step 2 The product obtained in step-1 (60 gm, 0.20 mole) was refluxed with tert-butyl carbazate (27 gm, 0.204 mole) in 300 ml of methanol for 3 hours. The reaction mixture was evaporated to dryness, treated with 200 ml of diethyl ether and filtered to obtain a schiff base (white solid). To the stirred solution of the solid obtained in 500 ml of methanol was added sodium cyanoborohydride solution (23 g, 0.37 mol) in
100 ml of methanol in portions at 0 ° C, followed by a catalytic amount of 4 ml of titanium chloride at 0 ° C. The reaction mixture was stirred at room temperature for 2 hours, evaporated, treated with 1000 ml of water and filtered. The precipitate obtained was dissolved in 1000 ml of dichloromethane and washed with water, dried over sodium sulfate and distilled to give the desired crude product (63 g, 80% yield).Step 3 The crude product obtained in step-2 (20 g, 0.045 mol) was brought to reflux with chloroacetyl-4-cyanothiazolidine (10.4 g, 0.052 mol) in 300 ml of dry tetrahydrofuran in the presence of potassium carbonate (7.5 g. , 0.052 moles) and potassium iodide (0.8 g, 0.005 moles) for 24 hours. The reaction mixture was then filtered, distilled and purified by column chromatography (eluent: 40% ethyl acetate-Hexane) to give 8 g of the required product (yield: 30%)
Step 4 The product obtained in step-3 was stirred in 25 ml of morpholine for 1.5 hours. The reaction mixture was then poured into 100 ml of ice water and filtered. The filtrate was extracted with dichloromethane. The organic layer was dried, distilled to give a solid (3.5 g, yield: 70%).
Step 5 The product or mixture in which it was added (6 g, 0.016 mols) was solved in 1 00 ml of tetrahydrofuran and N- [4-sulfonylaminophenyl] chloroacetamide (4.7 g, 0.019 moles), and carbonate were added. of potassium (2.8 g, 0 02 moles). The reaction mixture was then refluxed for 18 hours, filtered, evaporated and the residue purified by column chromatography (eluent: ethyl acetate: hexane, (70:30) 1.8 g, Yield: 20 g. %).
Step 6 The product obtained in step-5 (1.2 g, 0.002 mole) was stirred in 4-N-dioxane.HCl (8 ml) at room temperature for 3 hours. 20 ml of ethane and 50 ml of diethyl ether were added to the reaction mixture. The separated solid was filtered and washed with diethyl ether and dried with aspiration and finally the crude product was purified using a mixture of methanol-diethyl ether (1: 1) to yield the title compound dihydrochloride of 3- [1-oxo] -2- (1- (1- (2-oxo-2- (4-sulfonylaminophenyl) aminoethyl) piperidin-4-yl)) hydrazino] ethyl-4-cyanothiazouedin (Compound No. 142), (770) mg, yield: 70%).
The following representative compounds can be prepared following the synthetic route of Scheme IA.
EXAMPLE 2 3-H -oxo-2- (1 - (1 - (2-oxo-2- (5-chloropyridin-2-yl) aminoethyl) piperidin-4-yl)) hydrazinoethyl (s) tris-fluoroacetate (+) - 4-cyanothiazolidine (Compound No. 1)
Yield: 87% 1HNMR (d4-MeOH, 400 MHz): d 8.32-8.33 (d, 1 H), 8.16-8.18 (d, 1 H), 7.84-7.86 (dd, 1H), 5.32-5.33 (d, 1 H), 472-4.74 (d, 1 H), 4.64-4.66 (d, 1H), 4.03-4.15 (m, 4H), 3.67-3.69
(m, 2H), 3.54-3.57 (m, 1 H), 3.38-3.39 (d, 2H), 3.31-3.33 (m, 2H), 2.21-2.24 (m, 2H), 1.98- 2.02 (m, 2H) ) Mass (m / z): 438 (M ++ 1) IR (KBr, Cm'1): 2952, 2249, 1663 [a] D: + 37.9 ° (C = 0.5, MeOH)
EXAMPLE 3
3-H -oxo-2- (1 - (1 - (2-oxo-2- (5-bromothiazol-2-yl) aminoethyl) piperdin-4-yl)) hydrazinolethyl-4-tris-fluoroacetate -cyanothiazolidine (Compound No. 2)
Yield: 70% 1HNMR (d4-MeOH, 400MHz): d 7.46 (s, 1 H), 5.32-5 34 (t, 1H), 4.65-4.67 (d, 1H), 4.75-4.77 (d, 1 H) , 3.99-4.14 (m, 4H), 3.58-3.62 (m, 2H), 3.45-3.47 (m, 1H), 3.38-3.39 (d, 2H), 3.12-3.14 (m, 2H), 2.19-2.22 (m, m, 2H), 1.98-2.10 (m, 2H) Mass (m / z): 488 (M ++ 1), 512 (M * + Na) IR (KBr, Crn "): 2940, 2248, 1667
EXAMPLE 4 3-, 1-Oxo-2- (1 - (1 - (2-oxo-2-amino) ethyl) piperidin-4-yl)) hydrazino-ethyl-4-cyanothiazolidine bis (trifluoroacetate (Compound no. 3)
Yield: 50% 1HNMR (d4-MeOH, 400MHz) d 5.30-5.32 (t, 1 H), 4.64-4.66 (d, 1 H), 4.54-4.56 (d, 1H), 3.93-4.12 (m 4H), 3.64-3.69 (m, 2H), 3.48-3.50 (m, 1H), 3.37-3.38 (d, 2H), 3.18-3 20
(m, 2H), 2.48-2.50 (m, 2H), 2.17-2.20 (m, 2H) Mass (m / z): 327 (M ++ 1) IR (KBe, Cm-1): 2991, 2246, 1674
EXAMPLE 5 3-f1 -oxo-2- (1 - (1 - (2-oxo-2- (4,5-dimethylthiazol-2-yl) aminoethyl) piperidin-4-yl) hydrazinoethyl-4 tris-fluoroacetate cyanothiazolidine (Compound No. 4)
Yield: 50% 1HNMR (d4-MeOH, 400MHz): d 5.32-5.34 (t, 1 H), 4.72-4.75 (d, 1H), 4.63-4.66 (d,
1H), 4.03-4.18 (m, 4H), 3.65-3.67 (m, 2H), 3.51-3.53 (m, 1H), 3.38-3.39 (d, 2H), 3.10-3.15 (m, 2H), 2.29 ( s, 3H), 2.23-2.28 (m, 2H), 2.22 (s, 3H), 1.98-2.12 (m, 2H) Mass (m / z): 438 (M ++ 1), 460 (M ++ Na ) IR (KBr, Cm'1): 2939, 2248, 1671 [a] D: -36.15 ° (C = 0.5, MeOH) EXAMPLE 6 tris-fluoroacetate of 3- ri-oxo-2- (1- (1- (2-oxo-2 (5-cyanopyridin-2-yl) aminoethyl) piperidin-4-yl)) hydrazinoethyl-4-cyanothiazolidine (Compound No. 5)
Yield: 40% 1HNMR (d4-MeOH, 400MHz): d 8.70 (s, 1H), 8.29-8.30 (m, 1H), 8.16-8.17 (dd, 1H), 5.32-5.33 (t, 1 H), 472 -4.74 (d, 1 H), 4.64-4.66 (d, 1 H), 4.02-4.20 (m, 4H), 3.66-3.70 (m, 2H), 3.48-3.50 (m, 1 H), 3.38-3.39 (d, 2H), 3.14-3.17 (m, 2H), 2.23-2.29 (m, 2H), 2.03-2.09 (m, 2H) Mass (m / z): 429 (M ++ 1) IR (KBr, Cm'1): 2950, 2232, 1672
EXAMPLE 7 3-H -oxo-2- (1 - (1 - (2-oxo-2- (chloropyridyl-3-yl) aminoetiQpperidin-4-yl)) hydrazinoethyl-4-cyanothiazolidine tris-fluoroacetate (Compound No. 6)
Yield: 50% 1HNMR (d4-MeOH, 400MHz): d 8.44-8.46 (d, 1 H), 8.22-8.23 (dd, 1 H), 7.43-7.46 (dd, 1H), 5.32-5.35 (t, 1 H), 472-474 (d, 1 H), 4.64-4.66 (d, 1 H), 4.04-4.16 (m, 4H), 3.58-3.62 (m, 2H), 3.48-3.50 (m, 1 H) , 3.38-3.39 (d, 2H), 3.13-3.17 (m, 2H), 2.20-2.24 (m, 2H),
2. 00-2.04 (m, 2H) Mass (m / z): 438 (M ++ 1) IR (KBr, Crrf1): 2955, 2251, 1671 [a] D: -40.01 ° (C = 0.5, MeOH) EXAMPLE 8-bis-trifluoroacetate of 3-H -oxo-2- (1 - (1 - (2-oxo-2- (2-f luorobenzDaminoethyl) piperidin-4-yl)) hydrazino-ethyl-4-cyanothiazolidine , (Compound No. 7)
Yield: 45% 1HNMR (d4-MeOH, 400MHz): d 7.31-7.41 (m, 2H), 7.09-7.18 (m, 9H), 5.32-5.33 (t, 1H), 471-473 (d, 1H), 4.66-4.68 (d, 1 H), 4.51 (s, 2H), 4.01-4.17 (m, 2H), 3.98 (s, 2H), 3.61-3.65 (m, 2H), 3.48-3.52 (m, 1 H) ), 3.37-3.38 (d, 2H), 3.18-3.22 (m, 2H), 2.20-2.24 (m, 2H), 1.84-1.88 (m, 2H) Mass (m / z) 457 (M ++ Na) IR (KBr, Cm.!): 2578, 1668, 1639
EXAMPLE 9 3-RI-oxo-2- (1- (1-phenoxyethyl) piperidin-4-yl) hydrazinolethyl-4-cyano-thiazolidine trifluoroacetate (Compound No. 8)
Yield: 70% 1HNMR (d4-MeOH, 400MHz): d 7.31-7.35 (t, 2H), 7.01-7.04 (m, 3H), 5.32-5.34 (t, 1H), 471-474 (d, 1H) , 4.63-4.66 (d, 1H), 4.38-4.40 (t, 2H), 4.02-4.18 (m, 2H), 3.75-3.81 (m, 2H), 3.46-3.63 (m, 3H), 3.37-3.38 ( d, 2H), 3.13-3.16 (m, 2H), 2.23-2.27 (m, 2H), 1.93-1.96 (m, 2H) Mass (m / z): 390 (M ++ 1) 412 (M ++ Na) IR (KBr, Cm'1): 2249, 1667, 1594 EXAMPLE 10 3-p-Oxo-2- (1- (1- (2-oxo-2- (5-chloropyridin-2-tris-fluoroacetate) il) aminoeti-piperidin-4-yl)) hydrazino-1-yl-2-cyanopyrrolidine (Compound No. 9)
Yield: 70% 1HNMR (d4-MeOH, 4-OOMHz): d 8.32 (bs, 1 H), 8.16-8.18 (d, 1H), 7.84-7.86 (dd, 1H), 5.32-5.33 (d, 1 H ), 4.10-4.43 (m, 4H), 3.60-3.97 (m, 3H), 3.49-3.52 (m, 2H), 3.18-3.20 (m, 2H), 1.96-2.36 (m, 8H) Mass (m / z): 420 (M + +1), 442 (M + + +) IR (KBr, Cm "1): 2984, 2245, 1668
EXAMPLE 11 bis-trifluoroacetate of 3-f 1 -oxo-2- (1 - (1 - (2-oxo-2-cyclohexyl) aminoethyl) piperidn-4-yl) f? Idrazino1etl-4- cyanothiazoline (Compound No. 10)
Yield: 75% 1HNMR (d4-MeOH, 400MHz): d 5.32-5.34 (t, 1H), 473-476 (d, 1H), 4.62-4.65 (d, 1H), 4.04-4.20 (m, 2H), 3.91 (s, 2H), 3.63-374 (m, 4H), 3.47-3. 51 (m, 1H), 3.37-3.38 (d, 2H), 2.98-3.12 (m, 2H), 2.22-2.25 (m, 2H), 1.98-2.03 (m, 2H), 1.88-1.91 (m, 2H) ), 176-179 (m, 2H), 1.64-1.68 (m, 1 H), 1.17-1.43 (m, 4H) Mass (m / z): 409 (M ++ - |), 431 (M ++ Na) IR (KBr, Cm'1): 2934, 2249, 1666
EXAMPLE 12 bis-trifluoroacetate of 3-f (1-oxo-2- (1- (1- (2-oxo-2- (3-isopropoxy propan-1-yl aminoethyl) piperidin-4-yl)) hyrazinoet L-4-cyanothiazolidine (Compound No. 11)
Yield: 70% 1HNMR (d4-MeOH, 400MHz): d 5.32-5.34 (t, 1 H), 473-475 (d, 1H), 4.60-4.62 (d, 1H), 4.04-4.19 (m, 2H) , 3.94 (s, 2H), 3.56-3.62 (m, 4H), 3.47-3.50 (m, 3H), 3.36-3.38 (m, 3H), 2.98-3.12 (m, 2H), 2.22-2.25 (m, 2H), 1.97-2.11 (m, 2H), 174-1.80 (m, 2H), 1.14-1.16 (d, 6H) Mass (m / z): 426 (M ++ 1), 449 (M ++ Na ) IR (KBr, Cm'1): 2941, 2248, 1666
EXAMPLE 13 3-H-Oxo-2- (1 -d - (2-oxo-2- (2- (thiophen-2-yl) ethyl) aminoethyl) piperidin-4-yl)) hydrazinoethyl-4-bis (3-H-trifluoroacetate) -cyanothiazolidine (Compound No. 12)
Yield: 70% 1HNMR (d4-MeOH, 400MHz): d 7.23-7.24 (d, 1 H), 6.94-6.96 (t, 1H), 6.89-6.90 (d, 1H), 5.32-5.34 (t, 1 H ), 471-473 (d, 1 H), 4.59-4.61 (d, 1 H), 4.03-4.15 (m, 2H), 3.91 (s, 2H), 3.48-3.58 (m, 5H), 3.37-3.38 (d, 2H), 3.15-3.18 (m, 2H), 3.05-3.09 (t, 2H), 2.20-2.23 (m, 2H), 1.95-2.03 (m, 2H) Mass (m / z): 437 ( M ++ 1), 459
EXAMPLE 14 bis-trifluoroacetate of 3-H-oxo-2- (1- (1- (2-oxo-2- (3-chloro-4-fluoro-phenyl) aminoethyl) piperidin-4-yl)) hydrazinoethyl-4 -cyanothiazolidine (Compound No. 13) Yield: 60% HNMR (d4-MeOH, 400 MHz): d 7.89-7.91 (dd, 1H), 7.45-7.47 (m, 1H), 7.23-7.25 (t, 1H), 5.32-5.33 (t, 1H), 473-475 (d, 1H), 4.65-4.67 (d, 1H), 3.97-4.10 (m, 4H), 3.66-3.69 (m, 2H), 3.46-3.50 (m , 1 H), 3.37-3.38 (d, 2H), 3.12-3.16 (m, 2H), 2.20-2.24 (m, 2H), 2.00-2.03 (m, 2H) Mass (m / z): 477 (M ++ Na), 479 IR (KBr, Cm'1): 2947, 2249, 1674
EXAMPLE 15 3-RI-Oxo-2- (1- (1- (2-oxo-2- (4-ethoxycarbonyl-methylthiazole-2-yl) aminoethyl) -pyridin-4-yl tris-fluoroacetate )) hydrazino] ethyl-4-cyanothiazolidine (Compound No. 14)
Yield: 60% 1HNMR (d4-MeOH, 400MHz): d 7.00 (s, 1 H), 5.32-5 34 (t, 1 H), 473-475 (d, 1H), 4.65-4.67 (d, 1 H) ), 4.01-4.20 (m, 6H), 3.73 (s, 2H), 3.61-3.64 (m, 2H), 3.47-3.50 (m, 1H),
3. 38-3.39 (d, 2H), 3.15-3.18 (m, 2H), 2.21-2.24 (m, 2H), 1.99-2.01 (m, 2H), 1.25-1.28 (t, 3H) Mass (m / z) : 496 (M ++ 1) IR (KBr, Cm'1): 2943, 2250, 1677
EXAMPLE 16 bis-trifluoroacetate of 3-ri-oxo-2- (1- (1- (2-oxo-2- (3,4-methylenedioxyphenyl) aminoethyl) piperidin-4-yl)) hydrazinoethyl-4-cyanothiazolidine (Compound No. 15) Yield: 75% 1HNMR (d4-MeOH, 400MHz): d 7.28 (d, 1 H), 6.93-6.95 (dd, 1 H), 679-6.81 (d, 1H), 5.96 (s) , 2H), 5.33-5.35 (t, 1 H), 472-474 (d, 1 H), 4.64-4.66 (d, 1H), 4.04-4.16 (m, 4H), 3.68-370 (m, 2H) , 3.48-3.51 (m, 1 H), 3.38-3.39 (d, 2H), 3.14-3.16 (m, 2H), 2.25-2.28 (m, 2H), 2.01-2.03 (m, 2H) Mass (m / z): 447 (M ++ 1), 469 (M ++ l \ la) IR (KBr, Cm'1): 2900, 2250, 1563
EXAMPLE 17 bis-trifluoroacetate of 3-f1-oxo-2- (1- (1- (2-oxo-2- (4-aminosulfonylphenyl) aminoethyl) p -peridin-4-yl)) hydrazinoethyl-4-cyanothiazolidine (Compound No. 16)
Yield: 50% 1HNMR (d4-DMSO, 400MHz): d 774-779 (d, 2H), 7.72-7. 75 (d, 2H), 5.28-530 (t,
1H), 476-479 (d, 1 H), 4.61-4.64 (d, 1 H), 370-4.03 (m, 3H), 3.37-3.47 (m, 4H), 3.17-3.26 (m, 2H), 2.67-2.83 (m, 2H), 1.88-1.99 (m, 2H), 178-1.82 (m, 2H) Mass (m / z): 482 (M ++ 1) IR (KBr, Cm'1) 2940, 2247, 1674 [a] D: -33.10 ° (C = 0.5, MeOH)
EXAMPLE 18 bis-trif luoroacetate of 3-f 1 -oxo-2- (1 - (1 - (3-oxo-3-cyclopropyl) aminopropyl) piperidin-4-yl)) hydrazinoethyl-4-cyanothiazolidine, (Compound No. 17) Yield: 50% 1HNMR (d4-MeOH, 400MHz): d 5.32-5.33 (t, 1H), 472-474 (d, 1H), 4.64-4.66 (d, 1H), 4.01-4.12 (m , 2H), 3.68-371 (m, 2H), 3.50-3.53 (m, 3H), 3.37-3.38 (d, 2H), 3.06-3.08 (m, 2H), 2.69-271 (m, 3H), 2.22 -2.25 (m, 2H), 2.01-2.03 (m, 2H), 072-077 (m, 2H), 0.50-0.55 (m, 2H) Mass (m / z): 381 (M * + 1) IR ( KBr, Cm "1): 2946, 2248, 1674
EXAMPLE 19 3-f1-Oxo-2- (1- (1- (2-oxo-2- (5-chloropyridin-2-yl) aminoethyl) piperidin-4-yl) -2-methoxycarbonyl) hydrazinoic acid trichlorohydrate L-4-cyanothiazolidine (Compound No. 18)
Yield: 80% 1HNMR (d4-MeOH, 400MHz): d 8.32-8.33 (d, 1 H), 8.16-8.18 (d, 1 H), 7.84-7.86 (dd, 1H), 5.24-5.28 (t, 1 H), 4.67-5.00 (m, 2H), 4.16-4.19 (m, 2H), 375-3.97 (m, 4H), 3.53 (s,
3H), 3.46-3.48 (m, 1 H), 3.38-3.39 (d, 2H), 3.15-3.21 (m, 2H), 2.10-2.22 (m, 2H), 1.88-1.91 (m, 2H) Mass ( m / z): 496 (M + +1), 518 (M + + +) IR (KBr, Cm'1): 2946, 2244, 1702
EXAMPLE 19 3-f 1 -oxo-2- (1 - (1 - (2-oxo-2- (thiazol-2-yl) -aminoethyl) piperidin-4-yl) hydrazinoethyl-4-c tris-fluoroacetate anothiazolidine (Compound No. 19)
Yield: 60% 1HNMR (d4-MeOH), 400MHz): d 7.47-7.48 (d, 1 H), 7.20-7.21 (d, 1H), 5.33-5.35 (t, 1H), 472-474 (d, 1 H), 4.64-4.66 (d, 1 H), 4.24 (s, 2H), 4.06-4.13 (m, 2H), 365-370 (m, 2H), 3.61-3 63 (m, 1 H), 3.38 -3.39 (d, 2H), 3.28-3.32 (m, 2H), 2.25-2.28 (m, 2H), 2.01-2.05 (m, 2H)
Mass (m / z): 410 (M * + 1), 432 (M * + Na)
EXAMPLE 20 3-f 1 -oxo-2- (1 - (1 - (2-oxo-2- (thiazol-2-yl) -aminoethyl) piperidin-4-yl)) hydrazinoethyl-4-cyanothiazolidine tris-trifluoroacetate ( Compound No. 19)
Yield: 60% 1HNMR (d4-MeOH), 400 MHz): d 7. 47-7.48 (d, 1H), 7.20-7.21 (d, 1H), 5.33-5 35 (t, 1 H), 472-474 (d, 1 H), 4.64-4.66 (d, 1 H), 4.24 (s, 2H), 4.06-4.13 (m, 2H), 365-370 (m, 2H), 3.61-3.63 (m, 1 H) ), 3.38 - 3.39 (d, 2H), 3.28-3.32 (m, 2H), 2.25-2.28 (m, 2H), 2.01- 2.05 (m, 2H) Mass (m / z): 410 (M ++ 1 ), 432 (M ++ Na)
EXAMPLE 21 bis-trifluoroacetate 3-f 1 -oxo-2- (1 - (1 - (2-oxo-2- (2-methoxyethyl) aminoeti-piperidin-4-yl)) hydrazino-1-ethyl-4-cyanothiazolidine (Compound no. . twenty)
Yield: 50% 1HNMR (d4-MeOH, 400 MHz): d 5.32-5.33 (t, 1H), 472-474 (d, '1H), 4.61-4.63 (d, 1H), 4.02-4.19 (m, 2H ), 3.94 (s, 2H), 3.61-3.64 (m, 2H), 3.46-3.51 (m, 5H), 3.37-3.38 (d, 2H), 3.33 (s, 3H), 3.01-3.06 (m, 2H) ), 2.21-2.24 (m, 2H), 2.01-2.03 (m, 2H) Mass (m / z): 385 (M ++ 1), 407 (M ++ Na) IR (KBr, Cm "1): 2936, 2246, 1681
EXAMPLE 22 Tris-trifluoroacetate of 3-f1-oxo-2- (1- (1- (2-oxo-2- (pyridin-2-yl) aminoethyl) piperidin-4-yl)) hydrazinoethyl-4-cyanothiazolidine (Compound No. 21)
Yield: 50% 1HNMR (d4-MeOH, 400 MHz) d 8.34-8.35 (d, 1 H), 8.12 (bs, 1H), 7.81-7.84 (t, 1H),
7. 17-7.20 (t, 1 H), 5.33-5.34. (t, 1 H), 472-474 (d, 1 H), 4.64-4.66 (d, 1 H), 4.05-4.18 (m, 4H), 3.62-376 (m, 3H), 3.38-3.39 (d , 2H), 3.11-3.15 (m, 2H), 2.19-2.28 (m, 2H), 2.01-2.04 (m, 2H) Mass (m / z): 404 (M ++ 1), 426 (M ++) Na) IR (KBr, Cm "1): 2937, 2247, 1671
EXAMPLE 23 bis-trifluoroacetate of 3-f1-oxo-2- (1- (3-pyridylacetyl) piperidin-4-yl)) hydrazinoethyl-4-cyanothiazolidine (Compound No. 22)
Yield: 60% 1HNMR, (d4-MeOH, 400 MHz): 2 8.76 (bs, 2H), 8.43-8.45 (d, 1H), 7.99-8.03 (t, 1H), 5.33-5.36 (t, 1 H) , 473-475 (d, 1H), 4.62-4.64 (d, 1 H), 4.06-4.17 (m, 4H), 3.48-3.56 (m, 2H), 3.38-3.39 (d, 2H), 3.25-3.27 (m, 2H), 2.81-2.88 (m, 1H), 2.02-2.12 (m, 2H), 1.63-1.69 (m, 1H), 1.48-1.52 (m, 1H) Mass (m / z): 389 ( M ++ 1) IR (KBr, Cm'1): 2929, 1713, 1646
EXAMPLE 24 3-f 1 -oxo-2- (1 - (1 - (2-oxo-2- (benzothiazol-2-yl) piperidin-4-yl)) hydrazino-ethyl-4-cyanothiazolidine tris-trifluoroacetate ( Compound No. 23)
Yield: 70% 1HNMR (d4-MeOH, 400 MHz): d 7.89-7.91 (d, 1 H), 775-777 (d, 1H), 7.47-7.50 (t, 1H), 7.35-7.39 (t, 1 H), 5.33-5.35 (t, 1 H), 473-475 (d, 1 H), 4.61-4.63 (d, 1H), 4.18 (s, 2H),
4. 00-4.12 (m, 2H), 3.63-3.65 (m, 2H), 3.47-3.50 (m, 1H), 3.38-3.39 (d, 2H), 3.07-3.09 (m, 2H), 2.21-2.24 (m , 2H), 2.00-2.03 (m, 2H) Mass (m / z): 460 (M ++ 1) 482 (M ++ Na) IR (KBr, Cm'1): 2939, 2339, 1663 [a] : -12.47 ° (C = 0.5, MeOH)
EXAMPLE 25 3- f1-Oxo-2- (1- (1- (2-oxo-2- (5-cyano-pyridin-2-yl) aminoethyl) piperidin-4-yl)) hydrazino-ethyl-4- tris-trichlorohydrate cyanothiazolidine (Compound No. 25)
Yield: 80% 1 HNMR (d4-Methanol, 400 MHz): d 8.70 (s, 1 H), 8.30 (d, 1H), 8.15-8.18 (d, 1H), 5.36-5.37 (t, 1 H), 473-477 (d, 1 H), 471-473 (d, 1 H), 4.19-4.40 (m, 4H), 3.81-3.85 (m, 2H), 3.67-3.69 (m, 1 H), 3.50- 3. 54 (m, 2H), 3.38-3.41 (d, 2H), 2.25-2.35 (m, 2H), 2.01-2.06 (m, 2H) Mass (m / z): 428 (M ++ 1) IR (KBr , Cm'1): 2936, 2231, 1663
EXAMPLE 26 3-f 1 -oxo-2- (1 - (1 - (2-oxo-2- (2-chloropyridin-3-yl) aminoethyl) piperidin-4-yl)) hydrazinoethyl-4-cyanothiazolidine tris-trichlorohydrate (Compound No. 26)
Yield: 1HNMR (d4-Methanol, 400 MHz): d 8.38-8.40 (d, 1 H), 8.24-8.25 (d, 1H), 7.44-7.47 (t, 1 H), 5.34-5.36 (t, 1 H) ), 476-478 (d, 1 H), 4.64-4.66 (d, 1 H), 4.04-4.17 (m, 4H), 378-3.83
(m, 2H), 3.49-3.53 (m, 1 H), 3.14-3.18 (m, 2H), 3.37-3.39 (d, 2H), 2.23-2.31 (m, 2H), 2.00- 2.03 (m, 2H) ) Mass (m / z): 438 (M ++ 1) IR (KBr, Cm'1): 2941, 2247, 1665
EXAMPLE 27 3-f1-Oxo-2- (1- (1- (2-oxo-2- (4-aminosulfonyl phenyl) aminoethyl) piperidin-4-yl)) hydrazinoethyl-4-cyano thiazolidine dihydrochloride (Compound no. 27)
1HNMR (d4-Methanol, 400 MHz): d 7.88-7.91 (d, 2H), 7.82-7.84 (d, 2H), 5.36-5.37
(t, 1H), 473-477 (d, 1H), 4.66-4.68 (d, 1 H), 4. 1-4.35 (m, 4H), 377-3.86 (m, 2H), 3.67-3.69 (m , 1H), 3.50-3.53 (m, 2H), 3.37-3.39 (d, 2H), 2.24-2.32 (m, 2H), 2.01-2.06 (m, 2H), Mass (m / z): 504 (M ++ Na) IR (KBr, Cm'1): 2981, 1694, 1648 EXAMPLE 28 3-f1-Oxo-2- (1- (1- (2-oxo-2- (4-chlorophenyl) aminoethyl) dihydrochloride piperidin-4-l)) hydrazinoethyl-4-cyanothiazolidine (Compound No. 28)
1HNMR (d4-Methanol, 400 MHz): d 7.63-7.65 (d, 2H), 7.34-7.36 (d, 2H), 5.36-5.37 (t, 1H), 475-477 (d, 1H), 4.69-471 (d, 1 H), 4.10-4.24 (m, 4H), 377-3.83 (m, 2H), 3.49-3.52 (m, 1H), 3.40-3.42 (m, 2H), 3.35-3.37 (d, 2H) ), 2.23-2.33 (m, 2H), 2.01- 2.04 (m, 2H)
Mass (m / z): 437 (M ++ 1) IR (KBr, Cm "1): 2930, 2353, 1730
EXAMPLE 29 3-f1-Oxo-2- (1 - (1 - (2-oxo-2- (benzothiazol-2-yl) aminoethyl) piperidin-4-yl)) hydrazino-1-ethyl-4-cyanothiazolidine trichlorohydrate (Compound No. 29)
1HNMR (d4-Methanol, 400 MHz): d 7.89-7.91 (d, 1 H), 776-778 (d, 1H), 7.47-7.51 (t, 1H), 7.35-7.39 (t, 1 H), 5.34 -5.36 (t, 1 H), 474-476 (d, 1H), 4.68-470 (d, 1H), 4.38 (s, 2H), 4.11-4.17 (m, 2H), 378-3.83 (m, 2H) ), 3.61-3.63 (m, 1 H), 3.42-3.44 (m, 2H), 3.39-3.41 (d, 2H), 2.30 (m, 2H), 2.00-2.04 (m, 2H), Mass (m / z): 458 (M ++ 1) IR (KBr, Cm "1): 2931, 2342, 1652
EXAMPLE 30 3-RI-Oxo-2- (1- (1- (2- (4,5-dimethylthiazol-2-yl) aminoethyl) piperidin-4-yl) -hydrazinolethyl-4-cyanotizolidine trichlorohydrate (Compound no. 30) 1HNMR (d4-Methanol, 400 MHz): d 5.36-5.37 (t, 1 H), 478-4.80 (d, 1H), 470-472 (d, 1H), 4.51 (s, 2H), 4.11- 4.23 (m, 2H), 374-377 (m, 2H), 3.59-3.61 (m, 1H), 3.36-3.40 (m, 2H), 3.31-3.33 (d, 2H), 2.38 (s, 3H), 2.36 (s, 3H), 2.31-2.33 (m, 2H), 2.12-2.14 (m, 2H) Mass (m / z): 438 (M ++ 1) IR (KBr, Cm "1): 2920, 2342 1718
EXAMPLE 31 3-RI-Oxo-2- (1- (1- (2-Cyclopropyl-1-yl) aminoethyl) piperidin-4-yl) -hydrazinoethyl-4-cyanothiazolidine dihydrochloride (Compound No. 31)
1HNMR (d4-Methanol, 400 MHz): d 5.34-5.36 (t, 1 H), 473-475 (d, 1 H), 4.61-4.63 (d, 1 H), 4.09-4.22 (m, 2H), 3.97 (s, 2H), 372-377 (m, 2H), 3.61-3.63 (m, 1H), 3.43-3.46 (m, 2H), 3.32-3.34 (d, 2H), 2.75-2.77 (m, 1 H), 2.24-2.30 (m, 2H), 2.19 (m, 2H), 076-0.81 (q, 2H), 0.56 (q, 2H) Mass (m / z): 367 (M ++ 1), 389 (M ++ Na) IR (KBr, Cm "1): 2934, 2246, 1731 The following representative compounds can be prepared through the following synthetic route of Scheme I.
EXAMPLE 32 3-f 1 -oxo-2- (1 - (1 - (5-methy1pyzin-2-ylcarbonyl) amino-4-cyclohexyl)) hydrazinoethyl-4-cyanothiazolidine tris-trifluoroacetate (Compound No. 24)
Yield: 50% 1HNMR (d4-MeOH, 400 MHz): d 9.08 (bs, 1 H), 8.58 (bs, 1 H), 5.33-5.35 (t, 1 H), 4.72- 4.74 (d, 1H), 4.64-4.66 (d, 1H), 4.05-4.17 (m, 2H), 3.92-3.99 (m, 1H), 3.49-3.53 (m, 1H), 3.38-3.40 (d, 2H), 2.64 (s, 3H) ), 2.09-2.13 (m, 4H), 1.55-1.59 (m, 4H) Mass (m / z): 404 (M ++ 1), 426 (M ++ Na) IR (KBr, Cm "1): 2951, 2246, 1644
EXAMPLE 33 3-f-oxo-2- (2-tert-butyloxycarbonyl) hydrazinoethyl-4-cyanooxazolidine (Compound No. 32.).
Yield: 5% 1HNMR (d4-CHCl3, 400 MHz): d 3.41-5.12 (m, 7H) Mass (m / z): 293 (M + + +) IR (KBr, Cm "1): 2923, 2852, 1676 The compounds of the invention can also be prepared by the method of Schemes 2 and 3 as described above.
Pharmaceutical Compositions The pharmaceutical compositions can be prepared with pharmaceutically effective amounts of compounds of the general formula I, individually or in combination. It is a common practice to administer the compounds in the form of pharmaceutical dosage forms comprising a pharmaceutically acceptable excipient (s) and at least one active ingredient. These dosage forms can be administered through a variety of routes including oral, topical, transdermal, subcutaneous, intramuscular, intravenous, intranasal, pulmonary, etc. The administration of the agents according to the present invention can take place over an extended period of time at a dose level of, for example, up to 30 mg / kg. The pharmaceutical composition may be in the range of 0.5% to 90% by weight of the compound. The following suggested pharmaceutical formulations are by way of example and in no way restrict the ways in which they can be used.
Oral Formulations Oral formulations can be administered as solid dosage forms for example pills, powders, pads, or separate units such as tablets or capsules and the like. Other orally administered pharmaceutical preparations include single-phase or biphasic dosage forms either in ready-to-use forms or in descending forms for reconstitution such as mixtures, syrups, suspensions or emulsions. The preparations may further contain diluents, dispersing agents, pH regulators, stabilizers, solubilizers, surfactants, preservatives, chelating agents and / or other pharmaceutical additives as used. An aqueous or non-aqueous vehicle or its combination may be used and, if desired, may contain sweeteners, flavoring agents, or similar substances. In the case of a suspension or emulsion, a thickening agent or suspending agent or emulsification agent may also be present. Alternatively, the compounds can be administered as such in their pure form not associated with other additives for example as capsules or pads. They can also be administered with a vehicle. The pharmaceutical preparations can have a slow, delayed or controlled release of the active ingredients as provided through a matrix or controlled diffusion system.
When the present invention or its suitable salts or complexes are present as a different dosage form as tablets, it may contain in addition to the medically inert excipients as used herein in the art. Some examples of suitable excipients include lactose, cellulose, and their derivatives, such as microcrystalline cellulose, methylcellulose, hydroxy propyl methyl cellulose, ethylcellulose, various gums such as acacia, tragacanth, Santana, alginates and their derivatives, sorbitol, dextrose, xylitol, stearate magnesium, talcum, colloidal silicon dioxide, mineral oil, glyceryl mono stearate, glycerylbehenate, sodium starch glycolate, interlocked Providone, crosslinked carboxymethyl cellulose, various emulsifiers such as polyethylene glycol, sorbitol, fatty acid esters, polyethylene glycol alkyl ethers , sugar esters, polyoxypropylene polyoxyethylene block copolymers, polyethoxylated fatty acid monoesters, diesters and mixtures thereof.
Preparation of the oral dosage form: A typical tablet can have the following compositions:
Oral Formulation A tablet can be prepared according to the following compositions.
EXAMPLE 34
Ingredients Quantity (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 or more of the compounds Nos. 1-32
EXAMPLE 35
Ingredients Quantity (mg / tablet)
Active ingredient * 10.0 mg
Lactose 75.0 mg
Starch 50.0 mg
Polyvinyl pyrrolidone (10% solution in water 5 mg Sodium starch glycolate 2 mg Colloidal silicon dioxide 5 mg * Any one or more of the compounds Nos. 1-32
EXAMPLE 36
Ingredients Quantity (mg / tablet)
Active ingredient * 5.0 mg Microcrystalline cellulose 80.5 mg Starch 8.0 mg Talcum 3.3 mg Magnesium stearate 1.6 mg Colloidal silicon dioxide 1.6 mg * Any one or more of the compounds Nos. 1-32
The active ingredient, lactose and starch are sorted through the # 40 sieve and mixed. The mixture was then granulated with polyvinyl pyrrolidone solution. The resulting mass was sorted through a sieve of number 16. The granules produced afterwards were dried at 50-60 ° C and passed through the 16 mesh sieve. The sodium starch glycolate was separated, the magnesium stearate and the colloidal silicon dioxide through a 60 mesh screen and mixed with the granules. The resulting mixture was then compressed into tablets. The above ingredients can be mixed into tablets and any other conventional material.
Parenteral Formulation For parenteral administration, the compounds and their suitable salts or complexes thereof may be present in a sterile vehicle which may be an aqueous or non-aqueous vehicle or a combination thereof. Examples of vehicles are water, ethyl oleate, oils and derivatives of polyols, glycols and their derivatives. They may contain common additives in injectable preparations such as stabilizers, solubilizers, pH modifiers, antioxidants, cosolvents, complexing agents, tonicity modifiers, etc. Some suitable additives are for example, tartrate, citrate or similar pH regulators, alcohol, sodium chloride, dextrose, and high molecular weight polymers. Another alternative is the reconstitution of sterile powder. The compound can be administered in the form of injection by more than one daily administration, or intravenous infusion / immersion or preparation of the appropriate reservoir. For injectable administration, the active ingredient or its salt is dissolved or dispersed in a sterile vehicle. The vehicle can be aqueous or non-aqueous and can contain surfactants, solubilizers, pH regulators, stabilizers, surfactants, co-solvents, chelating agents, suitable tonicity modifiers, etc. Various commonly used excipients include propylene glycol, polyethylene glycol, mannitol, sodium chloride, ethyl oleate, polyethylene glycol fatty acid esters, polyethylene glycol castor oil, polyethylene glycol sorbitan fatty acid esters, sugar esters, various regulators of pH such as phosphate, succinate, citrate, borate, antioxidants such as sodium metabisulfite, etc. An injectable formulation containing the following ingredient can be prepared:
EXAMPLE 37
Ingredients Quantity Active ingredient * 1 mg Polyethylene glycol 0.1 mg Saline Isotonic / WFI at 1 ml Sodium Metasulphite 3.3 mg Magnesium stearate * Any one or more of the compounds Nos. 1- 32 OTHER FORMULATIONS
For dermatological application and for oral supply, the recommended formulations are gel, ointment, creams, patches, liniments, lotions, oral rinses, gargles, and toothpastes containing the appropriate compounds of the compounds of the general formula I. The examples The foregoing are presented by way of illustration alone and do not limit the scope of the invention in any way.
Claims (18)
1. A heterocyclic compound selected from the group consisting of: a) tris-trifluoroacetate (s) - (+) - 4-cyanothiazolidin of 3- [1-oxo-2- (1- (1- (2-oxo-2- ( 5- chloropyridin-2-yl) aminoethyl) piperidin-4-yl)) hydrazino] ethyl b) tris-trifluoroacetate of 3- [1-oxo-2- (1- (1- (2-oxo-2- (5 -bromothiazol-2-yl) aminoethyl) piperidin-4-yl)) hydrazino] ethyl-4-cyanothiazolidine c) 3- [1-oxo-2- (1- (1- (2-oxo-2) bis-trifluoroacetate] -amino) ethyl) piperidin-4-yl)) hydrazino-ethyl-4-cyanothiazolidine. d) 3- [1-Oxo-2- (1- (1- (2-oxo-2- (4,5-dimethylthiazol-2-yl) aminoethyl) piperidin-4-yl tris-trifluoroacetate) hydrazino] ethyl-4-cyanothiazolidine. e) 3- [1-Oxo-2- (1- (1-2-oxo-2- (5-cyanopyridin-2-yl) aminoethyl) piperidin-4-yl)) hydrazino] eti tris-fluoroacetate l-4-cyanothiazolidine. f) 3- [1-Oxo-2 - (- 1 - (- 1- (2-oxo-2- (2-chloropyridyl-3-yl) aminoethyl) piperdin-4-yl tris-fluoroacetate) hyrazinyl] ethyl-4-cyanothiazolidine. g) bis-trifluoroacetate 3- [1-oxo-2- (1- (1- (2-oxo-2- (2-flurobenzyl) aminoethyl) piperidin-4-yl)) hydrazino] ethyl-cyanothiazolidine, h) bis trifluoroacetate 3- [1-oxo-2- (1- (1-phenoxyethyl) piperidin-4-yl) hydrazino] ethyl-4-cyano-thiazolidine. i) 3- [1-Oxo-2- (1- (1- (2-oxo-2- (5-chloropyridin-2-yl) aminoethyl) piperidin-4-yl)) hydrazino-ethyl-tris-fluoroacetate 2-cyanopyrrolidine. j) 3- [1-Oxo-2- (1- (1- (2-oxo-2-cyclohexyl) aminoethyl] piperidin-4-yl) hydrazino] ethyl-4-cyanothiazoline bis-trifluoroacetate. k) 3 - [(1-Oxo-2- (1- (1- (2-oxo-2- (3-isopropoxy-propan-1-yl) -amino-ethyl) piperidin-4-yl)) hydrazino bis-trifluoroacetate ] ethyl-4-cyanothiazolidine.
I) 3- [1-oxo-2- (1- (1- (2-oxo-2- (2- (thiophen-2-yl) ethyl) amynoethyl) p -peridin-4-bis trifluoroacetate il)) hydrazino] ethyl-4-ciantothiazolidine. m) 3- [1-oxo-3- (1- (1- (2-oxo-3-chloro-4-fluoro-phenyl) aminoethyl) piperidin-4-yl) hydrazino] ethyl- trifluoroacetate 4-cyanothiazolidine. n) 3- [1-Oxo-2- (1- (1- (2-oxo-2- (4-ethoxycarbonyl methyl tlazole-2-yl) aminoethyl) piperidin-4-yl tris-fluoroacetate) hydrazyral] ethyl-4-cyanothiazolidine. o) 3- [1-oxo-2- (1- (1- (2-oxo-2- (3,4-methylenedioxyphenyl) aminoethyl) piperidin-4-yl)) hydrazino] ethyl-4- bis-trifluoroacetate cyanothiazolidine. p) 3- [1-oxo-2- (1- (1- (2-oxo-2- (4-aminosulfonylphenol) aminophenyl) piperidin-4-yl)) hydrazino] ethyl- bis- trifluoroacetate 4-cyanothiazolidine. q) 3- [1-oxo-2- (1- (1- (3-oxo-3-cyclopropyl) aminopropyl) piperidin-4-yl)) hydrazino] ethyl-4-cyanothiazolidine r) trichlorohydrate 3- [1-oxo-2- (1- (1- (2-oxo-2- (5-chloropyridin-2-yl) aminoethyl) piperidin-4-yl) -2-methoxycarbonyl) hydrazino] ethyl- 4-cyanothiazolidine. s) 3- [1-Oxo-2- (1- (1- (2-oxo-2- (thiazol-2-yl) -aminoethyl) piperidin-4-yl)) hydrazino] ethyl-4 tris-fluoroacetate -cyntothiazolidine. t) 3- [1-oxo-2- (1- (1- (2-oxo-2- (2-methoxyethyl) aminoethyl) piperidin-4-yl)) hydrazino] ethyl-4-ci bis trifluoroacetate antiarthidine u) 3- [1-oxo-2- (1- (1- (2-oxo-2- (pyridin-2-yl) aminoethyl) piperidin-4-yl)) hydrazino] ethyl-4- tris-fluoroacetate cyanothiazolidine. v) 3- [1-Oxo-2- (1- (1- (3-pyridylacetyl) piperidin-4-yl)) hydrazino] ethyl-4-cyanothiazolidine bis-trifluoroacetate. w) 3- [1-oxo-2- (1- (1- (2-oxo-2- (benzothiazol-2-yl) piperidin-4-yl)) hydrazino] ethyl-4-cyanothi tris-fluoroacetate azolidine x) 3- [1-oxo-2- (1- (1- (5-methylpyrazin-2-ylcarbonyl) amino-4-cyclohexyl)) hydrazino] ethyl-4-cyanothiazolidine tris-fluoroacetate. i) 3- [1-Oxo-2- (1- (1- (2-oxo-2- (5-cyano-pyridin-2-yl) aminoethyl) piperidin-4-yl)) hydrazino] ethyl-4 trichlorohydrate -cyanothiazolidine. z) 3- [1-oxo-2- (1- (1- (2-oxo-2- (2-chloro-pyridin-3-yl) aminoethyl) piperidin-4-yl)) hydrazinoethyl-4-cyanothiazole trichlorohydrate dyne. aa) 3- [1-oxo-2- (1- (1- (2-oxo-2- (4-aminosulfonyl phenyl) aminoethyl) piperidin-4-yl)) hydrazino] ethyl-4-cyanothiazolidine dihydrochloride. bb) 3- [1-oxo-2- (1- (1- (2-oxo-2- (4-chlorophenyl) aminoethyl) piperidin-4-yl)) hydrazino] ethyl-4-cyanothiazolidine dihydrochloride. ce) 3- [1-oxo-2- (1- (1-2-oxo-2- (benzothiazol-2-yl) aminoetiI) piperidin-4-yl) hydrazine] ethyl-4-cyanothiazouedin trichlorohydrate. dd) 3- [1-Oxo-2- (1- (1- (2- (4,5-dimethylthiazol-2-yl) aminoethyl) piperidin-4-yl) hydrazino] ethyl-4-cyanotizolidine trichlorohydrate. ee) 3- [1-oxo-2- (1- (1- (2-cyclopropyl-1-yl) aminoethyl) piperidin-4-yl)) hydrazino] ethyl-4-cyanothiazolidine dihydrochloride. ff) 3 - [- oxo-2- (2-tert-butyloxycarbonyl) hydrazino] ethyl-4-cyanoxazoazolidine. 2. A pharmaceutical composition comprising one or more compounds according to claim 1, its stereoisomers, or one or more pharmaceutically acceptable salts in association with a pharmaceutically acceptable carrier, diluent or excipient.
3. A method for inhibiting the DPP-IV enzyme in the body tissue of a mammal that includes a human being comprising administering an effective amount of one or more compounds according to claim 1, its stereoisomers, or pharmaceutically acceptable salts in association with a pharmaceutically acceptable carrier, diluent or excipient to a mammal in need thereof.
4. A method for cleaning the free radical of the body tissue of a mammal including the human being comprising the administration of an effective amount of one or more compounds according to claim 1, its stereoisomers, or pharmaceutically acceptable salts in association with a pharmaceutically acceptable carrier, diluent or excipient to a mammal in need thereof.
5. A method for the treatment and / or prophylaxis of glucose intolerance in a mammal that includes the human being comprising the administration of an effective amount of one or more compounds according to claim 1, its stereoisomers, or salts pharmaceutically acceptable in association with a pharmaceutically acceptable carrier, diluent or excipient to a mammal in need thereof.
6. A method for the treatment and / or prophylaxis of disorders associated with DPP-IV in a mammal that includes the human being comprising the administration of an effective amount of one or more compounds according to claim 1, its stereoisomers, or pharmaceutically acceptable salts to a mammal in need thereof, wherein said disorders are selected from the group consisting of: a) Cushing's syndrome; b) Hyperthyroidism; c) Obesity; d) Hyperglucagonemia; e) Diseases that include ulcers, and HIV infection; f) Disorders related to increased gastric emptying, acid secretion and hunger; g) Autoimmune disorders that include multiple sclerosis; h) Rheumatoid arthritis; i) Grave disease j) Diarrhea; k) Regeneration of the mucosa in patients with intestinal disease; I) Growth hormone deficiency; m) Neurological and neuropsychological disorders and n) Cancers and tumors.
7. A method for treating a mammal that includes the human being in disease conditions caused by the accumulation of free radicals in the cells of the body comprising the administration of an effective amount of one or more compounds according to claim 1, its stereoisomers, or pharmaceutically acceptable salts in association with a pharmaceutically acceptable carrier, diluent or excipient thereof.
8. The method of claim 7 wherein said disease condition is selected from the group consisting of (a) Neurodegenerative disorders such as Alzheimer's Disease, Parkinson's Disease, Parkinson's Disease, Huntington, Motor Neuron Disease, Prion Disease, etc., (b) Diabetic Diabetic and Diabetes Complications, (c) Intestinal Diseases such as Intestinal Ischemia, Radiation Enteritis, Inflammatory Spleen Disease, Gastric and Colorectal Cancers, etc. ., (d) Liver Diseases such as Liver Disease of Alcohol, Chronic Hepatitis C, etc., (e) Cancers such as P ulmon Cancer, C olorectal C ancer, C urvical C ancer, Breast Cancer, Malignant Melanoma, etc., (f) Cardiac Diseases, such as Atherosclerosis, Myocardial Infarction, Ischemic Shock, Endothelial Dysfunction, (g) Ophthalmic Disorders such as Cataract formation, / Macular degeneration, (h) HIV Diseases, (i) Respiratory Diseases, such as Chronic Obstructive Pulmonary Diseases, Asthma, etc., (j) Kidney Diseases such as Glomerulonephritis, Acute Renal Failure.
9. The use of the compounds according to claim 1, their stereoisomers, solvates or pharmaceutically acceptable salts in the manufacture of a medicament useful for inhibiting the enzyme DPP-IV in the body tissue of a mammal that includes the human. The use of the compounds according to claim 1, their stereoisomers, solvates or pharmaceutically acceptable salts in the manufacture of a medicament useful for cleaning the free radical of the body tissue of a mammal that includes the human being. 11. The use of the compounds according to claim 1, its stereoisomers, solvates or pharmaceutically acceptable salts in the manufacture of a medicament useful for the treatment and / or prophylaxis of glucose intolerance in a mammal that includes the human being. The use of the compounds according to claim 1, their stereoisomers, solvates or pharmaceutically acceptable salts in the manufacture of a medicament useful for the treatment and / or prophylaxis of disorders associated with DPP-IV in a mammal including the human being. 13. The use according to claim 12, wherein said disorder is selected from the group consisting of: a) Cushing's syndrome; b) Hyperthyroidism; c) Obesity; d) Hyperglucagonemia; e) Diseases that include ulcers, and HIV infection; f) Disorders related to increased gastric emptying, acid secretion and hunger; g) Autoimmune disorders that include multiple sclerosis; h) Rheumatoid arthritis; i) Grave disease j) Diarrhea; k) Regeneration of the mucosa in patients with intestinal disease; I) Growth hormone deficiency; m) Neurological and neuropsychological disorders and n) Cancers and tumors. 14. A process for the preparation of compounds of formula 11 or 12. eleven; X = CH2 12; X = S wherein R4 and X are as defined in claim 1, comprising the steps of: (a) reacting an N-protected cyclic ketone (11) Fmoc A = -N-, -CHNH- (1 ') with BocNHNH2 in alcoholic solvents under heating for 1-8 hours, followed by reduction in an alcoholic solvent at 0-35 ° C to obtain (21) terbary carbazate. N-2-substituted butyl. (b) -by coupling said carbazate derivative with 3 or 4 in the presence of a base and in an organic solvent under heating of 20-50 hours to obtain the coupled product (31) (c) the deprotection of 31 obtained in the previous step (b) is carried out using a base, preferably morpholine at 10-40 ° C for 1-4 hours, to obtain the compound (41) ( 4' ) (d) functionalization of the deprotected product (41) to obtain the compound of the formula 11 or 12 with the substituent R4 as desired. 15. The process according to claim 37, wherein (i) protecting the cyclic ketone (i) in step (a) is a Fmoc protection (ii) coupling the reaction in step (b) optionally carrying performed in the presence of potassium iodide and (iii) the base used in step (c) is morpholine. 16. Heterocyclic compounds such as are described herein particularly with reference to the examples. 17. The process for the preparation of the heterocyclic composition such as that described herein with reference to the examples. 18. The pharmaceutical composition as described herein particularly with reference to the examples.
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MXPA06002950A true MXPA06002950A (en) | 2006-12-13 |
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