WO2011005929A1 - Dérivé de pipéridine et son utilisation pour le traitement du diabète et de l'obésité - Google Patents

Dérivé de pipéridine et son utilisation pour le traitement du diabète et de l'obésité Download PDF

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Publication number
WO2011005929A1
WO2011005929A1 PCT/US2010/041325 US2010041325W WO2011005929A1 WO 2011005929 A1 WO2011005929 A1 WO 2011005929A1 US 2010041325 W US2010041325 W US 2010041325W WO 2011005929 A1 WO2011005929 A1 WO 2011005929A1
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methyl
carbonitrile
amino
disease
acetyl
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PCT/US2010/041325
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English (en)
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Robert M. Jones
Juerg Lehmann
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Arena Pharmaceuticals, Inc.
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Publication of WO2011005929A1 publication Critical patent/WO2011005929A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system

Definitions

  • the present invention relates to the GPRl 19 agonist, N-(2-fluoro-4-(methylsulfonyl) phenyl)-5-methyl-6-( 1 -(5-methylpyrazin-2-yl)piperidin-4-yloxy)pyrimidin-4-amine (Compound 1 , Formula (I)), and pharmaceutically acceptable salts, solvates, and hydrates thereof, that are useful in the treatment of GPRl 19-related disorders, such as, metabolic-related disorders and complications thereof, such as, diabetes and obesity.
  • Diabetes mellitus is a serious disease afflicting over 100 million people worldwide. In the United States, there are more than 12 million diabetics, with 600,000 new cases diagnosed each year.
  • Diabetes mellitus is a diagnostic term for a group of disorders characterized by abnormal glucose homeostasis resulting in elevated blood sugar.
  • IDDM insulin-dependent diabetes mellitus
  • NIDDM non-insulin-dependent diabetes mellitus
  • the etiology of the different types of diabetes is not the same; however, everyone with diabetes has two things in common: overproduction of glucose by the liver and little or no ability to move glucose out of the blood into the cells where it becomes the body's primary fuel.
  • Diabetes is a syndrome with interrelated metabolic, vascular, and neuropathic components.
  • the metabolic syndrome generally characterized by hyperglycemia, comprises alterations in carbohydrate, fat and protein metabolism caused by absent or markedly reduced insulin secretion and/or ineffective insulin action.
  • the vascular syndrome consists of abnormalities in the blood vessels leading to cardiovascular, retinal and renal complications. Abnormalities in the peripheral and autonomic nervous systems are also part of the diabetic syndrome.
  • IDDM is characterized by low or undetectable levels of endogenous insulin production caused by destruction of the insulin-producing ⁇ cells of the pancreas, the characteristic that most readily distinguishes IDDM from NIDDM. IDDM, once termed juvenile-onset diabetes, strikes young and older adults alike.
  • NIDDM type 2
  • NIDDM Approximately 90 to 95% of people with diabetes have type 2 (or NIDDM). NIDDM subjects produce insulin, but the cells in their bodies are insulin resistant: the cells don't respond properly to the hormone, so glucose accumulates in their blood. NIDDM is characterized by a relative disparity between endogenous insulin production and insulin requirements, leading to elevated blood glucose levels. In contrast to IDDM, there is always some endogenous insulin production in NIDDM; many NIDDM patients have normal or even elevated blood insulin levels, while other NIDDM patients have inadequate insulin production (Rotwein, R. et al. N. Engl. J. Med. 308, 65-71 (1983)). Most people diagnosed with NIDDM are age 30 or older, and half of all new cases are age 55 and older. Compared with whites and Asians, NIDDM is more common among Native Americans, African- Americans, Latinos, and Hispanics. In addition, the onset can be insidious or even clinically inapparent, making diagnosis difficult.
  • obesity is characterized by hyperinsulinemia and insulin resistance, a feature shared with NIDDM, hypertension and atherosclerosis.
  • Kidney disease also called nephropathy
  • Diabetes occurs when the kidney's "filter mechanism” is damaged and protein leaks into urine in excessive amounts and eventually the kidney fails. Diabetes is also a leading cause of damage to the retina at the back of the eye and increases risk of cataracts and glaucoma.
  • diabetes is associated with nerve damage, especially in the legs and feet, which interferes with the ability to sense pain and contributes to serious infections. Taken together, diabetes complications are one of the nation's leading causes of death.
  • Obesity and diabetes are among the most common human health problems in industrialized societies. In industrialized countries a third of the population is at least 20% overweight. In the United States, the percentage of obese people has increased from 25% at the end of the 1970's, to 33% at the beginning the 1990's. Obesity is one of the most important risk factors for NIDDM. Definitions of obesity differ, but in general, a subject weighing at least 20% more than the recommended weight for his/her height and build is considered obese. The risk of developing NIDDM is tripled in subjects 30% overweight, and three-quarters with NIDDM are overweight.
  • Obesity which is the result of an imbalance between caloric intake and energy expenditure, is highly correlated with insulin resistance and diabetes in experimental animals and human.
  • Whether someone is classified as overweight or obese can be determined by a number of different methods, such as, on the basis of their body mass index (BMI) which is calculated by dividing body weight (kg) by height squared (m 2 ).
  • BMI body mass index
  • m 2 height squared
  • Overweight is defined as a BMI in the range 25-30 kg/m 2
  • obesity as a BMI greater than 30 kg/m 2 (see TABLE below).
  • problems with this definition in that it does not take into account the proportion of body mass that is muscle in relation to fat (adipose tissue).
  • obesity can be defined on the basis of body fat content: greater than 25% and 30% in males and females, respectively.
  • Coronary insufficiency, atheromatous disease, and cardiac insufficiency are at the forefront of the cardiovascular complication induced by obesity. It is estimated that if the entire population had an ideal weight, the risk of coronary insufficiency would decrease by 25% and the risk of cardiac insufficiency and of cerebral vascular accidents by 35%. The incidence of coronary diseases is doubled in subjects less than 50 years of age who are 30% overweight.
  • Atherosclerosis is a complex disease characterized by inflammation, lipid accumulation, cell death and fibrosis. Atherosclerosis is characterized by cholesterol deposition and monocyte infiltration into the subendothelial space, resulting in foam cell formation. Thrombosis subsequent to atherosclerosis leads to myocardial infarction and stroke. Atherosclerosis is the leading cause of mortality in many countries, including the United States. (See, e.g., Ruggeri, Nat Med (2002) 8:1227-1234; Arehart et al, Circ Res, Circ. Res. (2008) 102:986-993.)
  • Osteoporosis is a disabling disease characterized by the loss of bone mass and microarchitectural deterioration of skeletal structure leading to compromised bone strength, which predisposes a patient to increased risk of fragility fractures. Osteoporosis affects more than 75 million people in Europe, Japan and the United States, and causes more than 2.3 million fractures in Europe and the United States alone. In the United States, osteoporosis affects at least 80 years. One in three women older than 50 years will have an osteoporotic fracture that causes a considerable social and financial burden on society. The disease is not limited to women; older men also can be affected. By 2050, the worldwide incidence of hip fracture in men is projected to increase by 310% and 240% in women.
  • IBD Inflammatory bowel disease
  • Crohn's disease ulcerative colitis
  • ulcerative proctitis U.S. medical costs of inflammatory bowel disease for 1990 have been estimated to be $1.4 to $1.8 billion. Lost productivity has been estimated to have added an additional $0.4 to $0.8 billion, making the estimated cost of inflammatory bowel disease $1.8 to $2.6 billion.
  • Enteritis refers to inflammation of the intestine, especially the small intestine, a general condition that can have any of numerous different causes. Enterocolitis refers to inflammation of the small intestine and colon.
  • CD Crohn's disease
  • Granulomatous colitis is another name for Crohn's disease that affects the colon.
  • Ileitis is CD of the ileum which is the third part of the small intestine.
  • Crohn's colitis is CD affecting part or all of the colon.
  • Ulcerative colitis (UC) is an inflammatory disease of the large intestine, commonly called the colon. UC causes inflammation and ulceration of the inner lining of the colon and rectum. The inflammation of UC is usually most severe in the rectal area with severity diminishing (at a rate that varies from patient to patient) toward the cecum, where the large and small intestine join. Inflammation of the rectum is called proctitis.
  • Inflammation of the sigmoid colon (located just above the rectum) is called sigmoiditis. Inflammation involving the entire colon is termed pancolitis. The inflammation causes the colon to empty frequently resulting in diarrhea. As the lining of the colon is destroyed ulcers form releasing mucus, pus and blood. Ulcerative proctitis is a form of UC that affects only the rectum.
  • GPRl 19 is a G protein-coupled receptor (GPRl 19; e.g., human GPRl 19, GenBank ® Accession No. AAP72125 and alleles thereof; e.g., mouse GPRl 19, GenBank ® Accession No. AY288423 and alleles thereof) and is selectively expressed on pancreatic beta cells. GPRl 19 activation leads to elevation of a level of intracellular cAMP, consistent with GPRl 19 being coupled to Gs.
  • GPRl 19 G protein-coupled receptor
  • GPRl 19 Agonists to GPRl 19 stimulate glucose-dependent insulin secretion in vitro and lower an elevated blood glucose level in vivo; see, e.g., International Applications WO 04/065380 and WO 04/076413, and EP 1338651, the disclosure of each of which is herein incorporated by reference in its entirety.
  • GPRl 19 has also been referred to as RUP3 (see, International Application WO 00/31258) and as Glucose-Dependent Insulinotropic Receptor
  • GPRl 19 agonists also stimulate the release of Glucose-dependent Insulinotropic
  • GIP Polypeptide
  • GLP-I Glucagon-Like Peptide- 1
  • PYY Peptide YY
  • GPRl 19 agonists enhance incretin release and therefore can be used in treatment of disorders related to the incretins, such as, GIP, GLP-I, and PYY.
  • GIP and GLP-I are substrates for the enzyme DPP-IV. Jones and co-workers (Jones, et al., Ann. Rep. Med.
  • G Glucose-dependent Insulinotropic Poloypeptide
  • GIP Glucose-dependent insulinotropic polypeptide
  • gastric inhibitory polypeptide is a peptide incretin hormone of 42 amino acids that is released from duodenal endocrine K cells after meal ingestion. The amount of GIP released is largely dependent on the amount of glucose consumed. GIP has been shown to stimulate glucose-dependent insulin secretion in pancreatic beta cells. GIP mediates its actions through a specific G protein-coupled receptor, namely GIPR.
  • GIP contains an alanine at position 2, it is an excellent substrate for dipeptidyl peptidase-4 (DPP-IV), an enzyme regulating the degradation of GIP.
  • DPP-IV dipeptidyl peptidase-4
  • Full-length GIP( 1 -42) is rapidly converted to bioinactive GIP(3-42) within minutes of secretion from the gut K cell. Inhibition of DPP-IV has been shown to augment GIP bioactivity.
  • GIP has been shown to promote bone formation.
  • GIP has been shown to activate osteoblastic receptors, resulting in increases in collagen type I synthesis and alkaline phosphatase activity, both associated with bone formation.
  • GIP has been shown to inhibit osteoclast activity and differentiation in vitro.
  • GIP administration has been shown to prevent the bone loss due to ovariectomy.
  • GIP receptor (GIPR) knockout mice evidence a decreased bone size, lower bone mass, altered bone microarchitecture and biochemical properties, and altered parameters for bone turnover, especially in bone formation.
  • GIP Glucagon-Like Peptide-1
  • Glucagon- like peptide-1 (GLP-I) is an incretin hormone derived from the
  • GLP-I mediates its actions through a specific G protein-coupled receptor (GPCR), namely GLP-IR.
  • GPCR G protein-coupled receptor
  • GLP- 1 is best characterized as a hormone that regulates glucose homeostasis. GLP- 1 has been shown to stimulate glucose-dependent insulin secretion and to increase pancreatic beta cell mass.
  • GLP- 1 has also been shown to reduce the rate of gastric emptying and to promote satiety.
  • the efficacy of GLP- 1 peptide agonists in controlling blood glucose in Type 2 diabetics has been demonstrated in several clinical studies [see, e.g., Nauck et al., Drug News Perspect (2003) 16:413-422], as has its efficacy in reducing body mass [Zander et al., Lancet (2002) 359:824- 830].
  • GLP- 1 receptor agonists are additionally useful in protecting against myocardial infarction and against cognitive and neurodegenerative disorders.
  • GLP-I has been shown to be cardioprotective in a rat model of myocardial infarction [Bose et al., Diabetes (2005) 54: 146- 151], and GLP-IR has been shown in rodent models to be involved in learning and
  • Type 2 diabetes are characterized by a deficiency in GLP- 1 [see, e.g., Nauck et al., Diabetes (2004) 53 Suppl 3 :S 190- 196].
  • Peptide YY is a 36 amino acid peptide originally isolated in 1980 from porcine intestine (Tatemoto et al, Nature (1980) 285:417-418). PYY is secreted from enteroendocrine L- cells within both the large and small intestine. It has been shown that in rat and human gut concentrations of immunoreactive PYY are low in duodenum and jenunum, high in ileum and colon, and highest in rectum (Lundberg et al, PNAS USA (1982) 79:4471-4475; Adrian et al, Gastroenterol.
  • PYY 3 _ 36 is generated from PYYi_ 36 by cleavage of the N-terminal Tyr and Pro residues by dipeptidyl peptidase IV.
  • PYY 3 _ 3 6 is the predominant form of PYY in human postprandial plasma (Grandt et al, Regul. Pept. (1994) 51 : 151-159).
  • PYYi_ 36 and PYY 3 _ 36 have been reported to have comparable agonist activity at NPY Y2 receptor (Y2R), a G protein- coupled receptor (Parker et al, Br. J. Pharmacol. (2008) 153:420-431); however, PYY 3 _ 36 has been reported to be a high-affinity Y2R selective agonist (Keire et al, Am. J. Physiol.
  • mice were treated with weight loss in mice after peripheral administration (Morley Qt ⁇ , Life Sciences (1987) 41 :2157-2165).
  • Peripheral administration of PYY 3 _ 36 has been reported to markedly reduce food intake and weight gain in rats, to decrease appetite and food intake in humans, and to decrease food intake in mice, but not in Y2R-null mice, which was said to suggest that the food intake effect requires the Y2R.
  • infusion of PYY 3 _ 3 6 was found to significantly decrease appetite and reduce food intake by 33% over 24 hours.
  • Peripheral administration of PYY 3 _ 3 6 has been reported to reduce food intake, body weight gain and glycemic indices in diverse rodent models of metabolic diseases of both sexes (Pittner et al, Int. J. Obes. Relat. Metab. Disord. (2004) 28:963-971). It has been reported that blockade of Y2R with the specific antagonist BIIE-246 attenuates the effect of peripherally administered endogenous and exogenous PYY 3 _ 36 for reducing food intake (Abbott et al, Brain Res (2005) 1043:139-144).
  • peripheral administration of a novel long- acting selective Y2R polyethylene glycol-conjugated peptide agonist reduces food intake and improves glucose metabolism (glucose disposal, plasma insulin and plasma glucose) in rodents (Ortiz et al, JPET (2007) 323:692-700; Lamb et al, J. Med. Chem. (2007) 50:2264-2268). It has been reported that PYY ablation in mice leads to the development of hyperinsulinemia and obesity (Boey et al, Diabetologia (2006) 49: 1360-1370). It has been reported that peripheral administration of a long-acting, potent and highly selective Y2R agonist inhibits food intake and promotes fat metabolism in mice (Balasubramaniam et al, Peptides (2007) 28:235-240).
  • Y2R agonists such as PYYi_36 and PYY3_36 can confer protection against epileptic seizures, such as against kainate seizures (El Bahh et al, Eur. J. Neurosci. (2005) 22: 1417-1430; Woldbye et al, Neurobiology of Disease (2005) 20:760-772).
  • Y2R agonists such as PYYi_ 36 and PYY 3 - 36 act as proabsorbtive (or anti-secretory) hormones, increasing upon intravenous administration the absorption of both water and sodium in various parts of the bowel (Bilchik et al, Gastroenterol. (1993) 105:1441-
  • Y2R agonists such as PYYi_36 and PYY3_36 can confer protection against inflammatory bowel disease such as ulcerative colitis and Crohn's disease (WO
  • PYY-deficient mice exhibit an osteopenic phenotype, i.e. that PYY can increase bone mass and/or can confer protection against loss of bone mass (e.g., decreases loss of bone mass) (Wortley et al, Gastroenterol. (2007) 133: 1534-1543). It has been reported that PYY 3 _ 36 can confer protection in rodent models of pancreatitis (Vona-Davis et al, Peptides (2007) 28:334-338).
  • PYY and Y2R agonists such as PYY3_36 can suppress tumor growth in the cases of, e.g., pancreatic cancer such as pancreatic ductal adenocarcinoma, breast cancer such as breast infiltrative ductal adenocarcinoma, colon cancer such as colon
  • Adiponectin is an adipokine with potent anti-inflammatory properties (Ouchi et al, Clin Chim Acta (2007) 380:24-30; TiIg et al,
  • Adiponectin exerts anti-atherogenic effects by targeting vascular endothelial cells and macrophages and insulin-sensitizing effects, predominantly in muscle and liver (Kubota et al, J. Biol. Chem. (2002) 277:25863-25866; Maeda et al, Nat. Med. (2002) 8:731-737).
  • Low adiponectin levels have been reported to be associated with atherogenic lipoproteins in dyslipidemia (elevated triglycerides, small dense LDL cholesterol, low HDL cholesterol) (Marso et al, Diabetes Care (2008) Feb 5 Epub ahead of print).
  • Adiponectin has been implicated in high density lipoprotein (HDL) assembly (Oku et al, FEBS Letters (2007)
  • Adiponectin has been found to ameliorate the abnormalities of metabolic syndrome, including insulin resistance, hyperglycemia, and dyslipidemia, in a mouse model of obesity-linked metabolic syndrome associated with decreased adiponectin levels (Hara et al,
  • Adiponectin has been reported to stimulate angiogenesis in response to tissue ischemia (Shibata et al, J. Biol. Chem. (2004) 279:28670-28674). Adiponectin has been reported to prevent cerebral ischemic injury through endothelial nitric oxide synthase- dependent mechanisms (Nishimura et al, Circulation (2008) 117:216-223). Adiponectin has been reported to confer protection against myocardial ischemia-reperfusion injury (Shibata et al, Nat
  • Adiponectin has been reported to confer protection against myocardial ischaemia-reperfusion injury via AMP- activated protein kinase, Akt, and nitric oxide (Gonon et al, Cardiovasc Res. (2008) 78:116-122).
  • Adiponectin has been reported to confer protection against the development of systolic dysfunction following myocardial infarction, through its abilities to suppress cardiac hypertrophy and interstitial fibrosis, and proctect against myocyte and capillary loss (Shibata et al, J. MoI. Cell Cardiol. (2007) 42: 1065-1074). Adiponectin has been reported to confer protection against inflammatory lung disease; adiponectin-deficient mice exhibit an emphysema-like phenotype (Summer et al, Am J. Physiol. Lung Cell MoI. Physiol (March 7, 2008)). Adiponectin has been reported to confer protection against allergic airway inflammation and airway
  • hyperresponsiveness such as may be associated with asthma (Shore et al, J. Allergy Clin.
  • Adiponectin has been suggested to confer protection against pulmonary arterial hypertension by virtue of its insulin-sensitizing effects (Hansmann et al, Circulation (2007) 115: 1275-1284). Adiponectin has been reported to ameliorate obesity-related hypertension, with said amelioration of hypertension being associated in part with upregulated prostacyclin expression (Ohashi et al, Hypertension (2006) 47:1108-1116).
  • Adiponectin has been reported to decrease tumor necrosis factor (TNF)- ⁇ - induced expression of the adhesion molecules VCAM-I, E-selectin and ICAM-I in human aortic endothelial cells (HAECs) (Ouchi et al, Circulation (1999) 100:2473-2476) and to inhibit production of TNF- ⁇ in macrophages (Yokota et al, Blood (2000) 96:1723-1732). Adiponectin has been reported to confer protection against restenosis after vascular intervention (Matsuda et al, J Biol Chem (2002) 277:37487-37491).
  • TNF- ⁇ -mediated inflammatory conditions encompass rheumatoid arthritis, inflammatory bowel disease such as Crohn's disease, ankylosing spondylitis, psoriasis, ischemic brain injury, cardiac allograft rejection, asthma, and the like (Bradley, J Pathol (2008) 214:149-160).
  • Figure 1 shows a powder X-ray diffraction (PXRD) pattern for Compound 1 as prepared according to the procedure described in Example 6.
  • FIG. 2 shows a thermogravimetric analysis (TGA) thermogram for Compound 1 as prepared according to the procedure described in Example 6.
  • FIG. 3 shows a differential scanning calorimetry (DSC) thermogram for Compound 1 as prepared according to the procedure described in Example 6.
  • the present invention is drawn to N-(2-fluoro-4-(methylsulfonyl) phenyl)-5-methyl-6-(l- (5-methylpyrazin-2-yl)piperidin-4-yloxy)pyrimidin-4-amine (Compound 1, Formula (I)) and pharmaceutically acceptable salts, solvates, and hydrates thereof, which bind to and modulate the activity of a GPCR, referred to herein as GPRl 19, and uses thereof.
  • GPRl 19, as used herein includes the human sequences found in GeneBank accession number AY288416, naturally-occurring allelic variants, mammalian orthologs, and recombinant mutants thereof.
  • a preferred human GPRl 19 for use in screening and testing of the compounds of the invention is provided in the nucleotide sequence of Seq. ID.No: 1 and the corresponding amino acid sequence in Seq. ID.No:2 found in PCT Application No. WO2005/007647, the disclosure which is herein incorporated by reference in its entirety.
  • One aspect of the present invention encompasses compounds selected from the following compound of Formula (I) and pharmaceutically acceptable salts, solvates, and hydrates thereof:
  • compositions comprising a compound, selected from the compound of Formula (I) and pharmaceutically acceptable salts, solvates, and hydrates thereof, and a pharmaceutically acceptable carrier.
  • compositions comprising a compound, selected from the compound of Formula (I) and pharmaceutically acceptable salts, solvates, and hydrates thereof, and an inhibitor of dipeptidyl peptidase IV (DPP-IV).
  • DPP-IV dipeptidyl peptidase IV
  • compositions wherein the inhibitor of DPP-IV is selected from the following compounds and pharmaceutically acceptable salts, solvates, and hydrates thereof:
  • compositions wherein the inhibitor of DPP-IV is selected from the following compounds and pharmaceutically acceptable salts, solvates, and hydrates thereof:
  • compositions wherein the inhibitor of DPP-IV is selected from the following compounds and pharmaceutically acceptable salts, solvates, and hydrates thereof:
  • Some embodiments of the present invention in regard to the inhibitor of DPP-IV include every combination of one or more inhibitors of DPP-IV and pharmaceutically acceptable salts, solvates, and hydrates thereof, selected from the following group:
  • the inhibitor of dipeptidyl peptidase IV is selected from the following compound and pharmaceutically acceptable salts, solvates, and hydrates thereof:
  • the inhibitor of dipeptidyl peptidase IV is 3(R)-amino-l-[3- (trifluoromethyl)-5,6,7,8-tetrahydro[l,2,4]triazolo[4,3-a]pyrazin-7-yl]-4-(2,4,5- trifluorophenyl)butan- 1 -one phosphate (1 : 1) monohydrate.
  • compositions further comprising a pharmaceutically acceptable carrier.
  • compositions wherein:
  • the compound is selected from the following compound of Formula (I) and pharmaceutically acceptable salts, solvates, and hydrates thereof:
  • the inhibitor of dipeptidyl peptidase IV is selected from the following compound and pharmaceutically acceptable salts, solvates, and hydrates thereof:
  • compositions further comprising a pharmaceutically acceptable carrier.
  • One aspect of the present invention pertains to methods of modulating the activity of a GPRl 19 receptor by contacting the receptor with a compound, selected from the compound of Formula (I) and pharmaceutically acceptable salts, solvates, and hydrates thereof, or a composition thereof.
  • One aspect of the present invention pertains to methods of agonizing a GPRl 19 receptor by contacting the receptor with a compound, selected from the compound of Formula (I) and pharmaceutically acceptable salts, solvates, and hydrates thereof, or a composition thereof.
  • One aspect of the present invention pertains to methods for the treatment of a GPRl 19 receptor related disorder in an individual, comprising administering to the individual in need thereof, a therapeutically effective amount of a compound, selected from the compound of Formula (I) and pharmaceutically acceptable salts, solvates, and hydrates thereof, or a composition thereof.
  • the GPRl 19 receptor related disorder is a metabolic-related disorder.
  • One aspect of the present invention pertains to methods for the treatment of a metabolic- related disorder in an individual, comprising administering to the individual in need thereof, a therapeutically effective amount of a compound, selected from the compound of Formula (I) and pharmaceutically acceptable salts, solvates, and hydrates thereof, or a composition thereof.
  • One aspect of the present invention pertains to methods for the treatment of a metabolic-related disorder selected from the group consisting of:
  • diabetes mellitus type 1 diabetes, type 2 diabetes, inadequate glucose tolerance, impaired glucose tolerance, insulin resistance, hyperglycemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, dyslipidemia, atherosclerosis, stroke, syndrome X, hypertension, pancreatic beta-cell insufficiency, enteroendocrine cell insufficiency, glucosuria, metabolic acidosis, cataracts, diabetic nephropathy, diabetic neuropathy, peripheral neuropathy, diabetic coronary artery disease, diabetic cerebrovascular disease, diabetic peripheral vascular disease, diabetic retinopathy, metabolic syndrome, a condition related to diabetes mellitus, myocardial infarction, learning impairment, memory impairment, a neurodegenerative disorder, a condition ameliorated by increasing a blood GLP- 1 level in an individual with a neurodegenerative disorder, excitotoxic brain damage caused by severe epileptic seizures, Alzheimer's disease, Parkinson's disease, Huntington's disease, prion-associated disease, stroke, motor-
  • One aspect of the present invention pertains to methods for the treatment of type 2 diabetes in an individual, comprising administering to the individual in need thereof, a therapeutically effective amount of a compound, selected from the compound of Formula (I) and pharmaceutically acceptable salts, solvates, and hydrates thereof, or a composition thereof.
  • One aspect of the present invention pertains to methods for the treatment of
  • hyperglycemia in an individual comprising administering to the individual in need thereof, a therapeutically effective amount of a compound, selected from the compound of Formula (I) and pharmaceutically acceptable salts, solvates, and hydrates thereof, or a composition thereof.
  • One aspect of the present invention pertains to methods for the treatment of
  • hyperlipidemia in an individual comprising administering to the individual in need thereof, a therapeutically effective amount of a compound, selected from the compound of Formula (I) and pharmaceutically acceptable salts, solvates, and hydrates thereof, or a composition thereof.
  • a compound selected from the compound of Formula (I) and pharmaceutically acceptable salts, solvates, and hydrates thereof, or a composition thereof.
  • One aspect of the present invention pertains to methods for the treatment of
  • hypertriglyceridemia in an individual comprising administering to the individual in need thereof, a therapeutically effective amount of a compound, selected from the compound of Formula (I) and pharmaceutically acceptable salts, solvates, and hydrates thereof, or a composition thereof.
  • One aspect of the present invention pertains to methods for the treatment of type 1 diabetes in an individual, comprising administering to the individual in need thereof, a therapeutically effective amount of a compound, selected from the compound of Formula (I) and pharmaceutically acceptable salts, solvates, and hydrates thereof, or a composition thereof.
  • One aspect of the present invention pertains to methods for the treatment of dyslipidemia in an individual, comprising administering to the individual in need thereof, a therapeutically effective amount of a compound, selected from the compound of Formula (I) and
  • One aspect of the present invention pertains to methods for the treatment of syndrome X in an individual, comprising administering to the individual in need thereof, a therapeutically effective amount of a compound, selected from the compound of Formula (I) and pharmaceutically acceptable salts, solvates, and hydrates thereof, or a composition thereof.
  • the individual is a mammal.
  • the mammal is a human.
  • One aspect of the present invention pertains to methods of treating obesity in an individual comprising administering to the individual in need of treatment a therapeutically effective amount of a compound, selected from the compound of Formula (I) and
  • One aspect of the present invention pertains to methods of decreasing food intake of an individual comprising administering to the individual in need thereof a therapeutically effective amount of a compound, selected from the compound of Formula (I) and pharmaceutically acceptable salts, solvates, and hydrates thereof, or a composition thereof.
  • One aspect of the present invention pertains to methods of inducing satiety in an individual comprising administering to the individual in need thereof a therapeutically effective amount of a compound, selected from the compound of Formula (I) and pharmaceutically acceptable salts, solvates, and hydrates thereof, or a composition thereof.
  • One aspect of the present invention pertains to methods of controlling or decreasing weight gain of an individual comprising administering to the individual in need thereof a therapeutically effective amount of a compound, selected from the compound of Formula (I) and pharmaceutically acceptable salts, solvates, and hydrates thereof, or a composition thereof.
  • One aspect of the present invention pertains to methods for the treatment of a GPRl 19 receptor related disorder in an individual, comprising administering to the individual in need thereof, a therapeutically effective amount of a compound according to claim 1 in combination with an inhibitor of DPP-IV, wherein the compound and the inhibitor of DPP-IV are administered simultaneously, separately, or sequentially.
  • the compound and the inhibitor of DPP-IV are administered simultaneously.
  • the compound and the inhibitor of DPP-IV are administered separately.
  • the compound and the inhibitor of DPP-IV are administered sequentially.
  • the GPRl 19 receptor related disorder is a metabolic-related disorder.
  • the metabolic-related disorder is selected from the group consisting of:
  • diabetes mellitus type 1 diabetes, type 2 diabetes, inadequate glucose tolerance, impaired glucose tolerance, insulin resistance, hyperglycemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, dyslipidemia, atherosclerosis, stroke, syndrome X, hypertension, pancreatic beta-cell insufficiency, enteroendocrine cell insufficiency, glucosuria, metabolic acidosis, cataracts, diabetic nephropathy, diabetic neuropathy, peripheral neuropathy, diabetic coronary artery disease, diabetic cerebrovascular disease, diabetic peripheral vascular disease, diabetic retinopathy, metabolic syndrome, a condition related to diabetes mellitus, myocardial infarction, learning impairment, memory impairment, a neurodegenerative disorder, a condition ameliorated by increasing a blood GLP- 1 level in an individual with a neurodegenerative disorder, excitotoxic brain damage caused by severe epileptic seizures, Alzheimer's disease, Parkinson's disease, Huntington's disease, prion-associated disease, stroke, motor-
  • the metabolic-related disorder is type 2 diabetes.
  • the metabolic-related disorder is hyperglycemia.
  • the metabolic-related disorder is hyperlipidemia.
  • the metabolic-related disorder is hypertriglyceridemia.
  • the metabolic-related disorder is type 1 diabetes.
  • the metabolic-related disorder is dyslipidemia.
  • the metabolic-related disorder is syndrome X.
  • One aspect of the present invention pertains to methods of treating obesity in an individual comprising administering to the individual in need of treatment a therapeutically effective amount of a compound according to claim 1 in combination with an inhibitor of DPP- IV, wherein the compound and the inhibitor of DPP-IV are administered simultaneously, separately, or sequentially.
  • One aspect of the present invention pertains to methods of decreasing food intake of an individual comprising administering to the individual in need thereof a therapeutically effective amount of a compound according to claim 1 in combination with an inhibitor of DPP-IV, wherein the compound and the inhibitor of DPP-IV are administered simultaneously, separately, or sequentially.
  • One aspect of the present invention pertains to methods of inducing satiety in an individual comprising administering to the individual in need thereof a therapeutically effective amount of a compound according to claim 1 in combination with an inhibitor of DPP-IV, wherein the compound and the inhibitor of DPP-IV are administered simultaneously, separately, or sequentially.
  • One aspect of the present invention pertains to methods of controlling or decreasing weight gain of an individual comprising administering to the individual in need thereof a therapeutically effective amount of a compound according to claim 1 in combination with an inhibitor of DPP-IV, wherein the compound and the inhibitor of DPP-IV are administered simultaneously, separately, or sequentially.
  • the compound and the inhibitor of DPP-IV are administered simultaneously.
  • the compound and the inhibitor of DPP-IV are administered separately.
  • the compound and the inhibitor of DPP-IV are administered sequentially.
  • One aspect of the present invention pertains to the use of a compound, selected from the compound of Formula (I) and pharmaceutically acceptable salts, solvates, and hydrates thereof, or a composition thereof in the manufacture of a medicament for modulating the activity of a GPRl 19 receptor.
  • One aspect of the present invention pertains to the use of a compound, selected from the compound of Formula (I) and pharmaceutically acceptable salts, solvates, and hydrates thereof, or a composition thereof in the manufacture of a medicament for agonizing a GPRl 19 receptor.
  • One aspect of the present invention pertains to the use of a compound, selected from the compound of Formula (I) and pharmaceutically acceptable salts, solvates, and hydrates thereof, or a composition thereof in the manufacture of a medicament for the treatment of a GPRl 19 receptor related disorder.
  • One aspect of the present invention pertains to the use of a compound, selected from the compound of Formula (I) and pharmaceutically acceptable salts, solvates, and hydrates thereof, or a composition thereof in the manufacture of a medicament for the treatment of a metabolic-related disorder.
  • One aspect of the present invention pertains to the use of a compound, selected from the compound of Formula (I) and pharmaceutically acceptable salts, solvates, and hydrates thereof, or a composition thereof in the manufacture of a medicament for the treatment of a metabolic- related disorder selected from the group consisting of:
  • diabetes mellitus type 1 diabetes, type 2 diabetes, inadequate glucose tolerance, impaired glucose tolerance, insulin resistance, hyperglycemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, dyslipidemia, atherosclerosis, stroke, syndrome X, hypertension, pancreatic beta-cell insufficiency, enteroendocrine cell insufficiency, glucosuria, metabolic acidosis, cataracts, diabetic nephropathy, diabetic neuropathy, peripheral neuropathy, diabetic coronary artery disease, diabetic cerebrovascular disease, diabetic peripheral vascular disease, diabetic retinopathy, metabolic syndrome, a condition related to diabetes mellitus, myocardial infarction, learning impairment, memory impairment, a neurodegenerative disorder, a condition ameliorated by increasing a blood GLP- 1 level in an individual with a neurodegenerative disorder, excitotoxic brain damage caused by severe epileptic seizures, Alzheimer's disease, Parkinson's disease, Huntington's disease, prion-associated disease, stroke, motor-
  • One aspect of the present invention pertains to the use of a compound, selected from the compound of Formula (I) and pharmaceutically acceptable salts, solvates, and hydrates thereof, or a composition thereof in the manufacture of a medicament for the treatment of type 2 diabetes.
  • One aspect of the present invention pertains to the use of a compound, selected from the compound of Formula (I) and pharmaceutically acceptable salts, solvates, and hydrates thereof, or a composition thereof in the manufacture of a medicament for the treatment of hyperglycemia.
  • One aspect of the present invention pertains to the use of a compound, selected from the compound of Formula (I) and pharmaceutically acceptable salts, solvates, and hydrates thereof, or a composition thereof in the manufacture of a medicament for the treatment of hyperlipidemia.
  • One aspect of the present invention pertains to the use of a compound, selected from the compound of Formula (I) and pharmaceutically acceptable salts, solvates, and hydrates thereof, or a composition thereof in the manufacture of a medicament for the treatment of
  • One aspect of the present invention pertains to the use of a compound, selected from the compound of Formula (I) and pharmaceutically acceptable salts, solvates, and hydrates thereof, or a composition thereof in the manufacture of a medicament for the treatment of type 1 diabetes.
  • One aspect of the present invention pertains to the use of a compound, selected from the compound of Formula (I) and pharmaceutically acceptable salts, solvates, and hydrates thereof, or a composition thereof in the manufacture of a medicament for the treatment of dyslipidemia.
  • One aspect of the present invention pertains to the use of a compound, selected from the compound of Formula (I) and pharmaceutically acceptable salts, solvates, and hydrates thereof, or a composition thereof in the manufacture of a medicament for the treatment of syndrome X.
  • One aspect of the present invention pertains to the use of a compound, selected from the compound of Formula (I) and pharmaceutically acceptable salts, solvates, and hydrates thereof, or a composition thereof in the manufacture of a medicament for the treatment of obesity.
  • One aspect of the present invention pertains to the use of a compound, selected from the compound of Formula (I) and pharmaceutically acceptable salts, solvates, and hydrates thereof, or a composition thereof in the manufacture of a medicament for decreasing food intake in an individual.
  • One aspect of the present invention pertains to the use of a compound, selected from the compound of Formula (I) and pharmaceutically acceptable salts, solvates, and hydrates thereof, or a composition thereof in the manufacture of a medicament for inducing satiety in an individual.
  • One aspect of the present invention pertains to the use of a compound, selected from the compound of Formula (I) and pharmaceutically acceptable salts, solvates, and hydrates thereof, or a composition thereof in the manufacture of a medicament for controlling or decreasing weight gain in an individual.
  • One aspect of the present invention pertains to compounds of the present invention or compositions thereof for use in a method of treatment of the human or animal body by therapy.
  • One aspect of the present invention pertains to compounds of the present invention or compositions thereof for use in a method of modulating the activity of a GPRl 19 receptor.
  • One aspect of the present invention pertains to compounds of the present invention or compositions thereof for use in a method of agonizing a GPRl 19 receptor.
  • One aspect of the present invention pertains to compounds of the present invention or compositions thereof for use in a method of treatment of a GPRl 19 receptor related disorder.
  • One aspect of the present invention pertains to compounds of the present invention or compositions thereof for use in a method of treatment of a metabolic-related disorder.
  • One aspect of the present invention pertains to compounds of the present invention or compositions thereof for use in a method of treatment of a metabolic-related disorder selected from the group consisting of:
  • diabetes mellitus type 1 diabetes, type 2 diabetes, inadequate glucose tolerance, impaired glucose tolerance, insulin resistance, hyperglycemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, dyslipidemia, atherosclerosis, stroke, syndrome X, hypertension, pancreatic beta-cell insufficiency, enteroendocrine cell insufficiency, glucosuria, metabolic acidosis, cataracts, diabetic nephropathy, diabetic neuropathy, peripheral neuropathy, diabetic coronary artery disease, diabetic cerebrovascular disease, diabetic peripheral vascular disease, diabetic retinopathy, metabolic syndrome, a condition related to diabetes mellitus, myocardial infarction, learning impairment, memory impairment, a neurodegenerative disorder, a condition ameliorated by increasing a blood GLP- 1 level in an individual with a neurodegenerative disorder, excitotoxic brain damage caused by severe epileptic seizures, Alzheimer's disease, Parkinson's disease, Huntington's disease, prion-associated disease, stroke, motor-
  • One aspect of the present invention pertains to compounds of the present invention or compositions thereof for use in a method of treatment of type 2 diabetes.
  • One aspect of the present invention pertains to compounds of the present invention or compositions thereof for use in a method of treatment of hyperglycemia.
  • One aspect of the present invention pertains to compounds of the present invention or compositions thereof for use in a method of treatment of hyperlipidemia.
  • One aspect of the present invention pertains to compounds of the present invention or compositions thereof for use in a method of treatment of hypertriglyceridemia.
  • One aspect of the present invention pertains to compounds of the present invention or compositions thereof for use in a method of treatment of type 1 diabetes.
  • One aspect of the present invention pertains to compounds of the present invention or compositions thereof for use in a method of treatment of dyslipidemia.
  • One aspect of the present invention pertains to compounds of the present invention or compositions thereof for use in a method of treatment of syndrome X.
  • One aspect of the present invention pertains to compounds of the present invention or compositions thereof for use in a method of treatment of obesity.
  • One aspect of the present invention pertains to compounds of the present invention or compositions thereof for use in decreasing food intake in an individual.
  • One aspect of the present invention pertains to compounds of the present invention for use in inducing satiety in an individual.
  • One aspect of the present invention pertains to compounds of the present invention or compositions thereof for use in controlling or decreasing weight gain in an individual.
  • the individual is a mammal. In some embodiments, the mammal is a human. In some embodiments, the human has a body mass index of about 18.5 to about 45 or greater. In some embodiments, the human has a body mass index of about 18.5 to about 45. In some embodiments, the human has a body mass index of about 25 to about 45. In some embodiments, the human has a body mass index of about 30 to about 45. In some embodiments, the human has a body mass index of about 35 to about 45.
  • the present invention includes every combination of one or more metabolic-related disorders selected from the group consisting of diabetes mellitus, type 1 diabetes, type 2 diabetes, inadequate glucose tolerance, impaired glucose tolerance, insulin resistance, hyperglycemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, dyslipidemia, atherosclerosis, stroke, syndrome X, hypertension, pancreatic beta-cell insufficiency, enteroendocrine cell insufficiency, glucosuria, metabolic acidosis, cataracts, diabetic nephropathy, diabetic neuropathy, peripheral neuropathy, diabetic coronary artery disease, diabetic cerebrovascular disease, diabetic peripheral vascular disease, diabetic retinopathy, metabolic syndrome, a condition related to diabetes mellitus, myocardial infarction, learning impairment, memory impairment, a neurodegenerative disorder, a condition ameliorated by increasing a blood GLP- 1 level in an individual with a neurodegenerative disorder, excitotoxic brain damage caused by severe epileptic seizures, Alzheimer's disease,
  • Some embodiments of the present invention include every combination of one or more metabolic-related disorder selected from the group consisting of type 2 diabetes, hyperglycemia, hyperinsulinemia, hyperlipidemia, hypertriglyceridemia, insulin resistance, type 1 diabetes, idiopathic type 1 diabetes (type Ib), latent autoimmune diabetes in adults (LADA), early-onset type 2 diabetes (EOD), youth-onset atypical diabetes (YOAD), maturity onset diabetes of the young (MODY), malnutrition-related diabetes, gestational diabetes, coronary heart disease, vascular restenosis, restenosis, restenosis after angioplasty, peripheral vascular disease, claudication, intermittent claudication, cell death associated with myocardial infarction (e.g.
  • necrosis and apoptosis dyslipidemia, post-prandial lipemia, conditions of impaired glucose tolerance (IGT), impaired glucose metabolism, conditions of impaired glucose metabolism, conditions of impaired fasting plasma glucose, metabolic acidosis, ketosis, arthritis, obesity, osteoporosis, hypertension, congestive heart failure, left ventricular hypertrophy, peripheral arterial disease, diabetic retinopathy, macular degeneration, cataract, diabetic nephropathy, glomerulosclerosis, chronic renal failure, diabetic neuropathy, metabolic syndrome, syndrome X, premenstrual syndrome, angina pectoris, thrombosis, atherosclerosis, ischemic stroke, transient ischemic attacks, stroke, erectile dysfunction, skin and connective tissue disorders, foot ulcerations, ulcerative colitis, endothelial dysfunction, and impaired vascular compliance.
  • ITT impaired glucose tolerance
  • impaired glucose metabolism conditions of impaired glucose metabolism, conditions of impaired fasting plasma glucose
  • metabolic acidosis ketosis
  • ketosis arthritis
  • obesity osteoporos
  • One aspect of the present invention pertains to methods of preparing compositions comprising the step of admixing a compound, selected from the compound of Formula (I) and pharmaceutically acceptable salts, solvates, and hydrates thereof, and a pharmaceutically acceptable carrier.
  • One aspect of the present invention pertains to methods of preparing pharmaceutically compositions comprising the step of admixing a compound, selected from the compound of Formula (I) and pharmaceutically acceptable salts, solvates, and hydrates thereof, and a pharmaceutically acceptable carrier.
  • One aspect of the present invention pertains to methods of preparing compositions comprising the step of admixing a compound, selected from the compound of Formula (I) and pharmaceutically acceptable salts, solvates, and hydrates thereof, and an inhibitor of DPP-IV.
  • One aspect of the present invention pertains to methods of preparing compositions comprising the step of admixing a compound, selected from the compound of Formula (I) and pharmaceutically acceptable salts, solvates, and hydrates thereof, with an inhibitor of DPP-IV, and a pharmaceutically acceptable carrier.
  • One aspect of the present invention pertains to methods of preparing compositions further comprising the step of preparing a unit dosage form from the composition.
  • One aspect of the present invention pertains to methods of preparing a dosage form of a pharmaceutical composition for the treatment of a GPRl 19 receptor related disorder in an individual, the pharmaceutical composition comprising a compound of Formula (I) and pharmaceutically acceptable salts, solvates, and hydrates thereof, and an inhibitor of DPP-IV; the method comprising:
  • One aspect of the present invention pertains to methods of preparing a dosage form of a pharmaceutical composition for the treatment of a GPRl 19 receptor related disorder selected from the group consisting of:
  • diabetes mellitus type 1 diabetes, type 2 diabetes, inadequate glucose tolerance, impaired glucose tolerance, insulin resistance, hyperglycemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, dyslipidemia, atherosclerosis, stroke, syndrome X, hypertension, pancreatic beta-cell insufficiency, enteroendocrine cell insufficiency, glucosuria, metabolic acidosis, cataracts, diabetic nephropathy, diabetic neuropathy, peripheral neuropathy, diabetic coronary artery disease, diabetic cerebrovascular disease, diabetic peripheral vascular disease, diabetic retinopathy, metabolic syndrome, a condition related to diabetes mellitus, myocardial infarction, learning impairment, memory impairment, a neurodegenerative disorder, a condition ameliorated by increasing a blood GLP- 1 level in an individual with a neurodegenerative disorder, excitotoxic brain damage caused by severe epileptic seizures, Alzheimer's disease,
  • Parkinson's disease Huntington's disease, prion-associated disease, stroke, motor-neuron disease, traumatic brain injury, spinal cord injury, and obesity.
  • the combined preparation is in the form of a twin pack.
  • the first pharmaceutically acceptable carrier and the second pharmaceutically acceptable carrier in steps (a) and (b) are different.
  • the first pharmaceutically acceptable carrier and the second pharmaceutically acceptable carrier in steps (a) and (b) are substantially the same.
  • the combined preparation is for simultaneous use.
  • the combined preparation is for separate use.
  • the combined preparation is for sequential use.
  • One aspect of the present invention pertains to methods of preparing a dosage form of a pharmaceutical composition for increasing blood GLP- 1 level in an individual, the
  • composition comprising a compound of Formula (I) and pharmaceutically acceptable salts, solvates, and hydrates thereof, and an inhibitor of DPP-IV; the method comprising:
  • the combined preparation is in the form of a twin pack.
  • the first pharmaceutically acceptable carrier and the second pharmaceutically acceptable carrier in steps (a) and (b) are different.
  • the first pharmaceutically acceptable carrier and the second pharmaceutically acceptable carrier in steps (a) and (b) are substantially the same.
  • the combined preparation is for simultaneous use.
  • the combined preparation is for separate use.
  • the combined preparation is for sequential use.
  • the amount of the compound of Formula (I) and pharmaceutically acceptable salts, solvates, and hydrates thereof, alone and the amount of the inhibitor of DPP-IV alone are therapeutically ineffective in increasing a blood GLP- 1 level in the individual.
  • One aspect of the present invention pertains to compounds of Formula (I) and pharmaceutically acceptable salts, solvates, and hydrates thereof, for use in combination with an inhibitor of DPP-IV for the treatment of a condition ameliorated by increasing a blood GLP- 1 level in a mammal.
  • the amount of compound of Formula (I) and pharmaceutically acceptable salts, solvates, and hydrates thereof, alone is therapeutically ineffective for treatment of a condition ameliorated by increasing a blood GLP- 1 level in a mammal.
  • One aspect of the present invention pertains to an inhibitor of DPP-IV for use in combination with compounds of Formula (I) and pharmaceutically acceptable salts, solvates, and hydrates thereof, for the treatment of a condition ameliorated by increasing a blood GLP- 1 level in a mammal.
  • the amount of the inhibitor of DPP-IV alone is therapeutically ineffective for treatment of a condition ameliorated by increasing a blood GLP- 1 level in a mammal.
  • condition ameliorated by increasing a blood GLP- 1 level is selected from the group consisting of:
  • diabetes mellitus type 1 diabetes, type 2 diabetes, inadequate glucose tolerance, impaired glucose tolerance, insulin resistance, hyperglycemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, dyslipidemia, atherosclerosis, stroke, syndrome X, hypertension, pancreatic beta-cell insufficiency, enteroendocrine cell insufficiency, glucosuria, metabolic acidosis, cataracts, diabetic nephropathy, diabetic neuropathy, peripheral neuropathy, diabetic coronary artery disease, diabetic cerebrovascular disease, diabetic peripheral vascular disease, diabetic retinopathy, metabolic syndrome, a condition related to diabetes mellitus, myocardial infarction, learning impairment, memory impairment, a neurodegenerative disorder, a condition ameliorated by increasing a blood GLP- 1 level in an individual with a neurodegenerative disorder, excitotoxic brain damage caused by severe epileptic seizures, Alzheimer's disease, Parkinson's disease, Huntington's disease, prion-associated disease, stroke, motor-
  • compositions comprising compounds of Formula (I) and pharmaceutically acceptable salts, solvates, and hydrates thereof, for use in combination with an inhibitor of DPP-IV for the treatment of a condition ameliorated by increasing a blood GLP- 1 level in a mammal.
  • the amount of the compound alone is therapeutically ineffective for treatment of a condition ameliorated by increasing a blood GLP- 1 level in a mammal.
  • One aspect of the present invention pertains to pharmaceutical compositions comprising an inhibitor of DPP-IV for use in combination with compounds of Formula (I) and
  • condition ameliorated by increasing a blood GLP- 1 level is selected from the group consisting of:
  • diabetes mellitus type 1 diabetes, type 2 diabetes, inadequate glucose tolerance, impaired glucose tolerance, insulin resistance, hyperglycemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, dyslipidemia, atherosclerosis, stroke, syndrome X, hypertension, pancreatic beta-cell insufficiency, enteroendocrine cell insufficiency, glucosuria, metabolic acidosis, cataracts, diabetic nephropathy, diabetic neuropathy, peripheral neuropathy, diabetic coronary artery disease, diabetic cerebrovascular disease, diabetic peripheral vascular disease, diabetic retinopathy, metabolic syndrome, a condition related to diabetes mellitus, myocardial infarction, learning impairment, memory impairment, a neurodegenerative disorder, a neurodegenerative disorder, excitotoxic brain damage caused by severe epileptic seizures, Alzheimer's disease, Parkinson's disease, Huntington's disease, prion-associated disease, stroke, motor-neuron disease, traumatic brain injury, spinal cord injury, and obesity.
  • One aspect of the present invention pertains to dosage forms of a pharmaceutical composition as described herein.
  • One aspect of the present invention pertains to combined preparations comprising a compound of Formula (I) and pharmaceutically acceptable salts, solvates, and hydrates thereof, and an inhibitor of DPP-IV for simultaneous, separate or sequential use for the treatment of diabetes mellitus or a condition related thereto.
  • the amount of the compound selected from compounds of Formula (I) and pharmaceutically acceptable salts, solvates, and hydrates thereof, alone and the amount of an inhibitor of DPP-IV are therapeutically ineffective in lowering blood glucose levels in a subject.
  • the compounds and inhibitors of DPP-IV are admixed with pharmaceutically acceptable carriers. In some embodiments, the compound and the inhibitor of DPP-IV are admixed with different pharmaceutically acceptable carriers.
  • the condition related to diabetes mellitus is selected from the group consisting of hyperglycemia, impaired glucose tolerance, insulin resistance, pancreatic beta-cell insufficiency, enteroendocrine cell insufficiency, glucosuria, metabolic acidosis, cataracts, diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, diabetic coronary artery disease, diabetic cerebrovascular disease, diabetic peripheral vascular disease, metabolic syndrome, hyperlipidemia, atherosclerosis, stroke, hypertension, and obesity.
  • twin packs comprising compounds of Formula (I) and pharmaceutically acceptable salts, solvates, and hydrates thereof, and inhibitors of DPP-IV as a combined preparation for the treatment of diabetes mellitus or a condition related thereto.
  • the compound and the inhibitor of DPP-IV are admixed with different pharmaceutically acceptable carriers.
  • the different pharmaceutically acceptable carriers are suitable for administration by different routes.
  • the condition related to diabetes mellitus is selected from the group consisting of hyperglycemia, impaired glucose tolerance, insulin resistance, pancreatic beta-cell insufficiency, enteroendocrine cell insufficiency, glucosuria, metabolic acidosis, cataracts, diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, diabetic coronary artery disease, diabetic cerebrovascular disease, diabetic peripheral vascular disease, metabolic syndrome, hyperlipidemia, atherosclerosis, stroke, hypertension, and obesity.
  • kits comprising (a) a first package comprising a compound according to claim 1 or a pharmaceutical composition thereof, and (b) a second package comprising an inhibitor of DPP-IV.
  • the present disclosure includes all isotopes of atoms occurring in the present compounds, salts and crystalline forms thereof.
  • Isotopes include those atoms having the same atomic number but different mass numbers.
  • isotopes of hydrogen include 2 H (deuterium) and 3 H (tritium).
  • isotopes of carbon include 13 C and 14 C.
  • agonist is intended to mean a moiety that interacts and activates the receptor, such as, the GPRl 19 receptor and initiates a physiological or pharmacological response characteristic of that receptor. For example, when moieties activate the intracellular response upon binding to the receptor, or enhance GTP binding to membranes.
  • composition is intended to mean a material comprising at least two components; for example, and without limitation, a composition comprising a compound of the present invention and a pharmaceutically acceptable carrier.
  • contacting is intended to mean bringing the indicated moieties together, whether in an in vitro system or an in vivo system.
  • "contacting" a GPRl 19 receptor with a compound of the invention includes the administration of a compound of the present invention to an individual, preferably a human, having a GPRl 19 receptor, as well as, for example, introducing a compound of the invention into a sample containing a cellular or more purified preparation containing a GPRl 19 receptor.
  • hydrate as used herein means a compound of the invention or a salt thereof, that further includes a stoichiometric or non- stoichiometric amount of water bound by non- covalent intermolecular forces.
  • in need of treatment and "in need thereof,” when referring to treatment are used interchangeably to mean a judgment made by a caregiver (e.g. physician, nurse, nurse practitioner, etc. in the case of humans; veterinarian in the case of animals, including non-human mammals) that an individual or animal requires or will benefit from treatment. This judgment is made based on a variety of factors that are in the realm of a caregiver's expertise, but that includes the knowledge that the individual or animal is ill, or will become ill, as the result of a disease, condition or disorder that is treatable by the compounds of the invention. Accordingly, the compounds of the invention can be used in a protective or preventive manner; or compounds of the invention can be used to alleviate, inhibit or ameliorate the disease, condition or disorder.
  • a caregiver e.g. physician, nurse, nurse practitioner, etc. in the case of humans; veterinarian in the case of animals, including non-human mammals
  • the term "individual” or “subject” is intended to mean any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, or primates and most preferably humans.
  • the individual is a human and in certain embodiments, the human is an infant, child, adolescent or adult.
  • the individual is at risk for developing a GPRl 19-related disorder.
  • the individual is at risk for developing a metabolic-related disease or disorder.
  • Individuals who are at risk include, but are not limited to, those with hereditary history of a metabolic-related disease or disorder, or those in a state of physical health which puts them at risk for a metabolic-related disease or disorder.
  • the individual has been determined, by the care-giver or someone acting under the guidance of the care-giver, to have a metabolic-related disease or disorder.
  • modulate or modulating is intended to mean an increase or decrease in the amount, quality, response or effect of a particular activity, function or molecule.
  • composition is intended to mean a composition comprising at least one active ingredient; including but not limited to, salts, solvates, and hydrates of compounds of the present invention; whereby the composition is amenable to investigation for a specified, efficacious outcome in a mammal (for example, without limitation, a human).
  • a mammal for example, without limitation, a human.
  • solvate means a compound of the invention or a salt, thereof, that further includes a stoichiometric or non- stoichiometric amount of a solvent bound by non- covalent intermolecular forces.
  • Preferred solvents are volatile, non-toxic, and/or acceptable for administration to humans in trace amounts.
  • terapéuticaally effective amount is intended to mean the amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue, system, animal, individual or human that is being sought by a researcher, veterinarian, medical doctor or other clinician or caregiver; or in an individual, which includes one or more of the following:
  • Preventing the disease for example, preventing a disease, condition or disorder in an individual that may be predisposed to the disease, condition or disorder but does not yet experience or display the pathology or symptomatology of the disease;
  • Inhibiting the disease for example, inhibiting a disease, condition or disorder in an individual that is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., arresting further development of the pathology and/or symptomatology); and
  • Ameliorating the disease for example, ameliorating a disease, condition or disorder in an individual that is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., reversing the pathology and/or symptomatology).
  • 6-(l-(5-methylpyrazin-2-yl)piperidin-4-yloxy)pyrimidin-4-amine is a "full agonist”.
  • the compound N-(2-fluoro-4-(methylsulfonyl)phenyl)-5-methyl-6-(l-(5-methylpyrazin-2- yl)piperidin-4-yloxy)pyrimidin-4-amine increased cAMP levels in CHO cells expressing human GPRl 19 (GDIR) with an observed EC 50 of 6 nM (see Example IA).
  • N-(2-fluoro-4- (methylsulfonyl)phenyl)-5-methyl-6-(l -(5-methylpyrazin-2-yl)piperidin-4-yloxy)pyrimidin-4- amine stimulated GLP-I release from mouse GLUTag cells with an observed EC 50 of 54.1 nM (see Example IB) and is a potent and efficacious GPRl 19 agonist in normal Sprague-Dawley rats in vivo.
  • N-(2-fluoro-4-(methylsulfonyl)phenyl)-5-methyl-6-(l-(5- methylpyrazin-2-yl)piperidin-4-yloxy)pyrimidin-4-amine potently increased glucose clearance during the oral glucose tolerance test (oGTT) (see Example 2). Further, N-(2-fluoro-4-(methylsulfonyl)phenyl)-5-methyl-6-(l-(5- methylpyrazin-2-yl)piperidin-4-yloxy)pyrimidin-4-amine potently increased glucose clearance during the oral glucose tolerance test (oGTT) (see Example 2). Further, N-(2-fluoro-4-
  • N-(2-fluoro-4-(methylsulfonyl)phenyl)-5- methyl-6-(l-(5-methylpyrazin-2-yl)piperidin-4-yloxy)pyrimidin-4-amine inhibited 3A4, 2C9, and
  • 2C19 with approximate IC 50 values for inhibition of 9.05 ⁇ M, 8.82 ⁇ M, and >10 ⁇ M, respectively and showed no inhibition of 1 A2 and 2D6.
  • the approximate IC 50 value of inhibition for 2C9 was 6 ⁇ M and for the other P450s tested (i.e., 2Cl 9 and 3A4) the IC 5 O values were >30 ⁇ M (see Examples 4 and 5).
  • One aspect of the present invention pertains to compounds selected from the following compound N-(2-fluoro-4-(methylsulfonyl)phenyl)-5-methyl-6-(l-(5-methylpyrazin-2- yl)piperidin-4-yloxy)pyrimidin-4-amine (Compound 1), as shown in Formula (I):
  • compounds of the invention are useful in the treatment of additional diseases. Without limitation, these include the following.
  • insulin resistance The most significant pathologies in type 2 diabetes are impaired insulin signaling at its target tissues ("insulin resistance") and failure of the insulin-producing cells of the pancreas to secrete an appropriate degree of insulin in response to a hyperglycemic signal.
  • Current therapies to treat the latter include inhibitors of the ⁇ -cell ATP-sensitive potassium channel to trigger the release of endogenous insulin stores, or administration of exogenous insulin. Neither of these achieves accurate normalization of blood glucose levels and both carry the risk of inducing hypoglycemia. For these reasons, there has been intense interest in the development of pharmaceuticals that function in a glucose-dependent action, i.e. potentiators of glucose signaling.
  • Physiological signaling systems which function in this manner are well-characterized and include the gut peptides GLPl, GIP and PACAP. These hormones act via their cognate G-protein coupled receptor to stimulate the production of cAMP in pancreatic ⁇ -cells. The increased cAMP does not appear to result in stimulation of insulin release during the fasting or preprandial state.
  • a series of biochemical targets of cAMP signaling including the ATP-sensitive potassium channel, voltage-sensitive potassium channels and the exocytotic machinery, are modified in such a way that the insulin secretory response to a postprandial glucose stimulus is markedly enhanced. Accordingly, agonists of novel, similarly functioning, ⁇ -cell GPCRs, including GPRl 19, would also stimulate the release of endogenous insulin and consequently promote normoglycemia in type 2 diabetes.
  • cAMP for example as a result of GLP- 1 stimulation, promotes ⁇ -cell proliferation, inhibits ⁇ -cell death and thus improves islet mass.
  • This positive effect on ⁇ -cell mass is expected to be beneficial in both type 2 diabetes, where insufficient insulin is produced, and type 1 diabetes, where ⁇ -cells are destroyed by an inappropriate autoimmune response.
  • Some ⁇ -cell GPCRs, including GPRl 19, are also present in the hypothalamus where they modulate hunger, satiety, decrease food intake, controlling or decreasing weight and energy expenditure. Hence, given their function within the hypothalamic circuitry, agonists or inverse agonists of these receptors mitigate hunger, promote satiety and therefore modulate weight.
  • the metabolic-related disorder is selected from the group consisting of type 2 diabetes, hyperglycemia, hyperinsulinemia, hyperlipidemia, hypertriglyceridemia, insulin resistance, type 1 diabetes, idiopathic type 1 diabetes (type Ib), latent autoimmune diabetes in adults (LADA), early-onset type 2 diabetes (EOD), youth-onset atypical diabetes (YOAD), maturity onset diabetes of the young (MODY), malnutrition-related diabetes, gestational diabetes, cardiovascular disease, coronary heart disease, vascular restenosis, restenosis, restenosis after angioplasty, peripheral vascular disease, claudication, intermittent claudication, cell death associated with myocardial infarction (e.g.
  • ITT impaired glucose tolerance
  • impaired glucose metabolism conditions of impaired glucose metabolism, conditions of impaired fasting plasma glucose, metabolic acidosis, ketosis, arthritis, obesity, osteoporosis, hypertension, congestive heart failure, left ventricular hypertrophy, peripheral arterial disease, diabetic retinopathy, macular degeneration, cataract, diabetic nephropathy, glomerulosclerosis, chronic renal failure, diabetic neuropathy, metabolic syndrome, syndrome X, premenstrual syndrome, angina pectoris, thrombosis, atherosclerosis, ischemic stroke, transient ischemic attacks, stroke, erectile dysfunction, skin and connective tissue disorders, foot ulcerations, ulcerative colitis, endothelial dysfunction, and impaired vascular compliance.
  • COMPOSITIONS AND SALTS impaired glucose tolerance
  • compositions comprising a compound selected from N-(2-fluoro-4-(methylsulfonyl)phenyl)-5-methyl-6-(l -(5-methylpyrazin-2- yl)piperidin-4-yloxy)pyrimidin-4-amine (Compound 1), and pharmaceutically acceptable salts, solvates, and hydrates thereof.
  • a further aspect of the present invention pertains to compositions comprising a compound selected from N-(2-fluoro-4-(methylsulfonyl)phenyl)-5-methyl-6-(l-(5-methylpyrazin- 2-yl)piperidin-4-yloxy)pyrimidin-4-amine (Compound 1), and pharmaceutically acceptable salts, solvates, and hydrates thereof, and one or more pharmaceutically acceptable carriers.
  • Compound 1 N-(2-fluoro-4-(methylsulfonyl)phenyl)-5-methyl-6-(l-(5-methylpyrazin- 2-yl)piperidin-4-yloxy)pyrimidin-4-amine
  • a further aspect of the present invention pertains to pharmaceutical compositions comprising a compound selected from N-(2-fluoro-4-(methylsulfonyl)phenyl)-5-methyl-6-(l-(5- methylpyrazin-2-yl)piperidin-4-yloxy)pyrimidin-4-amine (Compound 1), and pharmaceutically acceptable salts, solvates, and hydrates thereof, and one or more pharmaceutically acceptable carriers.
  • Compound 1 N-(2-fluoro-4-(methylsulfonyl)phenyl)-5-methyl-6-(l-(5- methylpyrazin-2-yl)piperidin-4-yloxy)pyrimidin-4-amine
  • compositions comprising N-(2- fluoro-4-(methylsulfonyl)phenyl)-5-methyl-6-(l-(5-methylpyrazin-2-yl)piperidin-4- yloxy)pyrimidin-4-amine and a pharmaceutically acceptable carrier.
  • composition comprising admixing N-(2-fluoro-4-(methylsulfonyl)phenyl)-5- methyl-6-(l-(5-methylpyrazin-2-yl)piperidin-4-yloxy)pyrimidin-4-amine or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
  • Compositions may be prepared by any suitable method, typically by uniformly mixing the active compound with liquids or finely divided solid carriers, or both, in the required proportions, and then, if necessary, forming the resulting mixture into a desired shape.
  • Liquid preparations for oral administration may be in the form of solutions, emulsions, aqueous or oily suspensions, and syrups.
  • the oral preparations may be in the form of dry powder that can be reconstituted with water or another suitable liquid vehicle before use.
  • Parenteral dosage forms may be prepared by dissolving the compound of the invention in a suitable liquid vehicle and filter sterilizing the solution before filling and sealing an appropriate vial or ampoule. These are just a few examples of the many appropriate methods well known in the art for preparing dosage forms.
  • a compound of the present invention can be formulated into pharmaceutical
  • compositions using techniques well known to those in the art. Suitable pharmaceutically- acceptable carriers, outside those mentioned herein, are known in the art; for example, see Remington, The Science and Practice of Pharmacy, 20th Edition, 2000, Lippincott Williams & Wilkins, (Editors: Gennaro, A. R., et al.).
  • a compound of the invention can, in an alternative use, be administered as a raw or pure chemical, it is preferable however to present the compound or active ingredient as a pharmaceutical formulation or composition further comprising a pharmaceutically acceptable carrier.
  • compositions comprising a compound of the invention or a pharmaceutically acceptable salt or derivative thereof together with one or more pharmaceutically acceptable carriers thereof and/or prophylactic ingredients.
  • the carrier(s) must be "acceptable” in the sense of being compatible with the other ingredients of the composition and not overly deleterious to the recipient thereof.
  • compositions include those suitable for oral, rectal, nasal, topical (including buccal and sub-lingual), vaginal or parenteral (including intramuscular, sub-cutaneous and intravenous) administration or in a form suitable for administration by inhalation, insufflation or by a transdermal patch.
  • Transdermal patches dispense a drug at a controlled rate by presenting the drug for absorption in an efficient manner with a minimum of degradation of the drug.
  • transdermal patches comprise an impermeable backing layer, a single pressure sensitive adhesive and a removable protective layer with a release liner.
  • a desired efficacious transdermal patch based upon the needs of the artisan.
  • compositions and unit dosages thereof may thus be placed into the form of pharmaceutical compositions and unit dosages thereof, and in such form may be employed as solids, such as tablets or filled capsules, or liquids such as solutions, suspensions, emulsions, elixirs, gels or capsules filled with the same, all for oral use, in the form of suppositories for rectal administration; or in the form of sterile injectable solutions for parenteral (including subcutaneous) use.
  • Such pharmaceutical compositions and unit dosage forms thereof may comprise conventional ingredients in conventional proportions, with or without additional active compounds or principles, and such unit dosage forms may contain any suitable effective amount of the active ingredient commensurate with the intended daily dosage range to be employed.
  • the pharmaceutical composition may be in the form of, for example, a tablet, capsule, suspension or liquid.
  • the pharmaceutical composition is preferably made in the form of a dosage unit containing a particular amount of the active ingredient.
  • Examples of such dosage units are capsules, tablets, powders, granules or a suspension, with conventional additives such as lactose, mannitol, corn starch or potato starch; with binders such as crystalline cellulose, cellulose derivatives, acacia, corn starch or gelatins; with disintegrators such as corn starch, potato starch or sodium carboxymethyl-cellulose; and with lubricants such as talc or magnesium stearate.
  • the active ingredient may also be administered by injection as a composition wherein, for example, saline, dextrose or water may be used as a suitable pharmaceutically acceptable carrier.
  • the dose when using the compounds of the present invention can vary within wide limits, and as is customary and known to the physician, it is to be tailored to the individual conditions in each individual case. It depends, for example, on the nature and severity of the illness to be treated, on the condition of the patient, on the compound employed or on whether an acute or chronic disease state is treated or prophylaxis is conducted or on whether further active compounds are administered in addition to the compounds of the present invention.
  • doses of the present invention include, but are not limited to, about 0.001 mg to about 5000 mg, about 0.001 to about 2500 mg, about 0.001 to about 1000 mg, 0.001 to about 500 mg, 0.001 mg to about 250 mg, about 0.001 mg to 100 mg, about 0.001 mg to about 50 mg, and about 0.001 mg to about 25 mg.
  • the desired dose may conveniently be presented in a single dose or as divided doses administered at appropriate intervals, for example, as two, three, four or more sub-doses per day.
  • the sub-dose itself may be further divided, e.g., into a number of discrete loosely spaced administrations. Depending on the individual and as deemed appropriate from the patient's physician or care-giver it may be necessary to deviate upward or downward from the doses described herein.
  • a compound of the invention, or pharmaceutically acceptable salt thereof, required for use in treatment will vary not only with the particular salt selected but also with the route of administration, the nature of the condition being treated and the age and condition of the patient and will ultimately be at the discretion of the attendant physician or clinician.
  • animal models include, but are not limited to, the rodent diabetes model as described in Example 1 , infra (as well as other animal models known in the art, such as those reported by Reed and Scribner in Diabetes, Obesity and Metabolism, 1, 1999, 75-86).
  • these extrapolations may merely be based on the weight of the animal in the respective model in comparison to another, such as a mammal, preferably a human, however, more often, these extrapolations are not simply based on weights, but rather incorporate a variety of factors.
  • Representative factors include, but are not limited to, the age, weight, sex, diet and medical condition of the patient, the severity of the disease, the route of administration, pharmacological considerations such as the activity, efficacy, pharmacokinetic and toxicology profiles of the particular compound employed, whether a drug delivery system is utilized, on whether an acute or chronic disease state is being treated or prophylaxis is conducted or on whether further active compounds are administered in addition to the compounds of the present invention and as part of a drug combination.
  • the dosage regimen for treating a disease condition with the compounds and/or compositions of this invention is selected in accordance with a variety of factors as cited above.
  • the actual dosage regimen employed may vary widely and therefore may deviate from a preferred dosage regimen and one skilled in the art will recognize that a dosage and a dosage regimen outside these typical ranges can be tested and, where appropriate, may be used in the methods of this invention.
  • the compounds of the present invention can be administered in a wide variety of oral and parenteral dosage forms. It will be obvious to those skilled in the art that the following dosage forms may comprise, as the active component, either a compound of the invention or a pharmaceutically acceptable salt of a compound of the invention.
  • a suitable pharmaceutically acceptable carrier can be either solid, liquid or a mixture of both.
  • Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules.
  • a solid carrier can be one or more substances which may also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material.
  • the carrier is a finely divided solid which is in a mixture with the finely divided active component.
  • the active component is mixed with the carrier having the necessary binding capacity in suitable proportions and compacted to the desired shape and size.
  • the powders and tablets may contain varying percentage amounts of the active compound.
  • a representative amount in a powder or tablet may contain from 0.5 to about 90 percent of the compound of the invention; however, an artisan would know when amounts outside of this range are necessary.
  • Suitable carriers for powders and tablets are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter, and the like.
  • preparation is intended to include the formulation of the active compound with encapsulating material as carrier providing a capsule in which the active component, with or without carriers, is surrounded by a carrier, which is thus in association with it.
  • carrier providing a capsule in which the active component, with or without carriers, is surrounded by a carrier, which is thus in association with it.
  • cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid forms suitable for oral administration.
  • a low melting wax such as an admixture of fatty acid glycerides or cocoa butter
  • the active component is dispersed homogeneously therein, as by stirring.
  • the molten homogenous mixture is then poured into convenient sized molds, allowed to cool, and thereby to solidify.
  • compositions suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or sprays containing in addition to the active ingredient such carriers as are known in the art to be appropriate.
  • Liquid form preparations include solutions, suspensions, and emulsions, for example, water or water-propylene glycol solutions.
  • parenteral injection liquid preparations can be formulated as solutions in aqueous polyethylene glycol solution.
  • injectable preparations for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol.
  • Suitable vehicles and solvents that may be employed are water, Ringer's solution, and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid find use in the preparation of injectables.
  • the compounds according to the present invention may thus be formulated for parenteral administration (e.g. by injection, for example bolus injection or continuous infusion) and may be presented in unit dose form in ampoules, pre-filled syringes, small volume infusion or in multi- dose containers with an added preservative.
  • the pharmaceutical compositions may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents.
  • the active ingredient may be in powder form, obtained by aseptic isolation of sterile solid or by lyophilization from solution, for constitution with a suitable vehicle, e.g. sterile, pyrogen- free water, before use.
  • Aqueous compositions suitable for oral use can be prepared by dissolving or suspending the active component in water and adding suitable colorants, flavors, stabilizing and thickening agents, as desired.
  • Aqueous suspensions suitable for oral use can be made by dispersing the finely divided active component in water with viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, or other well known suspending agents.
  • solid form preparations which are intended to be converted, shortly before use, to liquid form preparations for oral administration.
  • liquid forms include solutions, suspensions, and emulsions.
  • These preparations may contain, in addition to the active component, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like.
  • the compounds according to the invention may be formulated as ointments, creams or lotions, or as a transdermal patch.
  • Ointments and creams may, for example, be formulated with an aqueous or oily base with the addition of suitable thickening and/or gelling agents.
  • Lotions may be formulated with an aqueous or oily base and will in general also contain one or more emulsifying agents, stabilizing agents, dispersing agents, suspending agents, thickening agents, or coloring agents.
  • compositions suitable for topical administration in the mouth include lozenges comprising the active agent in a flavored base, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert base such as gelatin and glycerin or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier.
  • Solutions or suspensions are applied directly to the nasal cavity by conventional means, for example with a dropper, pipette or spray.
  • the compositions may be provided in single or multi-dose form. In the latter case of a dropper or pipette, this may be achieved by the patient administering an appropriate, predetermined volume of the solution or suspension. In the case of a spray, this may be achieved for example by means of a metering atomizing spray pump.
  • Administration to the respiratory tract may also be achieved by means of an aerosol composition in which the active ingredient is provided in a pressurized pack with a suitable propellant.
  • an aerosol composition in which the active ingredient is provided in a pressurized pack with a suitable propellant.
  • the compounds of the present invention or pharmaceutical compositions comprising them are administered as aerosols, for example as nasal aerosols or by inhalation, this can be carried out, for example, using a spray, a nebulizer, a pump nebulizer, an inhalation apparatus, a metered inhaler or a dry powder inhaler.
  • Pharmaceutical forms for administration of the compounds of the present invention as an aerosol can be prepared by processes well-known to the person skilled in the art.
  • solutions or dispersions of the compounds of the present invention in water, water/alcohol mixtures or suitable saline solutions can be employed using customary additives, for example benzyl alcohol or other suitable preservatives, absorption enhancers for increasing the bioavailability, solubilizers, dispersants and others, and, if appropriate, customary propellants, for example include carbon dioxide, CFCs, such as, dichlorodifluoromethane, trichlorofluoromethane, or dichlorotetrafluoroethane; and the like.
  • the aerosol may conveniently also contain a surfactant such as lecithin.
  • the dose of drug may be controlled by provision of a metered valve.
  • compositions intended for administration to the respiratory tract including intranasal compositions
  • the compound will generally have a small particle size for example of the order of 10 microns or less. Such a particle size may be obtained by means known in the art, for example by micronization.
  • compositions adapted to give sustained release of the active ingredient may be employed.
  • the active ingredients may be provided in the form of a dry powder, for example, a powder mix of the compound in a suitable powder base such as lactose, starch, starch derivatives such as hydroxypropylmethyl cellulose and polyvinylpyrrolidone (PVP).
  • a powder mix of the compound in a suitable powder base such as lactose, starch, starch derivatives such as hydroxypropylmethyl cellulose and polyvinylpyrrolidone (PVP).
  • the powder carrier will form a gel in the nasal cavity.
  • the powder composition may be presented in unit dose form for example in capsules or cartridges of, e.g., gelatin, or blister packs from which the powder may be administered by means of an inhaler.
  • the pharmaceutical preparations are preferably in unit dosage forms.
  • the preparation can be subdivided into unit doses containing appropriate quantities of the active component.
  • the unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as packeted tablets, capsules, and powders in vials or ampoules.
  • the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form.
  • Tablets or capsules for oral administration and liquids for intravenous administration are preferred compositions.
  • the compounds according to the invention may optionally exist as pharmaceutically acceptable salts including pharmaceutically acceptable acid addition salts prepared from pharmaceutically acceptable non-toxic acids including inorganic and organic acids.
  • the acid addition salts may be obtained as the direct product of compound synthesis.
  • the free base may be dissolved in a suitable solvent containing the appropriate acid, and the salt isolated by evaporating the solvent or otherwise separating the salt and solvent.
  • the compounds of this invention may form solvates with standard low molecular weight solvents using methods known to the skilled artisan.
  • GPRl 19 agonist and pharmaceutically acceptable salts, solvates and hydrates thereof are utilized as active ingredients in a composition, such as a pharmaceutical composition, that they are not necessarily intended for use in only humans, but in other non- human mammals as well.
  • active agents such as GPRl 19 receptor modulators
  • GPRl 19 receptor modulators for the treatment of obesity in domestic animals (e.g., cats and dogs), and GPRl 19 receptor modulators in other animals, such as livestock, where no disease or disorder is evident (e.g., food-oriented animals such as cows, chickens, fish, etc.).
  • the compounds of the present invention can be administrated in a wide variety of oral and parenteral dosage forms. It will be apparent to those skilled in the art that the following dosage forms may comprise, as the active component, a compound selected from the compound
  • one aspect of the present invention pertains to hydrates and solvates of N-(2-fluoro-4-(methylsulfonyl) phenyl)-5- methyl-6-(l -(5-methylpyrazin-2-yl)piperidin-4-yloxy)pyrimidin-4-amine and pharmaceutical acceptable salts, that can be isolated and characterized by one or more of the methods known in the art, such as, thermogravimetric analysis (TGA), TGA-mass spectroscopy, TGA-Infrared spectroscopy, powder X-ray diffraction (XRPD), Karl Fisher titration, high resolution X-ray diffraction, and the like.
  • TGA thermogravimetric analysis
  • TGA-mass spectroscopy TGA-mass spectroscopy
  • TGA-Infrared spectroscopy powder X-ray diffraction (XRPD)
  • Karl Fisher titration high resolution X-ray diffraction, and the like.
  • Polymorphism is the ability of a substance to exist as two or more crystalline phases that have different arrangements and/or conformations of the molecules in the crystal lattice.
  • Polymorphs show the same properties in the liquid or gaseous state but they behave differently in the solid state.
  • drugs can also exist as salts and other multicomponent crystalline phases.
  • solvates and hydrates may contain an API host and either solvent or water molecules, respectively, as guests.
  • the guest compound is a solid at room temperature, the resulting form is often called a cocrystal.
  • Salts, solvates, hydrates, and cocrystals may show polymorphism as well. Crystalline phases that share the same API host, but differ with respect to their guests, may be referred to as
  • Solvates contain molecules of the solvent of crystallization in a definite crystal lattice. Solvates, in which the solvent of crystallization is water, are termed hydrates. Because water is a constituent of the atmosphere, hydrates of drugs may be formed rather easily.
  • GPRl 19 receptor related diseases can be utilized for modulating the activity of GPRl 19 receptor related diseases, conditions and/or disorders as described herein.
  • modulating the activity of GPRl 19 receptor related diseases include the treatment of metabolic related disorders.
  • Metabolic related disorders include, but are not limited to, hyperlipidemia, type 1 diabetes, type 2 diabetes, and conditions associated therewith, such as, but not limited to coronary heart disease, ischemic stroke, restenosis after angioplasty, peripheral vascular disease, claudication, intermittent claudication, cell death associated with myocardial infarction (e.g.
  • necrosis and apoptosis necrosis and apoptosis
  • dyslipidemia post-prandial lipemia
  • ITT impaired glucose tolerance
  • conditions of impaired fasting plasma glucose metabolic acidosis, ketosis, arthritis, obesity, osteoporosis, hypertension, congestive heart failure, left ventricular pressure
  • hypertrophy peripheral arterial disease, diabetic retinopathy, macular degeneration, cataract, diabetic nephropathy, glomerulosclerosis, chronic renal failure, diabetic neuropathy, metabolic syndrome, syndrome X, premenstrual syndrome, coronary heart disease, angina pectoris, thrombosis, atherosclerosis, myocardial infarction, transient ischemic attacks, stroke, vascular restenosis, hyperglycemia, hyperinsulinemia, hyperlipidemia, hypertriglyceridemia, insulin resistance, impaired glucose metabolism, conditions of impaired glucose tolerance, conditions of impaired fasting plasma glucose, obesity, erectile dysfunction, skin and connective tissue disorders, foot ulcerations, ulcerative colitis, endothelial dysfunction and impaired vascular compliance.
  • metabolic related disorders include type 1 diabetes, type 2 diabetes, inadequate glucose tolerance, insulin resistance, hyperglycemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, dyslipidemia and syndrome X.
  • Other examples of modulating the activity of GPRl 19 receptor related diseases include the treatment of obesity and/or overweight by decreasing food intake, inducing satiation (i.e., the feeling of fullness), controlling weight gain, decreasing body weight and/or affecting metabolism such that the recipient loses weight and/or maintains weight.
  • a compound of the invention can be administered as the sole active pharmaceutical agent (i.e., mono-therapy), the compound can also be used in combination with one or more pharmaceutical agents (i.e., combination-therapy) either administered together or separately for the treatment of the diseases / conditions / disorders described herein. Therefore, another aspect of the present invention includes methods of treatment of a metabolic related disorder, including a weight related disorder, such as obesity, comprising administering to an individual in need of prophylaxis and/or treatment a therapeutically effective amount of a compound of the present invention in combination with one or more additional pharmaceutical agent as described herein.
  • a metabolic related disorder including a weight related disorder, such as obesity
  • Suitable pharmaceutical agents that can be used in combination with the compounds of the present invention include anti-obesity agents such as apolipoprotein-B secretion/microsomal triglyceride transfer protein (apo-B/MTP) inhibitors, MCR-4 agonists, cholescystokinin-A (CCK- A) agonists, serotonin and norepinephrine reuptake inhibitors (for example, sibutramine), sympathomimetic agents, ⁇ 3 adrenergic receptor agonists, dopamine agonists (for example, bromocriptine), melanocyte-stimulating hormone receptor analogues, cannabinoid 1 receptor antagonists [for example, SR141716: N-(piperidin-l-yi)-5-(4-chlorophenyl)-l-(2,4- dichlorophenyl)-4-methyl-lH-pyrazole-3-carboxamide], melanin concentrating hormone antagonists, leptons (the
  • GPP ghrelin receptor antagonists
  • histamine 3 receptor antagonists or reverse agonists neuromedin U receptor agonists
  • neuromedin U receptor agonists for example, noradrenergic anorectic agents (for example, phentermine, mazindol and the like) and appetite suppressants (for example, bupropion).
  • noradrenergic anorectic agents for example, phentermine, mazindol and the like
  • appetite suppressants for example, bupropion
  • anti-obesity agents including the agents set forth infra, are well known, or will be readily apparent in light of the instant disclosure, to one of ordinary skill in the art.
  • the anti-obesity agents are selected from the group consisting of orlistat, sibutramine, bromocriptine, ephedrine, leptin, and pseudoephedrine.
  • compounds of the present invention and combination therapies are administered in conjunction with exercise and/or a sensible diet.
  • combination-therapy of the compounds of the present invention with other anti-obesity agents, anorectic agents, appetite suppressant and related agents is not limited to those listed above, but includes in principle any combination with any pharmaceutical agent or pharmaceutical composition useful for the treatment of overweight and obese individuals.
  • combination-therapy of the compounds of the present invention with other pharmaceutical agents is not limited to those listed herein, supra or infra, but includes in principle any combination with any pharmaceutical agent or pharmaceutical composition useful for the treatment of diseases, conditions or disorders that are linked to metabolic related disorders.
  • Some embodiments of the present invention include methods of treatment of a disease, disorder, condition or complication thereof as described herein, comprising administering to an individual in need of such treatment a therapeutically effective amount or dose of a compound of the present invention in combination with at least one pharmaceutical agent selected from the group consisting of: sulfonylureas (for example, glyburide, glipizide, glimepiride and other sulfonylureas known in the art), meglitinides (for example, repaglinide, nateglinide and other meglitinides known in the art), biguanides (for example, biguanides include phenformin, metformin, buformin, and biguanides known in the art), ⁇ -glucosidase inhibitors [for example, acarbose, N-(l,3-dihydroxy-2-propyl)valiolamine (generic name; voglibose), miglitol, and ⁇
  • PPAR- ⁇ ) agonists for example, rosiglitazone, pioglitazone, tesaglitazar, netoglitazone, GW- 409544, GW-501516 and PPAR- ⁇ agonists known in the art
  • insulin insulin analogues
  • HMG- CoA reductase inhibitors for example, rosuvastatin, pravastatin and its sodium salt, simvastatin, lovastatin, atorvastatin, fluvastatin, cerivastatin, rosuvastatin, pitavastatin, BMS's "superstatin", and HMG-CoA reductase inhibitors known in the art
  • cholesterol-lowering drugs for example, fibrates that include: bezafibrate, beclobrate, binifibrate, ciplofibrate, clinofibrate, clofibrate, clofibric acid, etofibrate, fenofibrate,
  • Suitable pharmaceutical agents that can be used in conjunction with compounds of the present invention include, but not limited to, amylin agonists (for example, pramlintide), insulin secretagogues (for example, GLP-I agonists; exendin-4; insulinotropin (NN2211); acyl CoA cholesterol acetyltransferase inhibitors (for example, ezetimibe, eflucimibe, and like compounds), cholesterol absorption inhibitors (for example, ezetimibe, pamaqueside and like compounds), cholesterol ester transfer protein inhibitors (for example, CP-529414, JTT-705, CETi-I, and like compounds), microsomal triglyceride transfer protein inhibitors (for example, implitapide, and like compounds), cholesterol modulators (for example, NO- 1886, and like compounds), bile acid modulators (for example, GT103-279 and like compounds), insulin signaling pathway modulators, like inhibitors of protein tyrosine phosphatases (PTPases
  • PPCK phosphoenolpyruvate carboxykinase
  • PDHK pyruvate dehydrogenase kinase
  • insulin sensitivity enhancers insulin secretion enhancers
  • inhibitors of gastric emptying ⁇ 2 -adrenergic antagonists
  • PvXR retinoid X receptor
  • DPP-IV dipeptidyl peptidase-4
  • Dipeptidyl peptidase IV (DPP-IV, EC 3.4.14.5) exhibits catalytic activity against a broad range of peptide substrates that includes peptide hormones, neuropeptides, and chemokines.
  • GIP which stimulate glucose-dependent insulin secretion and otherwise promote blood glucose homeostasis, are rapidly cleaved by DPP-IV at the position 2 alanine leading to inactivation of their biological activity.
  • DPP-IV activity is associated with enhanced incretin action, increased insulin, and lower blood glucose in vivo. Genetic attenuation of DPP-IV activity has been shown to provide resistance to obesity and to improve insulin sensitivity.
  • Inhibitors of DPP-IV have shown to be useful as theraputics, for example, oral administration of vildagliptin (l-[2-(3-hydroxyadamant-l- ylamino)acetyl]pyrrolidine-2(S)-carbonitrile) or sitagliptin (3(R)-ammo-l-[3-(trifluoromethyl)- 5,6,7,8-tetrahydro[l,2,4]triazolo[4,3-a]pyrazin-7-yl]-4-(2,4,5-trifluorophenyl) butan-1-one) to human patients suffering with type 2 diabetes has been found to reduce fasting glucose and postprandial glucose excursion in association with significantly reduced HbAi c levels.
  • suitable pharmaceutical agents include inhibitors of DPP-IV that can be used in conjunction with compounds of the present invention either dosed separately or together.
  • Inhibitors of DPP-IV are well in the art or can be readily identified and their in vitro biological activity determined using any number of methods available, for example, O'Brien, M., Daily, B., Schurria, M., "Assay for DPPIV activity using a homogeneous, luminescent method," Cell Notes, Issue 11, 2005; see also the DPPIV-GloTM Protease Assay Technical Bulletin #TB339.
  • DPP-IV inhibitors are described in Villhauer et al., J Med Chem (2003)
  • DPP-IV inhibitors include, but are not limited to, dipeptide derivatives or dipeptide mimetics such as alanine-pyrrolidide, isoleucine-thiazolidide, and the pseudosubstrate N-valyl prolyl, O-benzoyl hydroxylamine, as described e.g. in U.S. Pat. No. 6,303,661.
  • DPP-IV inhibitors selected from the DPP-IV inhibitors found in U.S. Pat. Nos. 6,869,947, 6,867,205, 6,861,440, 6,849,622, 6,812,350, 6,803,357, 6,800,650, 6,727,261, 6,716,843, 6,710,040, 6,706,742, 6,645,995, 6,617,340, 6,699,871, 6,573,287, 6,432,969, 6,395,767, 6,380,398, 6,303,661, 6,242,422, 6,166,063, 6,100,234, and 6,040,145.
  • DPP-IV inhibitors selected from the DPP-IV inhibitors found in U.S. Patent Application
  • DPP-IV inhibitors selected from the DPP-IV inhibitors found in International Patent Application Publication Numbers: WO 2005/087235, WO 2005/082348, WO 2005/082849, WO
  • Some embodiments of the present invention include every combination of one or more DPP-IV inhibitors selected from the DPP-IV inhibitors found in Patent Publication Numbers: EP 1517907, EP 1513808, EP 1492777, EP 1490335, EP 1489088, EP 1480961, EP 1476435, EP 1476429, EP 1469873, EP 1465891, EP 1463727, EP 1461337, EP 1450794, EP 1446116, EP
  • the DPP-IV inhibitor has an IC 50 of less than about 10 ⁇ M, less than about 1 ⁇ M, less than about 100 nM, less than about 75 nM, less than about 50 nM, less than about 25 nM, less than about 20 nM, less than about 15 nM, less than about 10 nM, less than about 5 nM, less than about 4 nM, less than about 3 nM, less than about 2 nM, or less than about
  • the DPP-IV inhibitor has an IC 5 O of less than about 50 nM, less than about 25 nM, less than about 20 nM, less than about 15 nM, less than about 10 nM, less than about 5 nM, less than about 4 nM, less than about 3 nM, less than about 2 nM, or less than about I nM.
  • the DPP-IV inhibitor is a selective DPP-IV inhibitor, wherein the selective DPP-IV inhibitor has a selectivity for human plasma DPP-IV over one or more of the following enzymes, post proline cleaving enzyme (PPCE), dipeptidyl peptidase II (DPPII), dipeptidyl peptidase-8 (DPP-8), and dipeptidyl peptidase-9 (DPP-9) of at least about 10-fold, more preferably of at least about 100-fold, and most preferably of at least about 1000-fold.
  • PPCE post proline cleaving enzyme
  • DPPII dipeptidyl peptidase II
  • DPP-8 dipeptidyl peptidase-8
  • DPP-9 dipeptidyl peptidase-9
  • the DPP-IV inhibitor is orally active.
  • the DPP-IV inhibitor is an inhibitor of human DPP-IV.
  • Some embodiments of the present invention include every combination of one or more compounds selected from: 3(R)-amino-l-[3-(trifluoromethyl)-5,6,7,8-tetrahydro[l,2,4]triazolo[4,3-a]pyrazin-7-yl]- 4-(2,4,5-trifluorophenyl) butan- 1 -one; 1 -[2-(3-hydroxyadamant- 1 -ylamino)acetyl]pyrrolidine- 2(S)-carbonitrile; (lS,3S,5S)-2-[2(S)-amino-2-(3-hydroxyadamantan-l-yl)acetyl]-2- azabicyclo[3.1.0]hexane-3-carbonitrile; 2-[6-[3(R)-aminopiperidin-l-yl]-3-methyl-2,4-dioxo- l,2,3,4-tetrahydropyrimidin-l-ylmethyl
  • Some embodiments of the present invention include every combination of one or more compounds selected from: (2S,4S)-l-[(2S)-2-amino-3,3-bis(4-fluorophenyl)propanoyl]-4- fluoropyrrolidine-2-carbonitrile; (2S,5R)-5-ethynyl- 1 - ⁇ N-(4-methyl- 1 -(4-carboxy-pyridin-2- yl)piperidin-4-yl)glycyl ⁇ pyrrolidine-2-carbonitrile; and ( ⁇ S,6R)-?>- ⁇ [3-(trifluoromethyl)-5,6- dihydro[l,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]carbonyl ⁇ -6-(2,4,5-trifluorophenyl)cyclohex-3-en- 1 -amine; and pharmaceutically acceptable salts, solvates and hydrates thereof.
  • Sitagliptin phosphate (Januvia, MK-0431, dihydrogenphosphate salt of 3(R)-amino-l-[3- (trifluoromethyl)-5,6,7,8-tetrahydro[l,2,4]triazolo[4,3-a]pyrazin-7-yl]-4-(2,4,5-trifluorophenyl) butan-1-one) is marketed by Merck & Co. for once-daily oral treatment of type 2 diabetes.
  • the DPP-IV inhibitor of the present invention is selected from 3(R)-amino-l-[3-(trifluoromethyl)-5,6,7,8-tetrahydro[l,2,4]triazolo[4,3-a]pyrazin- 7-yl]-4-(2,4,5-trifluorophenyl) butan-1-one, and pharmaceutically acceptable salts, solvates, and hydrates thereof:
  • the dipeptidyl peptidase IV (DPP4) inhibitor is 3(R)-amino-l-[3- (trifluoromethyl)-5,6,7,8-tetrahydro[l,2,4]triazolo[4,3-a]pyrazin-7-yl]-4-(2,4,5-trifluorophenyl) butan-1-one phosphate:
  • the dipeptidyl peptidase IV (DPP4) inhibitor is crystalline 3(R)-amino-l-[3-(trifluoromethyl)-5,6,7,8-tetrahydro[l,2,4]triazolo[4,3-a]pyrazin-7- yl]-4-(2,4,5-trifluorophenyl) butan-1-one phosphate monohydrate.
  • Vildagliptin (Galvus, LAF-237, l-[2-(3-hydroxyadamant-l-ylamino)acetyl]pyrrolidine- 2( 1 S)-carbonitrile) is another dipeptidyl-peptidase IV (DPP-IV) inhibitor and was first commercialized in Brazil and Mexico by Novartis for oral, once-daily treatment of type 2 diabetes.
  • DPP-IV dipeptidyl-peptidase IV
  • MAA marketing authorization application
  • the compound, l-[2-(3-hydroxyadamant-l-ylamino)acetyl]pyrrolidine-2(S)-carbonitrile, is disclosed in international patent publication WO2000/034241.
  • Some embodiments of the present invention include every combination of one or more compounds selected from the DPP-IV inhibitors disclosed in WO2000/034241 and pharmaceutically acceptable salts, solvates, and hydrates thereof.
  • the DPP-IV inhibitor of the present invention is selected from 1- [2-(3-hydroxyadamant- 1 -ylamino)acetyl]pyrrolidine-2(S)-carbonitrile, and pharmaceutically acceptable salts, solvates, and hydrates thereof:
  • the DPP-IV inhibitor is l-[2-(3-hydroxyadamant-l-ylamino)acetyl]pyrrolidine-
  • Saxagliptin (Onglyza, BMS-477118, (l£,3£,5S)-2-[2(S)-amino-2-(3-hydroxyadamantan- l-yl)acetyl]-2-azabicyclo[3.1.0]hexane-3-carbonitrile) is another DPP-IV inhibitor and was launched in 2009 by AstraZeneca and Bristol-Myers Squibb in the U.S. for the treatment of type
  • the DPP-IV inhibitor of the present invention is selected from (lS,3S,5S)-2-[2(S)-amino-2-(3-hydroxyadamantan-l-yl)acetyl]-2-azabicyclo[3.1.0]hexane-3- carbonitrile, and pharmaceutically acceptable salts, solvates, and hydrates thereof:
  • SYR-322 (Alogliptin, 2-[6-[3(R)-aminopiperidin-l-yl]-3-methyl-2,4-dioxo-l,2,3,4- tetrahydropyrimidin- 1 -ylmethyl]benzonitrile) is a DPP-IV inhibitor which regulatory approval has been filed in Japan and the U.S. by Takeda for the once-daily, oral treatment of type 2 diabetes.
  • the compound, 2-[6-[3(R)-ammopiperidin-l-yi]-3-methyl-2,4-dioxo-l,2,3,4- tetrahydropyrimidin-l-ylmethyl]benzonitrile, and pharmaceutically acceptable salts thereof are disclosed in international patent publication WO 2005/095381.
  • Some embodiments of the present invention include every combination of one or more compounds selected from the DPP-IV inhibitors disclosed in WO 2005/095381 and pharmaceutically acceptable salts, solvates, and hydrates thereof.
  • the DPP-IV inhibitor of the present invention is selected from 2-[6-[3(R)-aminopiperidin- 1 -yl]-3-methyl-2,4-dioxo- 1 ,2,3,4-tetrahydropyrimidin- 1 - ylmethyljbenzonitrile, and pharmaceutically acceptable salts, solvates, and hydrates thereof:
  • the DPP-IV inhibitor is 2-[6-[3(R)-aminopiperidin- 1 -yl]-3-methyl-2,4-dioxo- 1,2,3,4-tetrahydropyrimidin- 1 - ylmethyljbenzonitrile benzoate:
  • BI- 1356 (Ondero, 8-[3(R)-aminopiperidin- 1 -yl]-7-(2-butynyl)-3-methyl- 1 -(4- methylquinazolin-2-ylmethyl)xanthine) is a DPP-IV inhibitor and is in phase III clinical development at Boehringer Ingelheim to evaluate its potential as an add-on therapy to metformin for the treatment of type 2 diabetes.
  • the compound, 8-[3(R)-aminopiperidin-l-yl]-7-(2-butynyl)- 3 -methyl- l-(4-methylquinazolin-2-ylmethyl)xanthine is disclosed in international patent publication WO2004/018468.
  • Some embodiments of the present invention include every combination of one or more compounds selected from the DPP-IV inhibitors disclosed in WO2004/018468 and pharmaceutically acceptable salts, solvates, and hydrates thereof.
  • the DPP-IV inhibitor of the present invention is selected from 8-[3(R)- aminopiperidin- 1 -yl]-7-(2-butynyl)-3-methyl- 1 -(4-methylquinazolin-2-ylmethyl)xanthine, and pharmaceutically acceptable salts, solvates, and hydrates thereof:
  • the DPP-IV inhibitor is a crystalline form of 8-[3(R)- aminopiperidin- 1 -yl]-7-(2-butynyl)-3-methyl- 1 -(4-methylquinazolin-2-ylmethyl)xanthine.
  • PHX-1149 (Dutogliptin, l-[N-[3(R)-pyrrolidinyl]glycyl]pyrrolidin-2(R)-yl boronic acid) is a DPP-IV inhibitor in phase III clinical trials by Phenomix and Forest for the oral, once-daily treatment of type 2 diabetes.
  • the compound, l-[N-[3(R)-pyrrolidinyl]glycyl] pyrrolidin-2(R)-yl boronic acid, and pharmaceutically acceptable salts are disclosed in international patent publication WO2005/047297.
  • Some embodiments of the present invention include every combination of one or more compounds selected from the DPP-IV inhibitors disclosed in WO2005/047297 and pharmaceutically acceptable salts, solvates, and hydrates thereof.
  • the DPP-IV inhibitor of the present invention is selected from 1-[N- [3 (R)- pyrrolidinyl]glycyl]pyrrolidin-2(R)-yl boronic acid, and pharmaceutically acceptable salts, solvates, and hydrates thereof:
  • the DPP-IV inhibitor is l-[N-[3(R)-pyrrolidinyl]glycyl]pyrrolidin-2(R)-yl boronic acid tartrate: GRC-8200 (Melogliptin, 4(5)-fluoro-l-[2-[(l ⁇ ,35)-3-(lH-l,2,4-triazol-l- ylmethyl)cyclopentylammo]acetyl]pyrrolidine-2(S)-carbonitrile) is a DPP-IV inhibitor and is currently undergoing phase II clinical trials by Glenmark Pharmaceuticals and Merck KGaA for the treatment of type 2 diabetes.
  • the compound, 4(5)-fluoro-l-[2-[(lR,35)-3-(lH-l,2,4-triazol-l- ylmethyl)cyclopentylammo]acetyl]pyrrolidine-2(S)-carbonitrile, is disclosed in international patent publication WO2006/040625.
  • Some embodiments of the present invention include every combination of one or more compounds selected from the DPP-IV inhibitors disclosed in WO2006/040625 and pharmaceutically acceptable salts, solvates, and hydrates thereof.
  • the DPP-IV inhibitor of the present invention is selected from 4(S)-fluoro-l-[2- [(lR,3S)-3-(lH-l,2,4-triazol-l-ylmethyl)cyclopentylamino]acetyl]pyrrolidine-2(S)-carbonitrile, and pharmaceutically acceptable salts, solvates, and hydrates thereof:
  • R- 1579 (Carmegliptin, l-[(2S,3S,l lbS)-2-amino-9,10-dimethoxy-2,3,4,6,7,l Ib- hexahydro-lH-pyrido[2,l-a]isoquinolin-3-yl]-4(S)-(fluoromethyl)pyrrolidin-2-one) is a DPP-IV inhibitor.
  • the compound, l-[(2S,3S,l lb£)-2-amino-9,10-dimethoxy-2,3,4,6,7,l lb-hexahydro-lH- pyrido[2,l-a]isoqumoh ' n-3-yl]-4(S)-(fluoromethyl)pyrroh ' din-2-one, is disclosed in international patent publication WO2005/000848.
  • Some embodiments of the present invention include every combination of one or more compounds selected from the DPP-IV inhibitors disclosed in WO2005/000848 and pharmaceutically acceptable salts, solvates, and hydrates thereof.
  • the DPP-IV inhibitor of the present invention is selected from l-[(2S,3S,l lbS)-2- amino-9,10-dimethoxy-2,3,4,6,7,l lb-hexahydro-lH-pyrido[2,l-a]isoquinolin-3-yl]-4(S)- (fluoromethyl)pyrrolidin-2-one, and pharmaceutically acceptable salts, solvates, and hydrates thereof:
  • the DPP- IV inhibitor of the present invention is selected from (2S,4S)-2-cyano-4-fluoro-l-[(2-hydroxy- l,l-dimethyl)ethylamino]acetylpyrrolidine, and pharmaceutically acceptable salts, solvates, and hydrates thereof:
  • Sanofi-Aventis disclosed a series of substituted bicyclic 8-pyrrolidineoxanthine derivatives as DPP-IV inhibitors in US publication US 2007/0167468 (incorporated by reference in its entirety). Some embodiments of the present invention include every combination of one or more compounds selected from the DPP-IV inhibitors disclosed in US publication 2007/0167468 and pharmaceutically acceptable salts, solvates, and hydrates thereof.
  • the DPP-IV inhibitor of the present invention is selected from 8-(cw-hexahydro-pyrrolo[3,2-b]pyrrol- 1 -yl)-3-methyl-7-(3-methyl-but-2-enyl)- 1 -(2-oxo-2-phenylethyl)-3,7-dihydro-purine-2,6-dione, and pharmaceutically acceptable salts, solvates, and hydrates thereof:
  • Pfizer disclosed a series of 3-amino-pyrrolidine-4-lactam derivatives as DPP-IV inhibitors in international patent publication WO2007/148185.
  • Some embodiments of the present invention include every combination of one or more compounds selected from the DPP-IV inhibitors disclosed in WO2007/148185 and pharmaceutically acceptable salts, solvates, and hydrates thereof.
  • One such compound is l-((3S,4S)-4-ammo-l-(4-(3,3-difluoropyrroridin-l-yl)- l,3,5-triazin-2-yl)pyrrolidin-3-yl)-5,5difluoropiperidin-2-one, and pharmaceutically acceptable salts thereof.
  • the DPP-IV inhibitor of the present invention is selected from 1 -((3S,4S)-4-amino- 1 -(4-(3,3-difluoropyrrolidin- 1 -yl)- 1 ,3,5-triazin-2-yl)pyrrolidin-3-yl)- 5,5difluoropiperidin-2-one, and pharmaceutically acceptable salts, solvates, and hydrates thereof:
  • Syrrx disclosed a series of substituted pyrimidine-2,4(lH,3H)-dione derivatives as DPP- IV inhibitors in international patent publication WO2005/095381.
  • Some embodiments of the present invention include every combination of one or more compounds selected from the DPP- IV inhibitors disclosed in WO2005/095381 and pharmaceutically acceptable salts, solvates, and hydrates thereof.
  • One such compound is (R)-2-((6-(3-aminopiperidm-l-yl)-3-methyl-2,4-dioxo- 3,4-dihydropyrimidin-l(2H)-yl)methyl)-4-fluorobenzonitrile, and pharmaceutically acceptable salts thereof.
  • the DPP-IV inhibitor of the present invention is selected from (R)-2-((6-(3-aminopiperidin- 1 -yl)-3-methyl-2,4-dioxo-3,4-dihydropyrimidin- 1 (2H)- yl)methyl)-4-fluorobenzonitrile, and pharmaceutically acceptable salts, solvates, and hydrates thereof:
  • One embodiment of the present invention pertains to any one or more crystalline forms of (R)-2-((6-(3-aminopiperidin-l-yl)-3-methyl-2,4- dioxo-3,4-dihydropyrimidin-l(2H)-yl)methyl)-4-fluorobenzonitrile succinic acid salt as described in international patent publication WO2005/0031335.
  • the dipeptidyl peptidase IV (DPP4) inhibitor is crystalline (R)-2-((6-(3-ammopiperidin-l-yl)-3-methyl-2,4- dioxo-3,4-dihydropyrimidin-l(2H)-yl)methyl)-4-fluorobenzonitrile succinic acid salt:
  • One such compound is 5- ⁇ (S)-2-[2-((S)-2-cyano-pyrrolid in-l-yl)-2-oxo- ethylamino] -propyl ⁇ -5-(lH-tetrazol-5-yl) 10, 11 -dihydro-5H-dibenzo[a,d]cycloheptene-2,8- dicarboxylic acid bis-dimethylamide, and pharmaceutically acceptable salts thereof.
  • the DPP-IV inhibitor of the present invention is selected from 5- ⁇ (S)-2-[2-((S)-2- cyano-pyrrolid in- 1 -yl)-2-oxo-ethylamino]-propyl ⁇ -5-(lH-tetrazol-5-yl) 10, 11 -dihydro-5H- dibenzo[a,d]cycloheptene-2,8-dicarboxylic acid bis-dimethylamide, and pharmaceutically acceptable salts, solvates, and hydrates thereof:
  • Some embodiments of the present invention include every combination of one or more compounds selected from the DPP- IV inhibitors disclosed in WO2002/0014271 and pharmaceutically acceptable salts, solvates, and hydrates thereof.
  • One such compound is ((2S,4S)-4-(4-(3-methyl- 1 -phenyl- lH-pyrazol-5- yl)piperazin-l-yl)pyrrolidin-2-yl)(thiazolidin-3-yl)methanone, and pharmaceutically acceptable salts thereof.
  • the DPP-IV inhibitor of the present invention is selected from ((2S,4S)-4-(4-(3-methyl- 1 -phenyl- lH-pyrazol-5-yl)piperazin- 1 -yl)pyrrolidin-2- yl)(thiazolidin-3-yl)methanone, and pharmaceutically acceptable salts, solvates, and hydrates thereof:
  • One embodiment of the present invention pertains to any one or more of the crystalline forms of ((2S, 4S)-4-(4-(3 -methyl- 1 -phenyl- lH-pyrazol-5-yl)piperazin- 1 -yl)pyrrolidin-2-yl)(thiazolidin-3- yl)methanone salt described in international patent publication WO2006/088129 and US publication 2009/0216016.
  • the DPP-IV inhibitor is crystalline ((2S,4S)-4- (4-(3 -methyl- 1 -phenyl- lH-pyrazol-5-yl)piperazin-l-yl)pyrrolidin-2-yl)(thiazolidin-3- yl)methanone 2.5 hydrobromide salt:
  • the dipeptidyl peptidase IV (DPP4) inhibitor is crystalline ((2S,45)-4-(4-(3-methyl-l-phenyl-lH-pyrazol-5-yl)piperazin-l- yl)pyrrolidin-2-yl)(thiazolidin-3-yl)methanone di-hydrobromide salt.
  • Kyorin disclosed a series of pyrrolidinecarbonitrile derivatives as DPP-IV inhibitors in international patent publication WO2008/114857 and US publication 2008/0146818. Some embodiments of the present invention include every combination of one or more compounds selected from the DPP-IV inhibitors disclosed in WO2008/114857 and US publication
  • the DPP-IV inhibitor of the present invention is selected from (2S,4S)-l-[2-[(4- ethoxycarbonylbicyclo[2.2.2]oct- 1 -yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile, and pharmaceutically acceptable salts, solvates, and hydrates thereof:
  • Dainippon Sumitomo disclosed a series of bicyclic pyrrole derivatives as DPP-IV inhibitors in international patent publication WO2006/068163 and US publication 2009/0192129.
  • Some embodiments of the present invention include every combination of one or more compounds selected from the DPP-IV inhibitors disclosed in WO2006/068163 and US publication 2009/0192129 and pharmaceutically acceptable salts, solvates, and hydrates thereof.
  • One such compound is 6-[(3R)-3-amino-piperidin-l-yl]-5-(2-chloro-5-fluoro-benzyl)-l,3- dimethyl-l,5dihydro-pyrrolo[3,2-d]pyrimidine-2,4-dione, and pharmaceutically acceptable salts thereof.
  • the DPP-IV inhibitor of the present invention is selected from (6- [(3R)-3-amino-piperidin- l-yl]-5-(2-chloro-5-fluoro-benzyl)- 1 ,3-dimethyl- 1 ,5dihydro-pyrrolo[3,2- d]pyrimidine-2,4-dione, and pharmaceutically acceptable salts, solvates, and hydrates thereof:
  • the DPP-IV inhibitor of the present invention is selected from 2-( ⁇ 6-[(3R)-3-amino-3-methylpiperidin- 1 -yl]- 1 ,3-dimethyl-2,4-dioxo- 1 ,2,3,4-tetrahydro- 5H-pyrrolo[3,2-d]pyrimidin-5-yl ⁇ methyl)-4-fluorobenzonitrile, and pharmaceutically acceptable salts, solvates, and hydrates thereof:
  • Some embodiments of the present invention include every combination of one or more compounds selected from the DPP- IV inhibitors disclosed in WO 03/037327 and pharmaceutically acceptable salts, solvates, and hydrates thereof.
  • One such compound is (2S)-l- ⁇ [2-(5-methyl-2-phenyl-oxazol-4-yl)- ethylamino]-acetyl ⁇ -pyrrolidine-2-carbonitrile, and pharmaceutically acceptable salts thereof.
  • the DPP-IV inhibitor of the present invention is selected from (2S)-I- ⁇ [2-(5- methyl-2-phenyl-oxazol-4-yl)-ethylamino]-acetyl ⁇ -pyrrolidine-2-carbonitrile, and
  • the DPP-IV inhibitor of the present invention is (2S)-l- ⁇ [2-(5-methyl-2-phenyl-oxazol-4-yl)-ethylamino]-acetyl ⁇ -pyrrolidine-2- carbonitrile methansulfonic acid salt (i.e., mesylate):
  • the DPP-IV inhibitor of the present invention is selected from (2S)- 1 - ⁇ [ 1 , 1 -dimethyl-3-(4-pyridin-3-yl-imidazol- 1 -yl)-propylamino]-acetyl ⁇ - pyrrolidine-2-carbonitrile, and pharmaceutically acceptable salts, solvates, and hydrates thereof:
  • the DPP-IV inhibitor of the present invention is (2S)- 1- ⁇ [1,1- dimethyl-3-(4-pyridin-3-yl-imidazol- 1 -yl)-propylamino]-acetyl ⁇ -pyrrolidine-2-carbonitrile methansulfonic acid:
  • the DPP-IV inhibitor of the present invention is (2S)-l- ⁇ [l,l-dimethyl-3-(4- pyridin-3-yl-imidazol-l-yl)-propylamino]-acetyl ⁇ -pyrrolidine-2-carbonitrile fumaric acid salt (i.e., fumarate):
  • Pfizer disclosed a series of proline derivatives as DPP-IV inhibitors in international patent publication WO2005/116014 (incorporated by reference in its entirety).
  • embodiments of the present invention include every combination of one or more compounds selected from the DPP-IV inhibitors disclosed in WO2005/116014 and pharmaceutically acceptable salts, solvates, and hydrates thereof.
  • One such compound is (3,3-difluoropyrrolidin-l- yl)-((2S,4S)-4-(4-(pyrimidin-2yl)piperazin- 1 -yl)pyrrolidin-2-yl)methanone, and pharmaceutically acceptable salts thereof.
  • the DPP-IV inhibitor of the present invention is selected from (3,3-difluoropyrrolidin- 1 -yl)-((2S,4S)-4-(4-(pyrimidin-2yl)piperazin- 1 - yl)pyrrolidin-2-yl)methanone, and pharmaceutically acceptable salts, solvates, and hydrates thereof:
  • Glaxo SmithKline disclosed a series of fluoropyrrolidine derivatives as DPP-IV inhibitors in international patent publication WO 03/002531.
  • Some embodiments of the present invention include every combination of one or more compounds selected from the DPP-IV inhibitors disclosed in WO 03/037327 and pharmaceutically acceptable salts, solvates, and hydrates thereof.
  • One such compound is (2S,4S)-l-[(2S)-2-amino-3,3-bis(4-fluorophenyl)propanoyi]-4- fluoropyrrolidine-2-carbonitrile (Denagliptin).
  • the DPP-IV inhibitor of the present invention is selected from (2S,4S)-l-[(2S)-2-amino-3,3-bis(4-fluorophenyl)propanoyl]-4- fluoropyrrolidine-2-carbonitrile, and pharmaceutically acceptable salts, solvates, and hydrates thereof:
  • One salt disclosed is (25 1 ,45)-l-[(25)-2-amino-3,3-bis(4- fluorophenyl)propanoyl]-4-fluoropyrrolidine-2-carbonitrile/>-toluenesulfonic acid salt (also referred to as (2S,45)-4-fluoro- 1 -[4-fluoro- ⁇ -(4-fluorophenyl)-L-phenylalanyl]-2- pyrrolidinecarbonitrile/>-toluenesulfonic acid salt, or Denagliptin tosylate).
  • (2S,45)-4-fluoro- 1 -[4-fluoro- ⁇ -(4-fluorophenyl)-L-phenylalanyl]-2- pyrrolidinecarbonitrile/>-toluenesulfonic acid salt or Denagliptin tosylate.
  • the DPP-IV inhibitor of the present invention is (2S,4S)-l-[(2S)-2-amino-3,3-bis(4- fluorophenyl)propanoyl]-4-fluoropyrrolidine-2-carbonitrile/>-toluenesulfonic acid salt:
  • Abbott disclosed a series of substituted pyrrolidinyl derivatives as DPP-IV inhibitors in international patent publication WO 2004/026822.
  • Some embodiments of the present invention include every combination of one or more compounds selected from the DPP-IV inhibitors disclosed in WO 2004/026822 and pharmaceutically acceptable salts, solvates, and hydrates thereof.
  • One such compound is (2S,5R)-5-ethynyl-l- ⁇ N-(4-methyl-l-(4-carboxy-pyridin-2- yl)piperidin-4-yl)glycyl ⁇ pyrrolidine-2-carbonitrile.
  • the DPP-IV inhibitor of the present invention is selected from (2S,5R)-5-ethynyl-l- ⁇ N-(4-methyl-l-(4-carboxy-pyridin- 2-yl)piperidin-4-yl)glycyl ⁇ pyrrolidine-2-carbonitrile, and pharmaceutically acceptable salts, solvates, and hydrates thereof:
  • Abbott has further disclosed a series of substituted cyclohexanyl/cyclohexenyl derivatives as DPP-IV inhibitors in international patent publication WO 2007/027651.
  • Some embodiments of the present invention include every combination of one or more compounds selected from the DPP-IV inhibitors disclosed in WO 2007/027651 and pharmaceutically acceptable salts, solvates, and hydrates thereof.
  • One such compound is (15,6R)-3- ⁇ [3- (trifluoromethyl)-5,6-dihydro[l,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]carbonyl ⁇ -6-(2,4,5- trifluorophenyl)cyclohex-3-en-l -amine.
  • the DPP-IV inhibitor of the present invention is selected from (lS,6R)-3- ⁇ [3-(trifluoromethyl)-5,6-dihydro[l,2,4]triazolo[4,3- a]pyrazin-7(8H)-yl]carbonyl ⁇ -6-(2,4,5-trifluorophenyl)cyclohex-3-en- 1 -amine, and
  • the combination can be used by mixing the respective active components, a compound of the present invention and pharmaceutical agent, either all together or independently with a physiologically acceptable carrier, excipient, binder, diluent, etc., as described herein above, and administering the mixture or mixtures either orally or non-orally as a pharmaceutical composition.
  • a compound or a mixture of compounds of the present invention are administered as a combination therapy with another active compound the therapeutic agents can be formulated as separate pharmaceutical compositions given at the same time or at different times; or the compound or a mixture of compounds of the present invention and the therapeutic agent(s) can be formulated together as a single unit dosage.
  • Another object of the present invention relates to radio-labeled compounds that are useful not only in radio-imaging but also in assays, both in vitro and in vivo, for localizing and quantitating the GPRl 19 receptor in tissue samples, including human, and for identifying GPRl 19 receptor ligands by inhibition binding of a radio-labeled compound. It is a further object of this invention to develop novel GPRl 19 receptor assays of which comprise such radio-labeled compounds.
  • Compounds of the invention can also include all isotopes of atoms occurring in the intermediates and/or the final compound and pharmaceutically acceptable salts, solvates and hydrates thereof.
  • Isotopes include those atoms having the same atomic number but different mass numbers.
  • An isotopically-labeled or radio-labeled compound is one which is identical to compounds disclosed herein, but for the fact that one or more atoms is replaced or substituted by an atom having an atomic mass or mass number different from the atomic mass or mass number typically found in nature (i.e., naturally occurring).
  • Suitable radionuclides that may be incorporated in compounds of the present invention include but are not limited to H (also written as D for deuterium), 3 H (also written as T for tritium), 11 C, 13 C, 14 C, 13 N, 15 N, 15 0, 17 0, 18 0, 18 F, 35 S, 36 Cl, 82 Br, 75 Br, 76 Br, 77 Br, 123 1, 124 1, 125 I and 131 I.
  • the radionuclide that is incorporated in the instant radio-labeled compounds will depend on the specific application for which the radio- labeled compound will be used.
  • a radio-labeled or labeled compound is a compound of the present invention that has incorporated at least one radionuclide; in some embodiments the radionuclide is selected from the group consisting of 3 H, 14 C, 125 1, 35 S, and 82 Br.
  • isotopically-labeled compounds of the present invention are useful in compound and/or substrate tissue distribution assays.
  • the radionuclide 3 H and/or 14 C isotopes are useful in these studies.
  • substitution with heavier isotopes such as deuterium (i.e., 2 H) may afford certain therapeutic advantages resulting from greater metabolic stability
  • Isotopically labeled compounds of the present invention can generally be prepared by following procedures analogous to those disclosed in the Schemes supra and Examples infra, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent. Other synthetic methods that are useful are discussed infra. Moreover, it should be understood that all of the atoms represented in the compounds of the invention can be either the most commonly occurring isotope of such atoms or a more scarce radio-isotope or nonradioactive isotope.
  • Synthetic methods for incorporating radio-isotopes into organic compounds are applicable to compounds of the invention and are well known in the art, for example, tritium gas exposure labeling. This procedure involves exposing precursors containing exchangeable protons to tritium gas in the presence of a suitable catalyst.
  • a radio-labeled GPRl 19 receptor compound of present invention can be used in a screening assay to identify/evaluate compounds.
  • a newly synthesized or identified compound i.e., test compound
  • the ability of a test compound to compete with the radio-labeled compound of the present invention for the binding to the GPRl 19 receptor directly correlates to its binding affinity.
  • the labeled compounds of the present invention bind to the GPRl 19 receptor.
  • the labeled compound has an IC 5 O less than about 500 ⁇ M, in another embodiment the labeled compound has an IC 50 less than about 100 ⁇ M, in yet another embodiment the labeled compound has an IC 50 less than about 10 ⁇ M, in yet another embodiment the labeled compound has an IC 50 less than about 1 ⁇ M, in still yet another embodiment the labeled inhibitor has an IC 50 less than about 0.1 ⁇ M, in still yet another embodiment the labeled inhibitor has an IC 50 less than about 0.01 ⁇ M, and in still yet another embodiment the labeled inhibitor has an IC 50 less than about 0.005 ⁇ M.
  • Example 1 Primary Pharmacology for ⁇ l-fluoro- ⁇ methylsulfonylJphenylJ-S-methyl- ⁇ - (l-(5-methylpyrazin-2-yl)piperidin-4-yloxy)pyrimidin-4-amine (Compound 1) - In Vitro Assays.
  • GDIR Glucose-Dependent Insulino tropic Receptor
  • CHO cells expressing human GDIR (AGDIR) and rat GDIR (rGDIR) were used. CHO cells were cultured in DMEM/F12K media containing pen/strep, 10% FBS and the appropriate antibiotic for selection (500 ⁇ g/mL G418 for rat and 3 ⁇ g/mL puromycin human clone cells). To establish assay conditions, 100 ⁇ L of cells were seeded at 5 x 105 cells/mL (2 x 105 cells/mL) into a lysine-coated 96 well culture plates and allowed to recover for 24 hours. After a 24-hour attachment and growth period, media was replaced with DMEM/F12 containing pen/strep, and 250 ⁇ M isobutylmethylxanthine (IBMX, phosphdiesterase inhibitor).
  • IBMX isobutylmethylxanthine
  • GluTag cells in growth medium (DMEM GIBCO Cat# 11995-065, 10% FBS GIBCO Cat# 16000-044) were seeded in a 96-well plate at 90,000 cells/well and incubated in a CO 2 incubator at 37 0 C for 24 hours.
  • the growth medium was removed by aspiration and 200 ⁇ L of assay medium (DMEM with 5 mM glucose and 0.1% BSA) was added to each well. After incubating at 37 0 C for 30 min, the assay medium was removed and each well was replenished with 175 ⁇ L of fresh assay medium with a DPP-IV inhibitor. Next, 25 ⁇ L of challenge solution was added to each well and the reaction was incubated for 2 hours at 37 0 C.
  • assay medium DMEM with 5 mM glucose and 0.1% BSA
  • Example 2 In vivo Effects of a Single Dose of ⁇ '-(2-fluoro-4-(methylsulfonyl)phenyl)-5- methyl-6-(l-(5-methylpyrazin-2-yl)piperidin-4-yloxy)pyrimidin-4-amine on Oral Glucose Tolerance Test (oGTT) in Male SD Rats (PK/PD study) at 0.3 and 3 mg/kg.
  • the oral glucose tolerance test measures the ability of an animal to metabolize a bolus of exogenous glucose. A decrease in glucose AUC excursion from baseline indicates better glucose control.
  • Male SD rats (6 - 7 weeks of age) were housed one rat per cage in a temperature- controlled room with 12-hour light/dark cycle. They were allowed ad libitum access to water and food. Rats were fasted overnight before the study. These rats were first dosed with vehicle (0.5%
  • HPMC HPMC
  • Compound 1 at 0.3, or 3 mg/kg doses via oral gavage at 8:30 am.
  • rats were administered glucose (2 g/kg, using 50% G) by oral gavage and the tail blood samples were collected to measure blood glucose and plasma insulin at 0, 30, 60, and 120 min.
  • a separate group of rats were dosed in similar fashion and blood samples collected at 1, 2, 4, 6, 8, and 24 h after dosing for PK analysis.
  • Compound 1 significantly reduced the blood glucose AUC during OGTT at both the 0.3 and 3 mg/kg doses.
  • the compound levels in the plasma showed a dose-related increase.
  • Example 3 Effects of Single Dose of ⁇ '-(2-fluoro-4-(methylsulfonyl)phenyl)-5-methyl-6-(l- (5-methylpyrazin-2-yl)piperidin-4-yloxy)pyrimidin-4-amine (Compound 1) on oGTT Conducted in Normal Male Cynomolgus Monkeys. The effect of Compound 1 on blood glucose control was tested in healthy male
  • Cynomolgus monkeys Na ⁇ ve, healthy, male Cynomolgus monkeys were used in this study. Monkeys were divided into 3 groups based on basal fasting blood glucose levels. Blood samples were collected before compound dosing, glucose administration, and at 30, 60, and 120 min after glucose nasal gavage (6 g/kg using 50% glucose solution). The results of this study indicate that Compound 1 at the 1.5 mg/kg dose significantly reduced blood glucose levels during oral glucose test.
  • Human cytochrome P450 proteins are a family of enzymes involved in the metabolism of endogenous substrates and detoxication of drugs and other foreign chemicals. P450 enzymes convert various compounds into more polar molecules, and converted molecules are easier to remove from the body. Drug-drug interactions occur when two drugs are co-administered and compete for the same P450 enzyme possibly resulting in incomplete detoxication. Conditions of the assay are summarized in the following table.
  • N-(2-Fluoro-4-(methylsulfonyl)phenyl)-5-methyl-6-(l-(5-methylpyrazin-2-yl)piperidin-4- yloxy)pyrimidin-4-amine was observed to inhibit isoenzymes 3A4, 2C9 and 2Cl 9 by roughly 50 % at 10 ⁇ M with IC 50 values of 9.05, 8.82 and > 10 ⁇ M, respectively. There was no observed inhibition of 1 A2 or 2D6.
  • Example 5 Inhibition of P450 2C9 and 2C19 in HLM by ⁇ -(2-Fluoro-4- (methylsulfonyl)phenyl)-5-methyl-6-(l-(5-methylpyrazin-2-yl)piperidin-4-yloxy)pyrimidin- 4-amine (Compound 1).
  • the metabolic incubations with standard probe substrates were conducted using a 96-well plate format.
  • the general incubation mixture contained 0.5 mg/mL microsomal protein, 0 ⁇ M to 50 ⁇ M N-(2-fluoro-4- (methylsulfonyl)phenyl)-5-methyl-6-(l-(5-methylpyrazin-2-yl)piperidin-4-yloxy)pyrimidin-4- amine (as inhibitor), 1 mM NADPH and 100 mM potassium phosphate buffer containing 3 mM MgCl 2 and 1 mM EDTA (pH 7.5) in a final volume of 100 ⁇ L.
  • CYP2C9 150 ⁇ M
  • tolbutamide was added to the reaction mixture and incubated for 10 min at 37 0 C.
  • 50 ⁇ M (S)-mephenytoin was added to the reaction mixture and incubated for 40 min at 37 0 C.
  • Parallel control incubations conducted with tolbutamide and (S)-mephenytoin, without the addition of Compound 1, were used as positive controls of the reactions. All of the assays were conducted in triplicate.
  • the incubations were terminated by the addition of 100 ⁇ L acetonitrile containing one of the following compounds as an internal standard: 4'-hydroxytolbutamide-d9 for CYP2C9 and 4'-hydroxymephenytoin-d 3 for CYP2C19 (final concentration 100 ng/mL).
  • the 96-well plates were centrifuged at 3000 rpm for 10 min and 100 ⁇ L supernatant was transferred to a clean 96-well plate for analysis by LC/MS/MS.
  • TLC Thin-layer chromatography
  • PK6F silica gel 60 A 1 mm plates (Whatman)
  • column chromatography was carried out on a silica gel column using Kieselgel 60, 0.063-0.200 mm (Merck). Evaporation was done in vacuo on a Buchi rotary evaporator. Celite 545 ® was used during palladium filtrations.
  • LCMS specs 1) PC: HPLC-pumps: LC-IOAD VP, Shimadzu Inc.; HPLC system controller: SCL-IOA VP, Shimadzu Inc; UV-Detector: SPD-IOA VP, Shimadzu Inc;
  • Example 6.2 Preparation of 4-Chloro-5-methyl-6-(l-(5-methylpyrazin-2-yl)piperidin-4- yloxy)pyrimidine.
  • This material was further characterized by powder X-ray diffraction (XRPD), thermogravimetric analysis (TGA), and differential scanning calorimetry (DSC).
  • XRPD powder X-ray diffraction
  • TGA thermogravimetric analysis
  • DSC differential scanning calorimetry
  • the powder X- ray diffraction (XRPD) pattern shows that the material is crystalline (see Figure 1).
  • the thermogravimetric analysis (TGA) thermogram shows the material has an initial weight loss of about -1.0% in the range of the melting temperature (from about 130 0 C to about 180 0 C, see Figure 2).
  • the differential scanning calorimetry (DSC) thermogram shows the material has a narrow endothermic event at a melting temperature with an onset and peak temperature of about 180.7 ° and about 182.8 0 C respectively, with an enthalpy of 74.3 J/g due to melting of the sample and subsequent exothermic decomposition (see Figure 3).

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Abstract

La présente invention porte sur l'agoniste du GPR119, la N-(2-fluoro-4-(méthylsulfonyl)phényl)-5-méthyl-6-(1-(5-méthylpyrazin-2-yl)pipéridin-4-yloxy)pyrimidin-4-amine (Composé 1, Formule (I)) et sur ses sels solvates et hydrates pharmaceutiquement acceptables, qui sont utiles dans le traitement de troubles associés à GPR119, tels que les troubles liés au métabolisme et leurs complications, comme le diabète et l'obésité.
PCT/US2010/041325 2009-07-09 2010-07-08 Dérivé de pipéridine et son utilisation pour le traitement du diabète et de l'obésité WO2011005929A1 (fr)

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* Cited by examiner, † Cited by third party
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WO2012099915A1 (fr) * 2011-01-19 2012-07-26 Hongwen Zhu Dérivés de thiazolidine et leur utilisation thérapeutique
WO2012170867A1 (fr) 2011-06-09 2012-12-13 Rhizen Pharmaceuticals Sa Nouveaux composes utilises comme modulateurs de gpr-119
WO2014011926A1 (fr) 2012-07-11 2014-01-16 Elcelyx Therapeutics, Inc. Compositions comportant des statines, des biguanides et d'autres agents pour réduire un risque cardiométabolique
US8933083B2 (en) 2003-01-14 2015-01-13 Arena Pharmaceuticals, Inc. 1,2,3-trisubstituted aryl and heteroaryl derivatives as modulators of metabolism and the prophylaxis and treatment of disorders related thereto such as diabetes and hyperglycemia
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US9776987B2 (en) 2013-11-26 2017-10-03 Chong Kun Dang Pharmaceutical Corp Amide derivatives for GPR119 agonist
US9944600B2 (en) 2012-06-12 2018-04-17 Chong Kun Dang Pharmaceutical Corp. Piperidine derivatives for GPR119 agonist
US10894787B2 (en) 2010-09-22 2021-01-19 Arena Pharmaceuticals, Inc. Modulators of the GPR119 receptor and the treatment of disorders related thereto
US11007175B2 (en) 2015-01-06 2021-05-18 Arena Pharmaceuticals, Inc. Methods of treating conditions related to the S1P1 receptor
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Citations (233)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1991016339A1 (fr) 1990-04-14 1991-10-31 New England Medical Center Hospitals, Inc. Inhibiteurs de dipeptidyl-aminopeptidase de type iv
DD296075A5 (de) 1989-08-07 1991-11-21 Martin-Luther-Universitaet Halle-Wittenberg,De Verfahren zur herstellung neuer inhibitoren der dipeptidyl peptidase iv
WO1993008259A2 (fr) 1991-10-22 1993-04-29 New England Medical Center Hospitals, Inc. Inhibiteurs de dipeptidyl-aminopeptidase de type iv
CA2123128A1 (fr) 1991-11-22 1993-05-27 Roger Snow Methode de fabrication d'un ester de prolineboronate
WO1995015309A1 (fr) 1993-12-03 1995-06-08 Ferring B.V. Inhibiteurs de la dp-iv-serine protease
WO1995029691A1 (fr) 1994-04-28 1995-11-09 Georgia Tech Research Corporation Derives de la proline phosphonate
US5571815A (en) * 1992-03-14 1996-11-05 Hoechst Aktiengesellschaft Substituted pyrimidines, process for their preparation, and their use as pesticides and fungicides
DE19616486A1 (de) 1996-04-25 1997-10-30 Knoell Hans Forschung Ev Verfahren zur Senkung des Blutglukosespiegels in Säugern
JPH1081666A (ja) 1996-06-12 1998-03-31 Ishihara Sangyo Kaisha Ltd フタルイミド誘導体又はその塩、それらの製造方法及びそれらを含有する医薬組成物
WO1998018763A1 (fr) 1996-10-25 1998-05-07 Tanabe Seiyaku Co., Ltd. Derives de tetrahydroisoquinoline
WO1998019998A2 (fr) 1996-11-07 1998-05-14 Novartis Ag 2-cyanopyrrolidines a substitution n
JPH10182613A (ja) 1996-10-25 1998-07-07 Tanabe Seiyaku Co Ltd テトラヒドロイソキノリン誘導体
CA2289124A1 (fr) 1997-05-07 1998-11-12 Trustees Of Tufts College Utilisation d'un inhibiteur du cd26 pour preparer un medicament traitant le vih
WO1998050066A1 (fr) 1997-05-07 1998-11-12 Trustees Of Tufts College Potentialisation de la reponse immunitaire par production de composes se fixant a une dipeptidase cytoplasmique
WO1999016864A1 (fr) 1997-09-29 1999-04-08 Point Therapeutics, Inc. Stimulation de cellules hematopoietiques in vitro
WO1999025719A1 (fr) 1997-11-18 1999-05-27 Zaidan Hojin Biseibutsu Kagaku Kenkyu Kai Substance physiologiquement active, la sulphostine, procede de fabrication et utilisation
WO1999056753A1 (fr) 1998-05-04 1999-11-11 Point Therapeutics, Inc. Stimulation hematopoietique
DE19823831A1 (de) 1998-05-28 1999-12-02 Probiodrug Ges Fuer Arzneim Neue pharmazeutische Verwendung von Isoleucyl Thiazolidid und seinen Salzen
WO1999062914A1 (fr) 1998-06-05 1999-12-09 Point Therapeutics, Inc. Composes cycliques de boroproline
WO1999067278A1 (fr) 1998-06-24 1999-12-29 Probiodrug Gesellschaft für Arzneimittelforschung mbH Promedicaments d'inhibiteurs de la dipeptidylpeptidase iv
DE19834591A1 (de) 1998-07-31 2000-02-03 Probiodrug Ges Fuer Arzneim Verfahren zur Steigerung des Blutglukosespiegels in Säugern
WO2000010549A1 (fr) 1998-08-21 2000-03-02 Point Therapeutics, Inc. Regulation de l'activite de substrat
WO2000023421A1 (fr) 1998-10-22 2000-04-27 Idun Pharmaceuticals, Inc. INHIBITEURS ACYLE(SUBSTITUE) DIPEPTIDYLE DE LA FAMILLE ICE/ced-3 DES CYSTEINES PROTEASES
WO2000031258A2 (fr) 1998-11-20 2000-06-02 Arena Pharmaceuticals, Inc. Recepteurs humains couples a la proteine g orphan
WO2000034241A1 (fr) 1998-12-10 2000-06-15 Novartis Ag 2-cyanopyrrolidines n-substitues
JP2000191616A (ja) 1998-12-24 2000-07-11 Senju Pharmaceut Co Ltd 新規ジペプチジルアルデヒド誘導体およびそれを含有する医薬
WO2000056296A2 (fr) 1999-03-23 2000-09-28 Ferring Bv Compositions favorisant la fecondite
WO2000056297A2 (fr) 1999-03-23 2000-09-28 Ferring B.V. Compositions favorisant la croissance
WO2000069868A1 (fr) 1999-05-17 2000-11-23 Zaidan Hojin Biseibutsu Kagaku Kenkyu Kai Analogues de la sulphostine et procede de preparation de la sulphostine et de ses analogues
WO2000071135A1 (fr) 1999-05-25 2000-11-30 Point Therapeutics, Inc. Agents anti-tumorales contenant des composes de boroproline
WO2001034594A1 (fr) 1999-11-12 2001-05-17 Guilford Pharmaceuticals, Inc. Inhibiteurs de la dipeptidyl peptidase iv; methodes de fabrication et d'utilisation desdits inhibiteurs
WO2001052825A2 (fr) 2000-01-21 2001-07-26 Novartis Ag Combinaisons comprenant un inhibiteur de la dipeptidylpeptidase - iv
WO2001055105A1 (fr) 2000-01-24 2001-08-02 Novo Nordisk A/S 2-cyanopyroles et -pyrrolines a substitution n inhibant l'enzyme dpp-iv
WO2001068603A2 (fr) 2000-03-10 2001-09-20 Bristol-Myers Squibb Co. Inhibiteurs de la dipeptidyl peptidase iv, a base de pyrrolidone fusionnee a du cyclopropyle, et procede
WO2001081304A1 (fr) 2000-04-26 2001-11-01 Ferring Bv Inhibiteurs de dipeptidyl peptidase iv
WO2001081337A1 (fr) 2000-04-26 2001-11-01 Ferring B.V. Inhibiteurs de dipeptidyl peptidase iv
WO2001096295A2 (fr) 2000-06-13 2001-12-20 Novartis Ag Composes organiques
WO2001097808A1 (fr) 2000-06-19 2001-12-27 Smithkline Beecham Plc Combinaisons d'inhibiteurs de peptidase iv de dipeptidyl et d'autres agents antidiabetiques pour traiter le diabete sucre
WO2002002560A2 (fr) 2000-07-04 2002-01-10 Novo Nordisk A/S Composes heterocycliques inhibiteurs de l'enzyme dpp-iv
US20020006899A1 (en) 1998-10-06 2002-01-17 Pospisilik Andrew J. Use of dipeptidyl peptidase IV effectors for lowering blood pressure in mammals
WO2002014271A1 (fr) 2000-08-10 2002-02-21 Mitsubishi Pharma Corporation Dérivés de proline et leur utilisation comme médicaments
WO2002030891A1 (fr) 2000-10-06 2002-04-18 Tanabe Seiyaku Co., Ltd. Composes aliphatiques azotes a noyau a cinq elements
US6380398B2 (en) 2000-01-04 2002-04-30 Novo Nordisk A/S Therapeutically active and selective heterocyclic compounds that are inhibitors of the enzyme DPP-IV
WO2002034900A1 (fr) 2000-10-27 2002-05-02 The University Of Sydney Dipeptidyl peptidases
WO2002038541A1 (fr) 2000-11-10 2002-05-16 Taisho Pharmaceutical Co., Ltd. Derives de cyanopyrrolidine
US6410508B1 (en) 1998-10-07 2002-06-25 Med College Georgia Res Inst Glucose-dependent insulinotropic peptide for use as an osteotropic hormone
WO2002051836A1 (fr) 2000-12-27 2002-07-04 Kyowa Hakko Kogyo Co., Ltd. Inhibiteur de dipeptidyl peptidase iv
WO2002055088A1 (fr) 2001-01-16 2002-07-18 Nippon Kayaku Kabushiki Kaisha Remedes destines au traitement de la suppression de la moelle osseuse et de maladies infectieuses et agents permettant d'augmenter la concentration leucocytaire du sang
US6432969B1 (en) 2000-06-13 2002-08-13 Novartis Ag N-(substituted glycyl)-2 cyanopyrrolidines, pharmaceutical compositions containing them and their use in inhibiting dipeptidyl peptidase-IV
WO2002062764A1 (fr) 2001-02-02 2002-08-15 Takeda Chemical Industries, Ltd. Composes heterocycliques condenses
WO2002068420A1 (fr) 2001-02-24 2002-09-06 Boehringer Ingelheim Pharma Gmbh & Co. Kg Derives xanthine, fabrication et utilisations en tant qu'agents pharmaceutiques
JP2002265439A (ja) 2001-03-08 2002-09-18 Mitsubishi Pharma Corp シアノピロリジン誘導体およびその医薬用途
EP1245568A1 (fr) 2001-03-28 2002-10-02 Les Laboratoires Servier Dérives sulfonyles d'-aminoacides et leur utilisation en tant qu'inhibiteurs de dipeptidyl-peptidase IV ( DPP IV)
WO2002076450A1 (fr) 2001-03-27 2002-10-03 Merck & Co., Inc. Inhibiteurs de peptidase dipeptidyl destines au traitement ou a la prevention du diabete
WO2002083109A1 (fr) 2001-04-11 2002-10-24 Ferring Bv Traitement du diabete de type 2 a l'aide d'inhibiteurs de dipeptidylpeptidase iv
WO2002083128A1 (fr) 2001-04-12 2002-10-24 Bristol-Myers Squibb Company Inhibiteurs a base de 2,1-oxazoline et 1,2-pyrazoline de la dipeptidyl peptidase iv et methode associee
EP1258476A1 (fr) 2001-05-15 2002-11-20 Les Laboratoires Servier Dérivés d'alpha-amino-acides, leur procédé de préparation ainsi que leur utilisation en tant qu'inhibiteurs de dipeptidyl-peptidase IV (DPP IV)
JP2002356472A (ja) 2000-10-06 2002-12-13 Tanabe Seiyaku Co Ltd 含窒素五員環化合物
JP2002356471A (ja) 2000-10-06 2002-12-13 Tanabe Seiyaku Co Ltd 脂肪族含窒素五員環化合物
WO2003000250A1 (fr) 2001-06-25 2003-01-03 Ferring Bv Agents antidiabetiques a base de 3-fluoro-pyrrolidines
WO2003000181A2 (fr) 2001-06-20 2003-01-03 Merck & Co., Inc. Inhibiteurs de dipeptidyl peptidase utilises dans le traitement du diabete
WO2003000180A2 (fr) 2001-06-20 2003-01-03 Merck & Co., Inc. Inhibiteurs de dipeptidyle peptidase pour le traitement du diabete
WO2003002530A2 (fr) 2001-06-27 2003-01-09 Smithkline Beecham Corporation Pyrrolidines servant d'inhibiteurs de dipeptidyl peptidase
WO2003002596A2 (fr) 2001-06-27 2003-01-09 Probiodrug Ag Nouvelle utilisation d'inhibiteurs de la dipeptidyl peptidase iv
WO2003002593A2 (fr) 2001-06-27 2003-01-09 Probiodrug Ag Structures peptidiques utiles pour la modulation competitive de la catalyse de dipeptidyle peptidase iv
WO2003002531A2 (fr) 2001-06-27 2003-01-09 Smithkline Beecham Corporation Fluoropyrrolidines inhibitrices de la dipeptidyl peptidase
WO2003002553A2 (fr) 2001-06-27 2003-01-09 Smithkline Beecham Corporation Fluoropyrrolidines inhibitrices de la dipeptidyl peptidase
WO2003004498A1 (fr) 2001-07-06 2003-01-16 Merck & Co., Inc. Pyrazines beta-amino tetrahydroimidazo (1, 2-a) et pyrazines tetrahydrotrioazolo (4, 3-a) utilisees en tant qu'inhibiteurs de la dipeptidyl peptidase dans le traitement ou la prevention du diabete
WO2003004496A1 (fr) 2001-07-03 2003-01-16 Novo Nordisk A/S Derives de purine inhibiteurs de dpp-iv pour le traitement du diabete
WO2003022871A2 (fr) 2001-09-06 2003-03-20 Probiodrug Ag Nouveaux inhibiteurs de dipeptidylpeptidase i
WO2003024965A2 (fr) 2001-09-19 2003-03-27 Novo Nordisk A/S Composes heterocycliques constituant des inhibiteurs de l'enzyme dpp-iv
WO2003024942A1 (fr) 2001-09-14 2003-03-27 Mitsubishi Pharma Corporation Derive thiazolidine et son utilisation medicamenteuse
WO2003035057A1 (fr) 2001-10-23 2003-05-01 Ferring B.V. Inhibiteurs de la dipeptidyl peptidase iv
WO2003035067A1 (fr) 2001-10-23 2003-05-01 Ferring B.V. Inhibiteurs de dipeptidyl peptidase iv (dp-iv) tenant lieu d'agents anti-diabetiques
WO2003037327A1 (fr) 2001-10-26 2003-05-08 F. Hoffmann-La-Roche Ag Derives de pyrrolidine n-substitues en tant qu'inhibiteurs de la dipeptidyl peptidase iv
WO2003038123A2 (fr) 2001-10-31 2003-05-08 Novartis Ag Procede de traitement du diabete et conditions apparentees basees sur des polymorphismes dans le gene tcf1
WO2003040174A2 (fr) 2001-11-09 2003-05-15 Probiodrug Ag Composes d'aminocetone substitues
WO2003045228A2 (fr) 2001-11-26 2003-06-05 Trustees Of Tufts College Techniques de traitement de maladies auto-immunes et reactifs associes
US20030105077A1 (en) 2001-07-03 2003-06-05 Kanstrup Anders Bendtz Heterocyclic compounds that are inhibitors of the enzyme DPP-IV
US20030119738A1 (en) 2001-09-06 2003-06-26 Andre Niestroj Novel inhibitors of dipeptidyl peptidase I
US20030119750A1 (en) 2001-06-27 2003-06-26 Hans-Ulrich Demuth Use of dipeptidyl peptidase IV inhibitors
US20030125304A1 (en) 2001-11-09 2003-07-03 Hans-Ulrich Demuth Substituted amino ketone compounds
US20030130199A1 (en) 2001-06-27 2003-07-10 Von Hoersten Stephan Dipeptidyl peptidase IV inhibitors and their uses as anti-cancer agents
WO2003055881A1 (fr) 2001-12-27 2003-07-10 F. Hoffmann-La Roche Ag Derives de pyrido(2,1-a)isoquinoline comme inhibiteurs dpp-iv
WO2003057144A2 (fr) 2001-12-26 2003-07-17 Guilford Pharmaceuticals Changement d'inhibiteurs de la dipeptidyl peptidase iv
WO2003068757A1 (fr) 2002-02-13 2003-08-21 F. Hoffmann-La Roche Ag Nouveaux derives de pyridine et de pyrimidine
WO2003068748A1 (fr) 2002-02-13 2003-08-21 F. Hoffmann-La Roche Ag Nouveaux derives de pyridine et de quinoline
EP1338651A1 (fr) 2000-12-01 2003-08-27 Yamanouchi Pharmaceutical Co. Ltd. Procede de depistage d'un remede
EP1338592A1 (fr) 2002-02-22 2003-08-27 Nippon Zoki Pharmaceutical Co., Ltd. Dérivés de 2-phénylpipérazine
JP2003238566A (ja) 2001-02-02 2003-08-27 Takeda Chem Ind Ltd 縮合複素環化合物
US20030162820A1 (en) 2002-02-28 2003-08-28 Hans-Ulrich Demuth Glutaminyl based DPIV inhibitors
WO2003072528A2 (fr) 2002-02-08 2003-09-04 Idun Pharmaceuticals, Inc. Inhibiteurs de dipeptidyle d'acide substitue de la famille ice/ced-3 des proteases de cysteine
US6617340B1 (en) 1999-07-29 2003-09-09 Novartis Ag N-(substituted glycyl)-pyrrolidines, pharmaceutical compositions containing them and their use in inhibiting dipeptidyl peptidase-IV
WO2003074500A2 (fr) 2002-03-06 2003-09-12 Sanofi-Aventis Nouveaux composes
WO2003080633A1 (fr) 2002-03-25 2003-10-02 Nippon Kayaku Kabushiki Kaisha Nouveau derive d'$g(a)-amino-n-(diaminophosphinyl)lactame
WO2003082817A2 (fr) 2002-03-25 2003-10-09 Merck & Co., Inc. Inhibiteurs de la dipeptidyl peptidase beta-amino heterocycliques pour le traitement ou la prevention du diabete
WO2003084940A1 (fr) 2002-04-08 2003-10-16 Alangudi Sankaranarayanan Thiazolidine-4-carbonitriles et analogues et leur utilisation comme inhibiteurs de dipeptidyl-peptidas
JP2003300977A (ja) 2002-04-10 2003-10-21 Sumitomo Pharmaceut Co Ltd キサンチン誘導体
JP2003327532A (ja) 2002-05-10 2003-11-19 Takeda Chem Ind Ltd ペプチダーゼ阻害剤
WO2003095425A1 (fr) 2002-05-09 2003-11-20 Taisho Pharmaceutical Co.,Ltd. Derives de cyanopyrrolidine
WO2003099279A1 (fr) 2002-05-29 2003-12-04 Novartis Ag Association d'un inhibiteur de dipeptidyl peptidase iv (dpp iv) et d'un compose cardio-vasculaire
WO2003101958A2 (fr) 2002-06-04 2003-12-11 Pfizer Products Inc. Amides cycliques fluores utilises comme inhibiteurs de la dipeptidyl peptidase iv
WO2003101448A1 (fr) 2002-06-03 2003-12-11 Novartis Ag Utilisation de cyanopyrrolidines substituees et de preparations de combinaison contenant celles-ci dans le traitement d'hyperlipidemie et de maladies associees
WO2003104229A1 (fr) 2002-06-06 2003-12-18 エーザイ株式会社 Nouveau derive d'imidazole fondu
WO2003106456A2 (fr) 2002-06-14 2003-12-24 Sanofi-Synthelabo Nouveaux composes
WO2003105763A2 (fr) 2002-06-14 2003-12-24 Amylin Pharmaceuticals, Inc. Prevention et/ou traitement de maladie enterique inflammatoire au moyen de peptides yy ou d'antagonistes de peptides yy
WO2004000327A1 (fr) 2002-06-24 2003-12-31 Zaidan Hojin Biseibutsu Kagaku Kenkyu Kai Agent therapeutique pour des diabetes de type 2
JP2004002368A (ja) 2002-04-04 2004-01-08 Tanabe Seiyaku Co Ltd 医薬組成物
JP2004002367A (ja) 2002-04-04 2004-01-08 Tanabe Seiyaku Co Ltd 医薬組成物
WO2004004661A2 (fr) 2002-07-09 2004-01-15 Point Therapeutics, Inc. Polytherapie a base de composes de boroproline
WO2004007468A1 (fr) 2002-07-15 2004-01-22 Merck & Co., Inc. Inhibiteurs de piperidino pyrimidine dipeptidyl peptidase utilises dans le traitement du diabete
WO2004007446A1 (fr) 2002-07-10 2004-01-22 Yamanouchi Pharmaceutical Co., Ltd. Nouveau derive de l'azetidine ou ses sels
WO2004009544A1 (fr) 2002-07-23 2004-01-29 Yamanouchi Pharmaceutical Co., Ltd. Derive de 2-cyano-4-fluoropyrrolidine ou de son sel
JP2004026820A (ja) 2002-05-09 2004-01-29 Taisho Pharmaceut Co Ltd ジペプチジルペプチダーゼｉｖ阻害剤
JP2004035574A (ja) 2000-10-06 2004-02-05 Tanabe Seiyaku Co Ltd 脂肪族含窒素五員環化合物
JP2004043429A (ja) 2002-02-25 2004-02-12 Eisai Co Ltd 新規キサンチン誘導体およびｄｐｐｉｖ阻害剤
WO2004014860A2 (fr) 2002-08-08 2004-02-19 Takeda Pharmaceutical Company Limited Composes heterocycliques fusionnes
WO2004018468A2 (fr) 2002-08-21 2004-03-04 Boehringer Ingelheim Pharma Gmbh & Co. Kg 8-[3-amino-piperidin-1-yl]-xanthines, leur production et leur utilisation comme medicament
WO2004018467A2 (fr) 2002-08-22 2004-03-04 Boehringer Ingelheim Pharma Gmbh & Co. Kg Derives de xanthine, leur production et leur utilisation comme medicaments
DE10238477A1 (de) 2002-08-22 2004-03-04 Boehringer Ingelheim Pharma Gmbh & Co. Kg Neue Purinderivate, deren Herstellung und deren Verwendung als Arzneimittel
DE10238243A1 (de) 2002-08-21 2004-03-04 Boehringer Ingelheim Pharma Gmbh & Co. Kg 8-[3-Amino-piperidin-1-yl]-xanthine, deren Herstellung und deren Verwendung als Arzneimittel
WO2004020407A1 (fr) 2002-08-29 2004-03-11 Taisho Pharmaceutical Co.,Ltd. Benzenesulfonate d'un derive de 4-fluoro-2-cyanopyrrolidine
US6710040B1 (en) 2002-06-04 2004-03-23 Pfizer Inc. Fluorinated cyclic amides as dipeptidyl peptidase IV inhibitors
WO2004026822A2 (fr) 2002-09-19 2004-04-01 Abbott Laboratories Compositions pharmaceutiques utiles comme inhibiteurs de la peptidase-iv dipeptidyl (dpp-iv)
WO2004032836A2 (fr) 2002-10-07 2004-04-22 Merck & Co., Inc. Inhibiteurs de la dipeptidyl peptidase heterocyclique beta-amino utiles pour le traitement ou la prevention du diabete
WO2004033455A2 (fr) 2002-10-08 2004-04-22 Novo Nordisk A/S Sels succiniques d'inhibiteurs heterocycliques de dpp-iv
US20040082570A1 (en) 2002-02-25 2004-04-29 Eisai Co., Ltd. Xanthine derivative and DPPIV inhibitor
WO2004037181A2 (fr) 2002-10-23 2004-05-06 Bristol-Myers Squibb Company Inhibiteurs de dipeptidyl peptidase iv a base de glycinenitrile et procedes correspondants
WO2004037169A2 (fr) 2002-10-18 2004-05-06 Merck & Co., Inc. Inhibiteurs de dipeptidylpeptidase heterocyclique beta-amino destines au traitement ou a la prevention de diabetes
DE10251927A1 (de) 2002-11-08 2004-05-19 Boehringer Ingelheim Pharma Gmbh & Co. Kg Neue Xanthinderivate, deren Herstellung und deren Verwendung als Arzneimittel
US20040097510A1 (en) 2002-08-21 2004-05-20 Boehringer Ingelheim Pharma Gmbh & Co. Kg 8-[3-amino-piperidin-1-yl]-xanthines, the preparation thereof and their use as pharmaceutical compositions
WO2004041795A1 (fr) 2002-10-30 2004-05-21 Guilford Pharmaceuticals Inc. Nouveaux inhibiteurs de dipeptidyl peptidase iv
WO2004043940A1 (fr) 2002-11-07 2004-05-27 Merck & Co., Inc. Derives de phenylalanine utilises comme inhibiteurs de la dipeptidyl peptidase dans le traitement ou la prevention du diabete
WO2004046106A1 (fr) 2002-11-18 2004-06-03 Pfizer Products Inc. Amides cycliques fluorés inhibant la dipeptidyl peptidase iv
WO2004048379A1 (fr) 2002-11-01 2004-06-10 Sumitomo Pharmaceuticals Co., Ltd. Compose de xanthine
WO2004050658A1 (fr) 2002-12-03 2004-06-17 Boehringer Ingelheim Pharma Gmbh & Co. Kg Nouvelles imidazo-pyridinones et imidazo-pyridazinones substituees, leur production et leur utilisation en tant que medicaments
WO2004050022A2 (fr) 2002-12-04 2004-06-17 Merck & Co., Inc. Derives de phenylalanine utilises comme inhibiteurs de la dipeptidylpeptisase pour le traitement ou la prevention de diabetes
WO2004052850A2 (fr) 2002-12-09 2004-06-24 Bristol-Myers Squibb Company Procedes et composes pour produire des inhibiteurs de la dipeptidyle-peptidase et leurs intermediaires
DE10256264A1 (de) 2002-12-03 2004-06-24 Boehringer Ingelheim Pharma Gmbh & Co. Kg Neue substituierte Imidazo-pyridinone und Imidazo-pyridazinone, ihre Herstellung und ihre Verwendung als Arzneimittel
WO2004052362A1 (fr) 2002-12-10 2004-06-24 Novartis Ag Combinaision d'un inhibiteur de dpp-iv et d'un compose ppar-alpha
WO2004058266A1 (fr) 2002-12-20 2004-07-15 Merck & Co., Inc. Derives de 3-amino-4-phenylbutanoique acide utilises en tant qu'inhibiteurs de dipeptidyl peptidase pour le traitement ou la prevention du diabete
US20040138214A1 (en) 2002-11-08 2004-07-15 Boehringer Ingelheim Pharma Gmbh & Co. Kg Xanthine derivatives, the preparation thereof and their use as pharmaceutical compositions
WO2004064778A2 (fr) 2003-01-17 2004-08-05 Merck & Co. Inc. Derives d'acide 3-amino-4-phenylbutanoique utilises comme inhibiteurs de la dipeptidyl peptidase pour le traitement ou la prevention du diabete
WO2004065380A1 (fr) 2003-01-14 2004-08-05 Arena Pharmaceuticals Inc. Derives aryles et heteroaryles tri-substitues en position 1,2,3 en tant que modulateurs de metabolisme et prophylaxie et traitement de troubles lies au metabolisme
WO2004067509A1 (fr) 2003-01-31 2004-08-12 Sanwa Kagaku Kenkyusho Co., Ltd. Composé inhibant la dipeptidyl peptidase iv
WO2004069162A2 (fr) 2003-01-31 2004-08-19 Merck & Co., Inc. Derives d'acide 3-amino-4-phenylbutanoique utilises comme inhibiteurs de dipeptidyle peptidase pour le traitement ou la prevention du diabete
WO2004071454A2 (fr) 2003-02-13 2004-08-26 Guilford Pharmaceuticals Inc. Composes d'azetidine substitues servant d'inhibiteurs de dipeptidyl peptidase iv
JP2004244412A (ja) 2003-01-20 2004-09-02 Kotobuki Seiyaku Kk ４位に置換基を有する２−シアノピロリジン誘導体及びその製造方法並びにそれを含有する薬剤
WO2004076433A1 (fr) 2003-02-28 2004-09-10 Aic Inhibiteurs de dipeptidyle peptidase
WO2004076413A2 (fr) 2003-02-24 2004-09-10 Arena Pharmaceuticals, Inc. Derives d'aryle et heteroaryle susbtitues tenant lieu de modulateurs du metabolisme du glucose et prophylaxie et traitement de troubles associes
WO2004076434A1 (fr) 2003-02-28 2004-09-10 Aic Inhibiteurs de dipeptidyl peptidases
WO2004085378A1 (fr) 2003-03-19 2004-10-07 Merck & Co. Inc. Procede pour preparer des derives d'acide amine beta chiraux par hydrogenation asymetrique
WO2004085661A2 (fr) 2003-03-24 2004-10-07 Merck & Co., Inc Procede de synthese de derives d'acides amines beta chiraux
US6803357B1 (en) 1998-02-02 2004-10-12 New England Medical Center Hospitals, Inc. Method of regulating glucose metabolism, and reagents related thereto
WO2004087053A2 (fr) 2003-03-25 2004-10-14 Syrrx, Inc. Inhibiteurs de dipeptidyle peptidase
WO2004087650A2 (fr) 2003-03-27 2004-10-14 Merck & Co. Inc. Procede et intermediaires pour la preparation d'inhibiteurs d'amide d'acide beta-amino de dipeptidyle peptidase-iv
EP1469873A2 (fr) 2001-11-26 2004-10-27 Trustees of Tufts College Inhibiteurs peptidomimetiques d'enzymes de clivage post-proline
WO2004092128A1 (fr) 2003-04-10 2004-10-28 Smithkline Beecham Corporation Formes cristallines anhydres de (2s, 4s)-1-{(2r)-2-amino-3-'4-methoxybenzyl)sulfonyl!-3-methylbutanoyl}-4-fluoropyrrolindine-2-carbonitrile
US6812350B2 (en) 2002-06-04 2004-11-02 Pfizer Inc. Synthesis of 3,3,4,4-tetrafluoropyrrolidine and novel dipeptidyl peptidase-IV inhibitor compounds
WO2004096806A1 (fr) 2003-04-30 2004-11-11 Sumitomo Pharmaceuticals Co. Ltd. Derive d'imidazole condense
JP2004315496A (ja) 2002-08-08 2004-11-11 Takeda Chem Ind Ltd 縮合複素環化合物
WO2004099134A2 (fr) 2003-05-05 2004-11-18 Prosidion Ltd. Inhibiteurs de la dp iv a base de glutaminyle
WO2004104216A2 (fr) 2003-05-21 2004-12-02 Bayer Healthcare Ag Diagnostics et agents therapeutiques destines a des maladies liees a une dipeptidylpeptidase iv (dpp4)
WO2004103276A2 (fr) 2003-05-14 2004-12-02 Merck & Co., Inc. Derives d'acide 3-amino-4-phenylbutanoique en tant qu'inhibiteurs de dipeptidyl peptidase dans le cadre du traitement ou de la prevention du diabete
WO2004104215A2 (fr) 2003-05-21 2004-12-02 Bayer Healthcare Ag Approches diagnostiques et therapeutiques des maladies associees a la dipeptidylpeptidase 7 (dpp7)
WO2004103993A1 (fr) 2003-05-14 2004-12-02 Syrrx, Inc. Inhibiteurs de dipeptidyl peptidase
WO2004108730A1 (fr) 2003-06-05 2004-12-16 Fujisawa Pharmaceutical Co., Ltd. Inhibiteur de l'enzyme dpp-iv
US20040259903A1 (en) 2003-06-20 2004-12-23 Markus Boehringer Pyrido [2,1-a] isoquinoline derivatives
WO2004110436A1 (fr) 2003-06-06 2004-12-23 Merck & Co., Inc. Indoles fusionnes en tant qu'inhibiteurs de dipeptidyle peptidase destines au traitement ou a la prevention des diabetes
WO2004111051A1 (fr) 2003-06-18 2004-12-23 Boehringer Ingelheim International Gmbh Derives d'imidazopyridazinones et d'imidazopyridones, leur preparation et leur utilisation comme medicaments
WO2004111041A1 (fr) 2003-06-12 2004-12-23 Fujisawa Pharmaceutical Co., Ltd. Compose de pyrrolidine, de thiazolidine et d'oxazolidine inhibant la dipeptidyl-peptidase-iv (dpp-iv)
WO2004110375A2 (fr) 2003-06-06 2004-12-23 Merck & Co., Inc. Polytherapie permettant de traiter le diabete
US20040259902A1 (en) 2003-06-20 2004-12-23 Markus Boehringer Pyrido [2,1-a] isoquinoline derivatives
WO2004112701A2 (fr) 2003-06-17 2004-12-29 Merck & Co., Inc. Derives de cyclohexylglycine servant d'inhibiteurs de la dipeptidyl peptidase pour le traitement ou la prevention du diabete
WO2005003135A1 (fr) 2003-06-24 2005-01-13 Merck & Co., Inc. Sel d'acide phosphorique d'un inhibiteur de la dipeptidyl peptidase iv
WO2005007647A1 (fr) 2003-07-11 2005-01-27 Arena Pharmaceuticals, Inc. Derives aryles et heteroaryles trisubstitues utilises en tant que modulateurs du metabolisme et prophylaxie et traitement de troubles afferents
JP2005023038A (ja) 2003-07-04 2005-01-27 Taisho Pharmaceut Co Ltd 慢性腎疾患治療薬
WO2005009956A1 (fr) 2003-07-21 2005-02-03 Smithkline Beecham Corporation Sel d'acide (2s,4s)-4-fluoro-1-[4-fluoro-beta-(4-fluorophenyl)-1-phenylalanyl]-2-pyrrolidinecarbonitrile p-toluenesulfonique, et certaines de ses formes crristallines anhydres
WO2005011581A2 (fr) 2003-07-31 2005-02-10 Merck & Co., Inc. Hexahydrodiazepinones utilises en tant qu'inhibiteurs de la dipeptidyl peptidase iv pour le traitement ou la prevention du diabete
WO2005012308A1 (fr) 2003-07-25 2005-02-10 Sanofi-Aventis Deutschland Gmbh Nouveaux cyanopyrrolidides, procedes pour leur production et leur utilisation comme medicament
WO2005012312A1 (fr) 2003-07-25 2005-02-10 Sanofi-Aventis Deutschland Gmbh Nouvelles cyanothiazolides, leur procede de production et leur utilisation comme medicament
WO2005012249A2 (fr) 2003-08-01 2005-02-10 Bristol-Myers Squibb Company Inhibiteurs a base d'adamantyglycine de la dipeptidyl peptidase iv et procedes associes
US20050043292A1 (en) 2003-08-20 2005-02-24 Pfizer Inc Fluorinated lysine derivatives as dipeptidyl peptidase IV inhibitors
WO2005020920A2 (fr) 2003-09-02 2005-03-10 Merck & Co., Inc. Nouvelles formes cristallines d'un sel d'acide phosphorique d'un inhibiteur de dipeptidyl peptidase-iv
US20050059724A1 (en) 2003-07-25 2005-03-17 Aventis Pharma Deutschland Gmbh Novel cyanopyrrolidides, process for their preparation and their use as medicaments
US20050059716A1 (en) 2003-07-25 2005-03-17 Aventis Pharma Deutschland Gmbh Novel bicyclic cyanoheterocycles, process for their preparation and their use as medicaments
WO2005023762A1 (fr) 2003-09-04 2005-03-17 Abbott Laboratories Derives de pyrrolidine-2-carbonitrile et leur utilisation comme inhibiteurs de la dipeptidyle peptidase-iv (dpp-iv)
WO2005026148A1 (fr) 2003-09-08 2005-03-24 Takeda San Diego, Inc. Inhibiteurs de la dipeptidylpeptidase
WO2005025554A2 (fr) 2003-09-09 2005-03-24 Japan Tobacco Inc. Inhibiteur de la dipeptidylpeptidase iv
WO2005030127A2 (fr) 2003-09-23 2005-04-07 Merck & Co., Inc. Nouvelle forme cristalline d'un sel d'acide phosphorique d'un inhibiteur de dipeptidyle peptase-iv
WO2005030751A2 (fr) 2003-09-08 2005-04-07 Takeda Pharmaceutical Company Limited Inhibiteurs de dipeptidyle peptidase
WO2005032590A1 (fr) 2003-10-03 2005-04-14 Takeda Pharmaceutical Company Limited Remede contre le diabete
WO2005033099A2 (fr) 2003-10-03 2005-04-14 Glenmark Pharmaceuticals Ltd. Nouveaux inhibiteurs de dipeptidylpeptidase iv, leurs procedes de preparation et compositions les contenant
WO2005034940A2 (fr) 2003-10-15 2005-04-21 Imtm Gmbh Inhibiteurs doubles d'alanyl-aminopeptidase et de dipeptidylpeptidase iv utilises pour influer de maniere fonctionnelle sur differentes cellules et pour traiter des affections immunologiques, inflammatoires, neuronales et autres
WO2005037828A1 (fr) 2003-10-20 2005-04-28 Lg Life Sciences Ltd. Inhibiteurs de dpp-iv, procedes d'elaboration correspondants, et compositions pharmaceutiques renfermant ces inhibiteurs comme principe actif
WO2005037779A2 (fr) 2003-10-15 2005-04-28 Imtm Gmbh Nouveaux inhibiteurs de dipeptidylpeptidases iv destines a influencer le fonctionnement de diverses cellules et a traiter des maladies immunologiques, inflammatoires, neuronales et autres
WO2005040095A1 (fr) 2003-10-16 2005-05-06 Astrazeneca Ab Inhibiteurs de la dipeptidyl-peptidase iv
WO2005042488A1 (fr) 2003-10-31 2005-05-12 Takeda Pharmaceutical Company Limited Composes pyridines utilises comme inhibiteurs de dipeptidyle peptidase iv
WO2005044195A2 (fr) 2003-11-04 2005-05-19 Merck & Co., Inc. Derives de phenylalanine fusionnes utilises comme inhibiteurs de la dipeptidyl peptidase-iv dans le traitement ou la prevention du diabete
WO2005047297A1 (fr) 2003-11-12 2005-05-26 Phenomix Corporation Composés heterocycliques d'acide boronique
WO2005049022A2 (fr) 2003-11-17 2005-06-02 Novartis Ag Utilisation de composes organiques
WO2005058849A1 (fr) 2003-12-15 2005-06-30 Glenmark Pharmaceuticals Ltd. Nouveaux inhibiteurs de dipeptidyle peptidase iv, leur procede de preparation et compositions les contenant
WO2005063750A1 (fr) 2003-12-23 2005-07-14 Boehringer Ingelheim International Gmbh Composes imidazol bicycliques, leur fabrication et leur utilisation comme medicaments
WO2005072530A1 (fr) 2004-01-16 2005-08-11 Merck & Co., Inc. Nouveau sel cristallin d'un inhibiteur de dipeptidyle peptidase-iv
WO2005075426A1 (fr) 2004-02-03 2005-08-18 Glenmark Pharmaceuticals Ltd. Nouveaux inhibiteurs de dipeptidyle peptidase iv, leur procedes de preparation et compositions en comportant
WO2005079795A2 (fr) 2004-02-20 2005-09-01 Novartis Ag Utilisation de composes organiques
WO2005082348A2 (fr) 2004-02-23 2005-09-09 Trustees Of Tufts College Inhibiteurs de la dipeptidylpeptidase iv
WO2005082849A1 (fr) 2004-02-23 2005-09-09 Trustees Of Tufts College Lactames utilisees comme inhibiteurs peptidomimetiques a contrainte conformationnelle
WO2005087235A1 (fr) 2004-03-09 2005-09-22 National Health Research Institutes Composes de pyrrolidine
WO2005095381A1 (fr) 2004-03-15 2005-10-13 Takeda Pharmaceutical Company Limited Inhibiteurs de la dipeptidyle peptidase
WO2005116014A1 (fr) 2004-05-12 2005-12-08 Pfizer Products Inc. Derives de proline et leur utilisation en tant qu'inhibiteurs de la dipeptidyl-peptidase iv
WO2006040625A1 (fr) 2004-10-12 2006-04-20 Glenmark Pharmaceuticals S.A. Nouveaux inhibiteurs de dipeptidyle peptidase iv, compositions pharmaceutiques en contenant, et leur procede de preparation
WO2006068163A1 (fr) 2004-12-24 2006-06-29 Dainippon Sumitomo Pharma Co., Ltd. Dérivés bicycliques de pyrrole
WO2006076231A2 (fr) 2005-01-10 2006-07-20 Arena Pharmaceuticals, Inc. Polytherapie destinee au traitement du diabete et de troubles lies au diabete et au traitement de troubles pouvant etre soignes par une augmentation du taux de glp-1 dans le sang
WO2006088129A1 (fr) 2005-02-18 2006-08-24 Mitsubishi Pharma Corporation Sel d'un dérivé de proline, solvate dudit sel, et méthode de production dudit sel
WO2006100181A2 (fr) 2005-03-22 2006-09-28 F. Hoffmann-La Roche Ag Nouveau sel et polymorphes de l'inhibiteur de dpp-iv
WO2006116157A2 (fr) 2005-04-22 2006-11-02 Alantos Pharmaceuticals Holding, Inc. Inhibiteurs de la dipeptidyl peptidase iv
WO2007019255A2 (fr) 2005-08-04 2007-02-15 Novartis Ag Nouveaux composes
WO2007027651A2 (fr) 2005-08-30 2007-03-08 Abbott Laboratories Compositions pharmaceutiques utilisees comme inhibiteurs de la dipeptidyl peptidase iv (dpp-iv)
WO2007035372A2 (fr) 2005-09-16 2007-03-29 Takeda Pharmaceutical Company Limited Formes polymorphes de sel benzoate de 2-[[6-[(3r)-3-amino-1-piperidinyl]-3,4-dihydro-3-methyl-2,4-dioxo-1(2h)-pyrimidinyl]methyl]-benzonitrile, et leurs procedes d'utilisation
WO2007071576A1 (fr) 2005-12-21 2007-06-28 F. Hoffmann-La Roche Ag Nouveau sel et polymorphe d’un inhibiteur de dpp-iv
US20070167468A1 (en) 2004-08-06 2007-07-19 Sanofi-Aventis Deutschland Gmbh Substituted bicyclic 8-pyrr0lidinoxanthines, methods for their production, pharmaceutical formulations and their use
WO2007120702A2 (fr) 2006-04-11 2007-10-25 Arena Pharmaceuticals, Inc. Agonistes du récepteur de gpr119 dans des procédés d'augmentation de la masse osseuse et de traitement de l'ostéoporose et autres états se caractérisant par une masse osseuse faible, et thérapie de combinaison associée
WO2007120689A2 (fr) 2006-04-11 2007-10-25 Arena Pharmaceuticals, Inc. Procédés d'utilisation du récepteur gpr119 pour identifier des composés utiles pour augmenter la masse osseuse chez un individu
WO2007128721A1 (fr) 2006-05-04 2007-11-15 Boehringer Ingelheim Internationalgmbh Polymorphes
WO2007148185A2 (fr) 2006-06-21 2007-12-27 Pfizer Products Inc. 3-amino-pyrrolidino-4-lactames substitués
WO2008027273A2 (fr) 2006-08-30 2008-03-06 Phenomix Corporation Sels citrates et tartrates solides d'inhibiteurs de la dpp-iv
EP1902730A1 (fr) 2005-06-09 2008-03-26 Banyu Pharmaceutical Co., Ltd. Agoniste de npy y2 pour une utilisation en tant qu agent thérapeutique contre une maladie s accompagnant de diarrhée
WO2008070692A2 (fr) * 2006-12-06 2008-06-12 Smithkline Beecham Corporation Composés chimiques et leurs utilisations
US20080146818A1 (en) 2004-02-05 2008-06-19 Yasumichi Fukuda Bicycloester Derivative
WO2008114857A1 (fr) 2007-03-22 2008-09-25 Kyorin Pharmaceutical Co., Ltd. Procédé de préparation d'un dérivé d'aminoacétylpyrrolidinecarbonitrile
WO2009084497A1 (fr) 2007-12-28 2009-07-09 Dainippon Sumitomo Pharma Co., Ltd. Dérivé de pipéridine substituée par un méthyle
WO2009126245A1 (fr) 2008-04-07 2009-10-15 Arena Pharmaceuticals, Inc. Procédés d'utilisation d'un récepteur couplé à la protéine g pour identifier des sécrétagogues du peptide yy (pyy) et composés utiles dans le traitement de pathologies modulées par le pyy

Patent Citations (401)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DD296075A5 (de) 1989-08-07 1991-11-21 Martin-Luther-Universitaet Halle-Wittenberg,De Verfahren zur herstellung neuer inhibitoren der dipeptidyl peptidase iv
WO1991016339A1 (fr) 1990-04-14 1991-10-31 New England Medical Center Hospitals, Inc. Inhibiteurs de dipeptidyl-aminopeptidase de type iv
EP0528858A1 (fr) 1990-04-14 1993-03-03 New England Medical Center Inc Inhibiteurs de dipeptidyl-aminopeptidase de type iv.
JPH05508624A (ja) 1990-04-14 1993-12-02 ニュー　イングランド　メデカル　センター　ホスピタルズ　インク ジペプチジル―アミノベプチダーゼ・４型の阻害剤
WO1993008259A2 (fr) 1991-10-22 1993-04-29 New England Medical Center Hospitals, Inc. Inhibiteurs de dipeptidyl-aminopeptidase de type iv
EP0610317A1 (fr) 1991-10-22 1994-08-17 New England Medical Center Inhibiteurs de dipeptidyl-aminopeptidase de type iv
EP1050540A2 (fr) 1991-10-22 2000-11-08 New England Medical Center Hospitals, Inc. Inhibiteurs de dipeptidyl-aminopeptidase de type IV
CA2123128A1 (fr) 1991-11-22 1993-05-27 Roger Snow Methode de fabrication d'un ester de prolineboronate
WO1993010127A1 (fr) 1991-11-22 1993-05-27 Boehringer Ingelheim Pharmaceuticals, Inc. Procede de production d'un ester de prolineboronate
JPH07501078A (ja) 1991-11-22 1995-02-02 ベーリンガー インゲルハイム ファーマシューティカルズ インコーポレイテッド プロリンボロネートエステルの製法
EP0641347A1 (fr) 1991-11-22 1995-03-08 Boehringer Ingelheim Pharmaceuticals Inc. Procede de production d'un ester de prolineboronate
US5571815A (en) * 1992-03-14 1996-11-05 Hoechst Aktiengesellschaft Substituted pyrimidines, process for their preparation, and their use as pesticides and fungicides
EP0731789A1 (fr) 1993-12-03 1996-09-18 Ferring B.V. Inhibiteurs de la dp-iv-serine protease
WO1995015309A1 (fr) 1993-12-03 1995-06-08 Ferring B.V. Inhibiteurs de la dp-iv-serine protease
WO1995029691A1 (fr) 1994-04-28 1995-11-09 Georgia Tech Research Corporation Derives de la proline phosphonate
DE19616486A1 (de) 1996-04-25 1997-10-30 Knoell Hans Forschung Ev Verfahren zur Senkung des Blutglukosespiegels in Säugern
WO1997040832A1 (fr) 1996-04-25 1997-11-06 Probiodrug Gesellschaft für Arzneimittelforschung mbH Utilisation d'effecteurs de la dipeptidyl peptidase iv pour abaisser la teneur en glucose dans le sang chez les mammiferes
JP2001510442A (ja) 1996-04-25 2001-07-31 プロビオドラッグ ゲゼルシャフト フュル アルツナイミッテルフォルシュング エムベーハー 哺乳動物の血糖値低下のためのジペプチジルペプチダーゼ▲ｉｖ▼エフェクターの使用
US6303661B1 (en) 1996-04-25 2001-10-16 Probiodrug Use of dipeptidyl peptidase IV effectors for lowering the blood glucose level in mammals
JPH1081666A (ja) 1996-06-12 1998-03-31 Ishihara Sangyo Kaisha Ltd フタルイミド誘導体又はその塩、それらの製造方法及びそれらを含有する医薬組成物
WO1998018763A1 (fr) 1996-10-25 1998-05-07 Tanabe Seiyaku Co., Ltd. Derives de tetrahydroisoquinoline
JPH10182613A (ja) 1996-10-25 1998-07-07 Tanabe Seiyaku Co Ltd テトラヒドロイソキノリン誘導体
WO1998019998A2 (fr) 1996-11-07 1998-05-14 Novartis Ag 2-cyanopyrrolidines a substitution n
JP2000511559A (ja) 1996-11-07 2000-09-05 ノバルティス アクチエンゲゼルシャフト Ｎ―置換２―シアノピロリジン
WO1998050066A1 (fr) 1997-05-07 1998-11-12 Trustees Of Tufts College Potentialisation de la reponse immunitaire par production de composes se fixant a une dipeptidase cytoplasmique
EP0980249A1 (fr) 1997-05-07 2000-02-23 Trustees Of Tufts College Utilisation d'un inhibiteur du cd26 pour preparer un medicament traitant le vih
CA2289124A1 (fr) 1997-05-07 1998-11-12 Trustees Of Tufts College Utilisation d'un inhibiteur du cd26 pour preparer un medicament traitant le vih
WO1998050046A1 (fr) 1997-05-07 1998-11-12 Trustees Of Tufts College Utilisation d'un inhibiteur du cd26 pour preparer un medicament traitant le vih
US6100234A (en) 1997-05-07 2000-08-08 Tufts University Treatment of HIV
CA2289125A1 (fr) 1997-05-07 1998-11-12 Trustees Of Tufts College Potentialisation de la reponse immunitaire par production de composes se fixant a une dipeptidase cytoplasmique
US6040145A (en) 1997-05-07 2000-03-21 Tufts University Potentiation of the immune response
EP0975359A1 (fr) 1997-05-07 2000-02-02 Trustees Of Tufts College Potentialisation de la reponse immunitaire par production de composes se fixant a une dipeptidase cytoplasmique
WO1999016864A1 (fr) 1997-09-29 1999-04-08 Point Therapeutics, Inc. Stimulation de cellules hematopoietiques in vitro
EP1043328A1 (fr) 1997-11-18 2000-10-11 Zaidan Hojin Biseibutsu Kagaku Kenkyu Kai Substance physiologiquement active, la sulphostine, procede de fabrication et utilisation
WO1999025719A1 (fr) 1997-11-18 1999-05-27 Zaidan Hojin Biseibutsu Kagaku Kenkyu Kai Substance physiologiquement active, la sulphostine, procede de fabrication et utilisation
US6803357B1 (en) 1998-02-02 2004-10-12 New England Medical Center Hospitals, Inc. Method of regulating glucose metabolism, and reagents related thereto
WO1999056753A1 (fr) 1998-05-04 1999-11-11 Point Therapeutics, Inc. Stimulation hematopoietique
EP1215207A2 (fr) 1998-05-28 2002-06-19 Probiodrug AG Sels d'isoleucyl-thiazolidine et -pyrrolidine et leur utilisation comme inhibiteurs de dipeptidylpeptidase
US20030134802A1 (en) 1998-05-28 2003-07-17 Hans-Ulrich Demuth Novel effectors of dipepetidyl peptidase IV
EP1304327A2 (fr) 1998-05-28 2003-04-23 Probiodrug AG Thiazolide et pyrrolide de glutamine ainsi que leur utilisation comme inhibiteurs de dipeptidylpeptidase IV
JP2002516318A (ja) 1998-05-28 2002-06-04 プロバイオドラッグ ゲゼルシャフト フュア アルツナイミッテルフォルシュンク エムベーハー ジペプチジル・ペプチダーゼｉｖの新規エフェクター
EP1082314A1 (fr) 1998-05-28 2001-03-14 Probiodrug Gesellschaft für Arzneimittelforschung mbH Nouveaux effecteurs de dipeptidylpeptidase iv
WO1999061431A1 (fr) 1998-05-28 1999-12-02 Probiodrug Gesellschaft für Arzneimittelforschung mbH Nouveaux effecteurs de dipeptidylpeptidase iv
DE19823831A1 (de) 1998-05-28 1999-12-02 Probiodrug Ges Fuer Arzneim Neue pharmazeutische Verwendung von Isoleucyl Thiazolidid und seinen Salzen
JP2002517401A (ja) 1998-06-05 2002-06-18 ポイント セラピューティクス， インコーポレイテッド 環状ボロプロリン化合物
WO1999062914A1 (fr) 1998-06-05 1999-12-09 Point Therapeutics, Inc. Composes cycliques de boroproline
JP2003524591A (ja) 1998-06-24 2003-08-19 プロバイオドラッグ ゲゼルシャフト フュア アルツナイミッテルフォルシュンク エムベーハー Ｄｐｉｖ阻害剤のプロドラッグ
WO1999067278A1 (fr) 1998-06-24 1999-12-29 Probiodrug Gesellschaft für Arzneimittelforschung mbH Promedicaments d'inhibiteurs de la dipeptidylpeptidase iv
DE19828113A1 (de) 1998-06-24 2000-01-05 Probiodrug Ges Fuer Arzneim Prodrugs von Inhibitoren der Dipeptidyl Peptidase IV
US20020049164A1 (en) 1998-06-24 2002-04-25 Hans-Ulrich Demuth Prodrugs of DP IV-inhibitors
DE19834591A1 (de) 1998-07-31 2000-02-03 Probiodrug Ges Fuer Arzneim Verfahren zur Steigerung des Blutglukosespiegels in Säugern
EP0995440A1 (fr) 1998-07-31 2000-04-26 Probiodrug Gesellschaft für Arzneimittelforschung mbH Procédé pour augmenter le taux de glucose dans le sang des mammifères
CA2339537A1 (fr) 1998-08-21 2000-03-02 Barbara Wallner Regulation de l'activite de substrat
WO2000010549A1 (fr) 1998-08-21 2000-03-02 Point Therapeutics, Inc. Regulation de l'activite de substrat
EP1104293A1 (fr) 1998-08-21 2001-06-06 Point Therapeutics, Inc. Regulation de l'activite de substrat
US20020006899A1 (en) 1998-10-06 2002-01-17 Pospisilik Andrew J. Use of dipeptidyl peptidase IV effectors for lowering blood pressure in mammals
US6410508B1 (en) 1998-10-07 2002-06-25 Med College Georgia Res Inst Glucose-dependent insulinotropic peptide for use as an osteotropic hormone
US6242422B1 (en) 1998-10-22 2001-06-05 Idun Pharmacueticals, Inc. (Substituted)Acyl dipeptidyl inhibitors of the ice/ced-3 family of cysteine proteases
EP1123272A1 (fr) 1998-10-22 2001-08-16 Idun Pharmaceuticals, Inc. Inhibiteurs acyle(substitue) dipeptidyle de la famille ice/ced-3 des cysteines proteases
WO2000023421A1 (fr) 1998-10-22 2000-04-27 Idun Pharmaceuticals, Inc. INHIBITEURS ACYLE(SUBSTITUE) DIPEPTIDYLE DE LA FAMILLE ICE/ced-3 DES CYSTEINES PROTEASES
JP2002527504A (ja) 1998-10-22 2002-08-27 アイドゥン ファーマシューティカルズ， インコーポレイテッド システインプロテアーゼのＩＣＥ／ｃｅｄ−３系の置換アシルジペプチジル抑制剤
WO2000031258A2 (fr) 1998-11-20 2000-06-02 Arena Pharmaceuticals, Inc. Recepteurs humains couples a la proteine g orphan
JP2002531547A (ja) 1998-12-10 2002-09-24 ノバルティス アクチエンゲゼルシャフト Ｎ置換されている２−シアノピロリジン
WO2000034241A1 (fr) 1998-12-10 2000-06-15 Novartis Ag 2-cyanopyrrolidines n-substitues
EP1137635A1 (fr) 1998-12-10 2001-10-04 Novartis AG 2-cyanopyrrolidines n-substitues
US6166063A (en) 1998-12-10 2000-12-26 Novartis Ag N-(substituted glycyl)-2-cyanopyrrolidines, pharmaceutical compositions containing them and their use in inhibiting dipeptidyl peptidase-IV
JP2000191616A (ja) 1998-12-24 2000-07-11 Senju Pharmaceut Co Ltd 新規ジペプチジルアルデヒド誘導体およびそれを含有する医薬
WO2000056297A2 (fr) 1999-03-23 2000-09-28 Ferring B.V. Compositions favorisant la croissance
WO2000056296A2 (fr) 1999-03-23 2000-09-28 Ferring Bv Compositions favorisant la fecondite
JP2000327689A (ja) 1999-05-17 2000-11-28 Microbial Chem Res Found スルフォスチン類縁体、並びにスルフォスチン及びその類縁体の製造方法
WO2000069868A1 (fr) 1999-05-17 2000-11-23 Zaidan Hojin Biseibutsu Kagaku Kenkyu Kai Analogues de la sulphostine et procede de preparation de la sulphostine et de ses analogues
WO2000071135A1 (fr) 1999-05-25 2000-11-30 Point Therapeutics, Inc. Agents anti-tumorales contenant des composes de boroproline
US6617340B1 (en) 1999-07-29 2003-09-09 Novartis Ag N-(substituted glycyl)-pyrrolidines, pharmaceutical compositions containing them and their use in inhibiting dipeptidyl peptidase-IV
WO2001034594A1 (fr) 1999-11-12 2001-05-17 Guilford Pharmaceuticals, Inc. Inhibiteurs de la dipeptidyl peptidase iv; methodes de fabrication et d'utilisation desdits inhibiteurs
EP1228061A1 (fr) 1999-11-12 2002-08-07 Guilford Pharmaceuticals Inc. Inhibiteurs de la dipeptidyl peptidase iv; methodes de fabrication et d'utilisation desdits inhibiteurs
JP2003535034A (ja) 1999-11-12 2003-11-25 ギルフォード ファーマシューティカルズ インコーポレイテッド ジペプチジルペプチダーゼｉｖ阻害剤並びにジペプチジルペプチダーゼｉｖ阻害剤の製造及び使用法
US6380398B2 (en) 2000-01-04 2002-04-30 Novo Nordisk A/S Therapeutically active and selective heterocyclic compounds that are inhibitors of the enzyme DPP-IV
EP1248604A2 (fr) 2000-01-21 2002-10-16 Novartis AG Combinaisons comprenant un inhibiteur de la dipeptidylpeptidase - iv
WO2001052825A2 (fr) 2000-01-21 2001-07-26 Novartis Ag Combinaisons comprenant un inhibiteur de la dipeptidylpeptidase - iv
JP2003520849A (ja) 2000-01-24 2003-07-08 ノボ ノルディスク アクティーゼルスカブ 酵素ｄｐｐ−ｉｖの阻害剤であるｎ−置換２−シアノピロールおよび−ピロリン
EP1254113A1 (fr) 2000-01-24 2002-11-06 Novo Nordisk A/S 2-cyanopyroles et -pyrrolines a substitution n inhibant l'enzyme dpp-iv
US6645995B2 (en) 2000-01-24 2003-11-11 Novo Nordisk A/S Therapeutically active and selective heterocyclic compounds that are inhibitors of the enzyme DPP-IV
US20020103384A1 (en) 2000-01-24 2002-08-01 Anders Kanstrup Therapeutically active and selective heterocyclic compounds that are inhibitors of the enzyme DPP-IV
WO2001055105A1 (fr) 2000-01-24 2001-08-02 Novo Nordisk A/S 2-cyanopyroles et -pyrrolines a substitution n inhibant l'enzyme dpp-iv
US6395767B2 (en) 2000-03-10 2002-05-28 Bristol-Myers Squibb Company Cyclopropyl-fused pyrrolidine-based inhibitors of dipeptidyl peptidase IV and method
EP1261586A2 (fr) 2000-03-10 2002-12-04 Bristol-Myers Squibb Company Inhibiteurs de la dipeptidyl peptidase iv, a base de pyrrolidone fusionnee a du cyclopropyle, et procede
WO2001068603A2 (fr) 2000-03-10 2001-09-20 Bristol-Myers Squibb Co. Inhibiteurs de la dipeptidyl peptidase iv, a base de pyrrolidone fusionnee a du cyclopropyle, et procede
JP2003531118A (ja) 2000-03-10 2003-10-21 ブリストル−マイヤーズ スクイブ カンパニー シクロプロピル縮合ピロリジン骨格を有するジペプチジルペプチダーゼｉｖの阻害剤及び方法
WO2001081304A1 (fr) 2000-04-26 2001-11-01 Ferring Bv Inhibiteurs de dipeptidyl peptidase iv
EP1282600A1 (fr) 2000-04-26 2003-02-12 Ferring BV Inhibiteurs de dipeptidyl peptidase iv
JP2003531204A (ja) 2000-04-26 2003-10-21 フェリング ベスローテン フェンノートシャップ ジペプチジルペプチダーゼｉｖの阻害剤
JP2003531191A (ja) 2000-04-26 2003-10-21 フェリング ベスローテン フェンノートシャップ ジペプチジル・ペプチダーゼｉｖの阻害剤
WO2001081337A1 (fr) 2000-04-26 2001-11-01 Ferring B.V. Inhibiteurs de dipeptidyl peptidase iv
US20030216450A1 (en) 2000-04-26 2003-11-20 Evans David Michael Inhibitors of dipeptidyl peptidase IV
EP1280797A1 (fr) 2000-04-26 2003-02-05 Ferring B.V. Inhibiteurs de dipeptidyl peptidase iv
WO2001096295A2 (fr) 2000-06-13 2001-12-20 Novartis Ag Composes organiques
US6432969B1 (en) 2000-06-13 2002-08-13 Novartis Ag N-(substituted glycyl)-2 cyanopyrrolidines, pharmaceutical compositions containing them and their use in inhibiting dipeptidyl peptidase-IV
JP2004503531A (ja) 2000-06-13 2004-02-05 ノバルティス　アクチエンゲゼルシャフト ２−シアノピロリジン誘導体および薬剤としてのそれらの使用
EP1296974A2 (fr) 2000-06-13 2003-04-02 Novartis AG Composes organiques
JP2003535898A (ja) 2000-06-19 2003-12-02 スミスクライン ビーチャム パブリック リミテッド カンパニー 真性糖尿病の治療用のジペプチジルペプチダーゼｉｖ阻害剤および他の抗糖尿病剤の組み合わせ
WO2001097808A1 (fr) 2000-06-19 2001-12-27 Smithkline Beecham Plc Combinaisons d'inhibiteurs de peptidase iv de dipeptidyl et d'autres agents antidiabetiques pour traiter le diabete sucre
EP1301187A2 (fr) 2000-07-04 2003-04-16 Novo Nordisk A/S Composes heterocycliques inhibiteurs de l'enzyme dpp-iv
US20040034014A1 (en) 2000-07-04 2004-02-19 Kanstrup Anders Bendtz Heterocyclic compounds, which are inhibitors of the enzyme DPP-IV
WO2002002560A2 (fr) 2000-07-04 2002-01-10 Novo Nordisk A/S Composes heterocycliques inhibiteurs de l'enzyme dpp-iv
WO2002014271A1 (fr) 2000-08-10 2002-02-21 Mitsubishi Pharma Corporation Dérivés de proline et leur utilisation comme médicaments
US20040229926A1 (en) 2000-10-06 2004-11-18 Tanabe Seiyaku Co., Ltd. Aliphatic nitrogen - containing 5 - membered ring compound
JP2002356472A (ja) 2000-10-06 2002-12-13 Tanabe Seiyaku Co Ltd 含窒素五員環化合物
WO2002030891A1 (fr) 2000-10-06 2002-04-18 Tanabe Seiyaku Co., Ltd. Composes aliphatiques azotes a noyau a cinq elements
WO2002030890A1 (fr) 2000-10-06 2002-04-18 Tanabe Seiyaku Co., Ltd. Composes azotes a noyau a cinq elements
JP2002356471A (ja) 2000-10-06 2002-12-13 Tanabe Seiyaku Co Ltd 脂肪族含窒素五員環化合物
US20040063935A1 (en) 2000-10-06 2004-04-01 Kosuke Yasuda Aliphatic nitrogenous five-membered ring compounds
US6849622B2 (en) 2000-10-06 2005-02-01 Tanabe Seiyaku Co., Ltd. Aliphatic nitrogenous five-membered ring compounds
JP2004035574A (ja) 2000-10-06 2004-02-05 Tanabe Seiyaku Co Ltd 脂肪族含窒素五員環化合物
WO2002034900A1 (fr) 2000-10-27 2002-05-02 The University Of Sydney Dipeptidyl peptidases
WO2002038541A1 (fr) 2000-11-10 2002-05-16 Taisho Pharmaceutical Co., Ltd. Derives de cyanopyrrolidine
EP1333025A1 (fr) 2000-11-10 2003-08-06 Taisho Pharmaceutical Co., Ltd Derives de cyanopyrrolidine
US20070112059A1 (en) 2000-11-10 2007-05-17 Taisho Pharmaceutical Co., Ltd. Cyanopyrrolidine derivatives
US20040072892A1 (en) 2000-11-10 2004-04-15 Hiroshi Fukushima Cyanopyrrolidine derivatives
EP1338651A1 (fr) 2000-12-01 2003-08-27 Yamanouchi Pharmaceutical Co. Ltd. Procede de depistage d'un remede
US20040180925A1 (en) 2000-12-27 2004-09-16 Kenji Matsuno Dipeptidylpeptidase-IV inhibitor
WO2002051836A1 (fr) 2000-12-27 2002-07-04 Kyowa Hakko Kogyo Co., Ltd. Inhibiteur de dipeptidyl peptidase iv
CA2433090A1 (fr) 2000-12-27 2002-07-04 Kyowa Hakko Kogyo Co., Ltd. Inhibiteur de dipeptidyl peptidase iv
EP1354882A1 (fr) 2000-12-27 2003-10-22 Kyowa Hakko Kogyo Co., Ltd. Inhibiteur de dipeptidyl peptidase iv
WO2002055088A1 (fr) 2001-01-16 2002-07-18 Nippon Kayaku Kabushiki Kaisha Remedes destines au traitement de la suppression de la moelle osseuse et de maladies infectieuses et agents permettant d'augmenter la concentration leucocytaire du sang
EP1355886A1 (fr) 2001-02-02 2003-10-29 Takeda Chemical Industries, Ltd. Composes heterocycliques condenses
JP2003238566A (ja) 2001-02-02 2003-08-27 Takeda Chem Ind Ltd 縮合複素環化合物
WO2002062764A1 (fr) 2001-02-02 2002-08-15 Takeda Chemical Industries, Ltd. Composes heterocycliques condenses
US20020198205A1 (en) 2001-02-24 2002-12-26 Frank Himmelsbach Xanthine derivatives, the preparation thereof and their use as pharmaceutical compositions
JP2004522786A (ja) 2001-02-24 2004-07-29 ベーリンガー インゲルハイム ファルマ ゲゼルシャフト ミット ベシュレンクテル ハフツング ウント コンパニー コマンディトゲゼルシャフト キサンチン誘導体、それらの調製及び医薬組成物としてのそれらの使用
WO2002068420A1 (fr) 2001-02-24 2002-09-06 Boehringer Ingelheim Pharma Gmbh & Co. Kg Derives xanthine, fabrication et utilisations en tant qu'agents pharmaceutiques
US20040077645A1 (en) 2001-02-24 2004-04-22 Frank Himmelsbach Xanthine derivatives,production and use thereof as medicament
US20040087587A1 (en) 2001-02-24 2004-05-06 Boehringer Ingelheim Pharma Gmbh & Co. Kg Xanthine derivatives, the preparation thereof and their use as pharmaceutical compositions
JP2002265439A (ja) 2001-03-08 2002-09-18 Mitsubishi Pharma Corp シアノピロリジン誘導体およびその医薬用途
JP2004525929A (ja) 2001-03-27 2004-08-26 メルク　エンド　カムパニー　インコーポレーテッド 糖尿病の治療または予防用のジペプチジルペプチダーゼ阻害薬
EP1385508A1 (fr) 2001-03-27 2004-02-04 Merck & Co., Inc. Inhibiteurs de peptidase dipeptidyl destines au traitement ou a la prevention du diabete
US20040106656A1 (en) 2001-03-27 2004-06-03 Ashton Wallace T Dipeptidyl peptidase inhibitors for the treatment or prevention of diabetes
WO2002076450A1 (fr) 2001-03-27 2002-10-03 Merck & Co., Inc. Inhibiteurs de peptidase dipeptidyl destines au traitement ou a la prevention du diabete
US20030087950A1 (en) 2001-03-28 2003-05-08 Denanteuil Guillaume New alpha-amino acid sulphonyl compounds
FR2822826A1 (fr) 2001-03-28 2002-10-04 Servier Lab Nouveaux derives sulfonyles d'alpha-amino-acides, leur procede de preparation et les compositions pharmaceutiques qui les contiennent
EP1245568A1 (fr) 2001-03-28 2002-10-02 Les Laboratoires Servier Dérives sulfonyles d'-aminoacides et leur utilisation en tant qu'inhibiteurs de dipeptidyl-peptidase IV ( DPP IV)
US6716843B2 (en) 2001-03-28 2004-04-06 Les Laboratoires Servier Alpha-amino acid sulphonyl compounds
WO2002083109A1 (fr) 2001-04-11 2002-10-24 Ferring Bv Traitement du diabete de type 2 a l'aide d'inhibiteurs de dipeptidylpeptidase iv
JP2004525179A (ja) 2001-04-11 2004-08-19 フェリング ベスローテン フェンノートシャップ ジペプチジルペプチダーゼｉｖ阻害剤でのｉｉ型糖尿病の処置
US6573287B2 (en) 2001-04-12 2003-06-03 Bristo-Myers Squibb Company 2,1-oxazoline and 1,2-pyrazoline-based inhibitors of dipeptidyl peptidase IV and method
WO2002083128A1 (fr) 2001-04-12 2002-10-24 Bristol-Myers Squibb Company Inhibiteurs a base de 2,1-oxazoline et 1,2-pyrazoline de la dipeptidyl peptidase iv et methode associee
US20020183367A1 (en) 2001-04-12 2002-12-05 Sulsky Richard B. 2,1-Oxazoline and 1,2-pyrazoline-based inhibitors of dipeptidyl peptidase IV and method
EP1377288A1 (fr) 2001-04-12 2004-01-07 Bristol-Myers Squibb Company Inhibiteurs a base de 2,1-oxazoline et 1,2-pyrazoline de la dipeptidyl peptidase iv et methode associee
JP2004532220A (ja) 2001-04-12 2004-10-21 ブリストル−マイヤーズ　スクイブ　カンパニー ジペプチジル・ペプチダーゼｉｖの２，１−オキサゾリンおよび１，２−ピラゾリンに基づくインヒビターおよび方法
EP1258476A1 (fr) 2001-05-15 2002-11-20 Les Laboratoires Servier Dérivés d'alpha-amino-acides, leur procédé de préparation ainsi que leur utilisation en tant qu'inhibiteurs de dipeptidyl-peptidase IV (DPP IV)
US20030078247A1 (en) 2001-05-15 2003-04-24 De Nanteuil Guillaume Alpha-amino-acid compounds
FR2824825A1 (fr) 2001-05-15 2002-11-22 Servier Lab Nouveaux derives d'alpha-amino-acides, leur procede de preparation et les compositions pharmaceutiques qui les contiennent
US6706742B2 (en) 2001-05-15 2004-03-16 Les Laboratories Servier Alpha-amino-acid compounds
JP2002363157A (ja) 2001-05-15 2002-12-18 Lab Servier 新規α−アミノ酸化合物、その調製方法及びそれを含有する医薬組成物
EP1406622A2 (fr) 2001-06-20 2004-04-14 Merck & Co., Inc. Inhibiteurs de dipeptidyl peptidase utilises dans le traitement du diabete
WO2003000181A2 (fr) 2001-06-20 2003-01-03 Merck & Co., Inc. Inhibiteurs de dipeptidyl peptidase utilises dans le traitement du diabete
EP1406872A2 (fr) 2001-06-20 2004-04-14 Merck & Co., Inc. Inhibiteurs de dipeptidyle peptidase pour le traitement du diabete
WO2003000180A2 (fr) 2001-06-20 2003-01-03 Merck & Co., Inc. Inhibiteurs de dipeptidyle peptidase pour le traitement du diabete
JP2005500308A (ja) 2001-06-20 2005-01-06 メルク　エンド　カムパニー　インコーポレーテッド 糖尿病を治療するためのジペプチジルペプチダーゼ阻害剤
JP2004535433A (ja) 2001-06-20 2004-11-25 メルク　エンド　カムパニー　インコーポレーテッド 糖尿病治療用のジペプチジルペプチダーゼ阻害薬
JP2004534815A (ja) 2001-06-25 2004-11-18 フェリング ベスローテン フェンノートシャップ 抗糖尿病薬としての３−フルオロ−ピロリジン
EP1399154A1 (fr) 2001-06-25 2004-03-24 Ferring BV Agents antidiabetiques a base de 3-fluoro-pyrrolidines
WO2003000250A1 (fr) 2001-06-25 2003-01-03 Ferring Bv Agents antidiabetiques a base de 3-fluoro-pyrrolidines
JP2005500321A (ja) 2001-06-27 2005-01-06 スミスクライン ビーチャム コーポレーション ジペプチジルペプチダーゼ阻害剤としてのフルオロピロリジン類
WO2003002553A2 (fr) 2001-06-27 2003-01-09 Smithkline Beecham Corporation Fluoropyrrolidines inhibitrices de la dipeptidyl peptidase
JP2004521149A (ja) 2001-06-27 2004-07-15 プロバイオドラッグ アーゲー 新規なジペプチジルぺプチダ−ゼｉｖ阻害剤およびそれらの抗癌剤としての使用
US20030119750A1 (en) 2001-06-27 2003-06-26 Hans-Ulrich Demuth Use of dipeptidyl peptidase IV inhibitors
JP2004534836A (ja) 2001-06-27 2004-11-18 プロバイオドラッグ アーゲー ジペプチジルぺプチダ−ゼｉｖ阻害剤の新規な使用
JP2004535445A (ja) 2001-06-27 2004-11-25 スミスクライン ビーチャム コーポレーション ジペプチジルペプチダーゼ阻害剤としてのフルオロピロリジン類
US20030130199A1 (en) 2001-06-27 2003-07-10 Von Hoersten Stephan Dipeptidyl peptidase IV inhibitors and their uses as anti-cancer agents
WO2003002530A2 (fr) 2001-06-27 2003-01-09 Smithkline Beecham Corporation Pyrrolidines servant d'inhibiteurs de dipeptidyl peptidase
EP1399469A2 (fr) 2001-06-27 2004-03-24 Probiodrug AG Structures peptidiques utiles pour la modulation competitive de la catalyse de dipeptidyle peptidase iv
WO2003002596A2 (fr) 2001-06-27 2003-01-09 Probiodrug Ag Nouvelle utilisation d'inhibiteurs de la dipeptidyl peptidase iv
EP1399470A2 (fr) 2001-06-27 2004-03-24 Probiodrug AG Nouveaux inhibiteurs de dipeptidylpeptidase iv et leurs utilisations en tant qu'agents anti-cancereux
EP1399433A2 (fr) 2001-06-27 2004-03-24 Smithkline Beecham Corporation Fluoropyrrolidines inhibitrices de la dipeptidyl peptidase
WO2003002531A2 (fr) 2001-06-27 2003-01-09 Smithkline Beecham Corporation Fluoropyrrolidines inhibitrices de la dipeptidyl peptidase
EP1406873A2 (fr) 2001-06-27 2004-04-14 Smithkline Beecham Corporation Fluoropyrrolidines inhibitrices de la dipeptidyl peptidase
WO2003072556A1 (fr) 2001-06-27 2003-09-04 Prosidion Ltd. Inhibiteurs de dpiv a base de groupes glutaminyl
EP1399471A2 (fr) 2001-06-27 2004-03-24 Probiodrug AG Utilisation d'inhibiteurs de la dipeptidyl peptidase iv comme agents pour la therapie des maladies neurologiques
EP1399420A2 (fr) 2001-06-27 2004-03-24 SmithKline Beecham Corporation Pyrrolidines servant d'inhibiteurs de dipeptidyl peptidase
WO2003002593A2 (fr) 2001-06-27 2003-01-09 Probiodrug Ag Structures peptidiques utiles pour la modulation competitive de la catalyse de dipeptidyle peptidase iv
JP2004530729A (ja) 2001-06-27 2004-10-07 プロバイオドラッグ アーゲー ジペプチジルペプチダーゼｉｖ触媒作用の拮抗調節に有用なペプチド構造
WO2003002595A2 (fr) 2001-06-27 2003-01-09 Probiodrug Ag Nouveaux inhibiteurs de dipeptidylpeptidase iv et leurs utilisations en tant qu'agents anti-cancereux
EP1404675A1 (fr) 2001-07-03 2004-04-07 Novo Nordisk A/S Derives de purine inhibiteurs de dpp-iv pour le traitement du diabete
JP2005502624A (ja) 2001-07-03 2005-01-27 ノボ　ノルディスク　アクティーゼルスカブ 糖尿病を治療するための、ｄｐｐ−ｉｖを阻害するプリン誘導体
WO2003004496A1 (fr) 2001-07-03 2003-01-16 Novo Nordisk A/S Derives de purine inhibiteurs de dpp-iv pour le traitement du diabete
US20030105077A1 (en) 2001-07-03 2003-06-05 Kanstrup Anders Bendtz Heterocyclic compounds that are inhibitors of the enzyme DPP-IV
US6869947B2 (en) 2001-07-03 2005-03-22 Novo Nordisk A/S Heterocyclic compounds that are inhibitors of the enzyme DPP-IV
US20030100563A1 (en) 2001-07-06 2003-05-29 Edmondson Scott D. Beta-amino heterocyclic dipeptidyl peptidase inhibitors for the treatment or prevention of diabetes
WO2003004498A1 (fr) 2001-07-06 2003-01-16 Merck & Co., Inc. Pyrazines beta-amino tetrahydroimidazo (1, 2-a) et pyrazines tetrahydrotrioazolo (4, 3-a) utilisees en tant qu'inhibiteurs de la dipeptidyl peptidase dans le traitement ou la prevention du diabete
EP1412357A1 (fr) 2001-07-06 2004-04-28 Merck & Co., Inc. Pyrazines beta-amino tetrahydroimidazo (1, 2-a) et pyrazines tetrahydrotrioazolo (4, 3-a) utilisees en tant qu'inhibiteurs de la dipeptidyl peptidase dans le traitement ou la prevention du diabete
US6699871B2 (en) 2001-07-06 2004-03-02 Merck & Co., Inc. Beta-amino heterocyclic dipeptidyl peptidase inhibitors for the treatment or prevention of diabetes
JP2004536115A (ja) 2001-07-06 2004-12-02 メルク　エンド　カムパニー　インコーポレーテッド 糖尿病を治療又は予防するためのジペプチジルペプチダーゼ阻害薬としてのβ−アミノテトラヒドロイミダゾ（１，２−Ａ）ピラジン類及びテトラヒドロトリアゾロ（４，３−Ａ）ピラジン類
WO2003015775A1 (fr) 2001-08-17 2003-02-27 Probiodrug Ag Inhibiteurs de dipeptidyl peptidase iv et leurs utilisations pour diminuer la pression sanguine
JP2005505531A (ja) 2001-08-17 2005-02-24 プロビオドルグ アーゲー 新規ジペプチジルペプチダーゼｉｖ阻害剤および血圧レベルを低下させるためのそれらの使用
DE10143840A1 (de) 2001-09-06 2003-03-27 Probiodrug Ag Neue Inhibitoren der Dipeptidylpeptidase I
WO2003022871A2 (fr) 2001-09-06 2003-03-20 Probiodrug Ag Nouveaux inhibiteurs de dipeptidylpeptidase i
US20030119738A1 (en) 2001-09-06 2003-06-26 Andre Niestroj Novel inhibitors of dipeptidyl peptidase I
US20040259883A1 (en) 2001-09-14 2004-12-23 Hiroshi Sakashita Thiazolidine derivative and medicinal use thereof
EP1426366A1 (fr) 2001-09-14 2004-06-09 Mitsubishi Pharma Corporation Derive thiazolidine et son utilisation medicamenteuse
WO2003024942A1 (fr) 2001-09-14 2003-03-27 Mitsubishi Pharma Corporation Derive thiazolidine et son utilisation medicamenteuse
US20030199528A1 (en) 2001-09-19 2003-10-23 Kanstrup Anders B. Hetrocyclic compounds that are inhibitors of the enzyme DPP-IV
WO2003024965A2 (fr) 2001-09-19 2003-03-27 Novo Nordisk A/S Composes heterocycliques constituant des inhibiteurs de l'enzyme dpp-iv
EP1463727A2 (fr) 2001-09-19 2004-10-06 Novo Nordisk A/S Composes heterocycliques constituant des inhibiteurs de l'enzyme dpp-iv
WO2003035067A1 (fr) 2001-10-23 2003-05-01 Ferring B.V. Inhibiteurs de dipeptidyl peptidase iv (dp-iv) tenant lieu d'agents anti-diabetiques
EP1450794A1 (fr) 2001-10-23 2004-09-01 Ferring B.V. Inhibiteurs de dipeptidyl peptidase iv (dp-iv) tenant lieu d'agents anti-diabetiques
WO2003035057A1 (fr) 2001-10-23 2003-05-01 Ferring B.V. Inhibiteurs de la dipeptidyl peptidase iv
EP1446116A1 (fr) 2001-10-23 2004-08-18 Ferring B.V. Inhibiteurs de la dipeptidyl peptidase iv
US20050004205A1 (en) 2001-10-23 2005-01-06 Evans David M Novel dipeptidyl peptidase iv (dp-iv) inhibitors as anti-diabetic agents
WO2003037327A1 (fr) 2001-10-26 2003-05-08 F. Hoffmann-La-Roche Ag Derives de pyrrolidine n-substitues en tant qu'inhibiteurs de la dipeptidyl peptidase iv
US20030130281A1 (en) 2001-10-26 2003-07-10 Markus Boehringer DPP IV inhibitors
EP1441719A1 (fr) 2001-10-26 2004-08-04 F. Hoffmann-La Roche Ag Derives de pyrrolidine n-substitues en tant qu'inhibiteurs de la dipeptidyl peptidase iv
US6861440B2 (en) 2001-10-26 2005-03-01 Hoffmann-La Roche Inc. DPP IV inhibitors
WO2003038123A2 (fr) 2001-10-31 2003-05-08 Novartis Ag Procede de traitement du diabete et conditions apparentees basees sur des polymorphismes dans le gene tcf1
JP2005507261A (ja) 2001-10-31 2005-03-17 ノバルティス アクチエンゲゼルシャフト Ｔｃｆ１遺伝子における多型に基づく糖尿病および関連状態の治療方法
EP1442049A2 (fr) 2001-11-09 2004-08-04 Probiodrug AG Composes d'aminocetone substitues
US20030125304A1 (en) 2001-11-09 2003-07-03 Hans-Ulrich Demuth Substituted amino ketone compounds
WO2003040174A2 (fr) 2001-11-09 2003-05-15 Probiodrug Ag Composes d'aminocetone substitues
EP1469873A2 (fr) 2001-11-26 2004-10-27 Trustees of Tufts College Inhibiteurs peptidomimetiques d'enzymes de clivage post-proline
WO2003045228A2 (fr) 2001-11-26 2003-06-05 Trustees Of Tufts College Techniques de traitement de maladies auto-immunes et reactifs associes
CA2466870A1 (fr) 2001-11-26 2003-06-05 Trustees Of Tufts College Techniques de traitement de maladies auto-immunes et reactifs associes
WO2003057144A2 (fr) 2001-12-26 2003-07-17 Guilford Pharmaceuticals Changement d'inhibiteurs de la dipeptidyl peptidase iv
EP1465891A2 (fr) 2001-12-26 2004-10-13 Guilford Pharmaceuticals Inc. Inhibiteurs de la dipeptidyl peptidase iv
WO2003057666A2 (fr) 2001-12-26 2003-07-17 Guilford Pharmaceuticals Inhibiteurs de la dipeptidyl peptidase iv
US20040176406A1 (en) 2001-12-27 2004-09-09 Gobbi Luca Claudio Pyrido [2,1-a] isoquinoline derivatives
WO2003055881A1 (fr) 2001-12-27 2003-07-10 F. Hoffmann-La Roche Ag Derives de pyrido(2,1-a)isoquinoline comme inhibiteurs dpp-iv
EP1461337A1 (fr) 2001-12-27 2004-09-29 F. Hoffmann-La Roche Ag Derives de pyrido(2,1-a)isoquinoline comme inhibiteurs dpp-iv
US6727261B2 (en) 2001-12-27 2004-04-27 Hoffman-La Roche Inc. Pyrido[2,1-A]Isoquinoline derivatives
US20030149071A1 (en) 2001-12-27 2003-08-07 Gobbi Luca Claudio Pyrido [2,1-a] isoquinoline derivatives
WO2003072528A2 (fr) 2002-02-08 2003-09-04 Idun Pharmaceuticals, Inc. Inhibiteurs de dipeptidyle d'acide substitue de la famille ice/ced-3 des proteases de cysteine
US20030232788A1 (en) 2002-02-08 2003-12-18 Idun Pharmaceuticals, Inc. (Substituted)acyl dipeptidyl inhibitors of the ICE/ced-3 family of cysteine proteases
EP1476429A1 (fr) 2002-02-13 2004-11-17 F. Hoffmann-La Roche Ag Nouveaux derives de pyridine et de quinoline
US20030216382A1 (en) 2002-02-13 2003-11-20 Markus Boehringer Pyridine and pyrimidine derivatives
US6800650B2 (en) 2002-02-13 2004-10-05 Hoffmann-La Roche Inc. Pyridine and quinoline derivatives
EP1476435A1 (fr) 2002-02-13 2004-11-17 F. Hoffmann-La Roche Ag Nouveaux derives de pyridine et de pyrimidine
WO2003068757A1 (fr) 2002-02-13 2003-08-21 F. Hoffmann-La Roche Ag Nouveaux derives de pyridine et de pyrimidine
US6867205B2 (en) 2002-02-13 2005-03-15 Hoffman-La Roche Inc. Pyridine and pyrimidine derivatives
US20030195188A1 (en) 2002-02-13 2003-10-16 Markus Boehringer Pyridine and quinoline derivatives
WO2003068748A1 (fr) 2002-02-13 2003-08-21 F. Hoffmann-La Roche Ag Nouveaux derives de pyridine et de quinoline
EP1338592A1 (fr) 2002-02-22 2003-08-27 Nippon Zoki Pharmaceutical Co., Ltd. Dérivés de 2-phénylpipérazine
US20040082570A1 (en) 2002-02-25 2004-04-29 Eisai Co., Ltd. Xanthine derivative and DPPIV inhibitor
JP2004043429A (ja) 2002-02-25 2004-02-12 Eisai Co Ltd 新規キサンチン誘導体およびｄｐｐｉｖ阻害剤
US20030162820A1 (en) 2002-02-28 2003-08-28 Hans-Ulrich Demuth Glutaminyl based DPIV inhibitors
EP1480961A1 (fr) 2002-02-28 2004-12-01 Prosidion Limited Inhibiteurs de dpiv a base de groupes glutaminyl
WO2003074500A2 (fr) 2002-03-06 2003-09-12 Sanofi-Aventis Nouveaux composes
WO2003080633A1 (fr) 2002-03-25 2003-10-02 Nippon Kayaku Kabushiki Kaisha Nouveau derive d'$g(a)-amino-n-(diaminophosphinyl)lactame
WO2003082817A2 (fr) 2002-03-25 2003-10-09 Merck & Co., Inc. Inhibiteurs de la dipeptidyl peptidase beta-amino heterocycliques pour le traitement ou la prevention du diabete
EP1490335A2 (fr) 2002-03-25 2004-12-29 Merck & Co., Inc. Inhibiteurs de la dipeptidyl peptidase beta-amino heterocycliques pour le traitement ou la prevention du diabete
EP1489088A1 (fr) 2002-03-25 2004-12-22 Nippon Kayaku Kabushiki Kaisha Nouveau derive d'alpha-amino-n-(diaminophosphinyl)lactame
JP2004002367A (ja) 2002-04-04 2004-01-08 Tanabe Seiyaku Co Ltd 医薬組成物
JP2004002368A (ja) 2002-04-04 2004-01-08 Tanabe Seiyaku Co Ltd 医薬組成物
EP1492777A1 (fr) 2002-04-08 2005-01-05 Torrent Pharmaceuticals Ltd Thiazolidine-4-carbonitriles et analogues et leur utilisation comme inhibiteurs de dipeptidyl-peptidas
WO2003084940A1 (fr) 2002-04-08 2003-10-16 Alangudi Sankaranarayanan Thiazolidine-4-carbonitriles et analogues et leur utilisation comme inhibiteurs de dipeptidyl-peptidas
US20030225102A1 (en) 2002-04-08 2003-12-04 Torrent Pharmaceuticals Ltd. Novel compounds and therapeutic uses thereof
JP2003300977A (ja) 2002-04-10 2003-10-21 Sumitomo Pharmaceut Co Ltd キサンチン誘導体
JP2004026820A (ja) 2002-05-09 2004-01-29 Taisho Pharmaceut Co Ltd ジペプチジルペプチダーゼｉｖ阻害剤
WO2003095425A1 (fr) 2002-05-09 2003-11-20 Taisho Pharmaceutical Co.,Ltd. Derives de cyanopyrrolidine
JP2003327532A (ja) 2002-05-10 2003-11-19 Takeda Chem Ind Ltd ペプチダーゼ阻害剤
WO2003099279A1 (fr) 2002-05-29 2003-12-04 Novartis Ag Association d'un inhibiteur de dipeptidyl peptidase iv (dpp iv) et d'un compose cardio-vasculaire
WO2003101448A1 (fr) 2002-06-03 2003-12-11 Novartis Ag Utilisation de cyanopyrrolidines substituees et de preparations de combinaison contenant celles-ci dans le traitement d'hyperlipidemie et de maladies associees
WO2003101958A2 (fr) 2002-06-04 2003-12-11 Pfizer Products Inc. Amides cycliques fluores utilises comme inhibiteurs de la dipeptidyl peptidase iv
US6710040B1 (en) 2002-06-04 2004-03-23 Pfizer Inc. Fluorinated cyclic amides as dipeptidyl peptidase IV inhibitors
US20040242898A1 (en) 2002-06-04 2004-12-02 Pfizer Inc Synthesis of 3,3,4,4-tetrafluoropyrrolidine and novel dipeptidyl peptidase-IV inhibitor compounds
EP1513808A2 (fr) 2002-06-04 2005-03-16 Pfizer Products Inc. Amides cycliques fluores utilises comme inhibiteurs de la dipeptidyl peptidase iv
US6812350B2 (en) 2002-06-04 2004-11-02 Pfizer Inc. Synthesis of 3,3,4,4-tetrafluoropyrrolidine and novel dipeptidyl peptidase-IV inhibitor compounds
WO2003104229A1 (fr) 2002-06-06 2003-12-18 エーザイ株式会社 Nouveau derive d'imidazole fondu
US20040116328A1 (en) 2002-06-06 2004-06-17 Eisai Co., Ltd. Condensed imidazole derivatives
EP1517907A2 (fr) 2002-06-14 2005-03-30 Sanofi-Aventis Derives d'azabicyclo-octane et nonane ayant une activite inhibitrice de ddp-iv
WO2003106456A2 (fr) 2002-06-14 2003-12-24 Sanofi-Synthelabo Nouveaux composes
WO2003105763A2 (fr) 2002-06-14 2003-12-24 Amylin Pharmaceuticals, Inc. Prevention et/ou traitement de maladie enterique inflammatoire au moyen de peptides yy ou d'antagonistes de peptides yy
WO2004000327A1 (fr) 2002-06-24 2003-12-31 Zaidan Hojin Biseibutsu Kagaku Kenkyu Kai Agent therapeutique pour des diabetes de type 2
JP2004026678A (ja) 2002-06-24 2004-01-29 Microbial Chem Res Found ２型糖尿病治療剤
WO2004004661A2 (fr) 2002-07-09 2004-01-15 Point Therapeutics, Inc. Polytherapie a base de composes de boroproline
WO2004007446A1 (fr) 2002-07-10 2004-01-22 Yamanouchi Pharmaceutical Co., Ltd. Nouveau derive de l'azetidine ou ses sels
WO2004007468A1 (fr) 2002-07-15 2004-01-22 Merck & Co., Inc. Inhibiteurs de piperidino pyrimidine dipeptidyl peptidase utilises dans le traitement du diabete
WO2004009544A1 (fr) 2002-07-23 2004-01-29 Yamanouchi Pharmaceutical Co., Ltd. Derive de 2-cyano-4-fluoropyrrolidine ou de son sel
JP2004315496A (ja) 2002-08-08 2004-11-11 Takeda Chem Ind Ltd 縮合複素環化合物
WO2004014860A2 (fr) 2002-08-08 2004-02-19 Takeda Pharmaceutical Company Limited Composes heterocycliques fusionnes
US20040097510A1 (en) 2002-08-21 2004-05-20 Boehringer Ingelheim Pharma Gmbh & Co. Kg 8-[3-amino-piperidin-1-yl]-xanthines, the preparation thereof and their use as pharmaceutical compositions
DE10238243A1 (de) 2002-08-21 2004-03-04 Boehringer Ingelheim Pharma Gmbh & Co. Kg 8-[3-Amino-piperidin-1-yl]-xanthine, deren Herstellung und deren Verwendung als Arzneimittel
WO2004018468A2 (fr) 2002-08-21 2004-03-04 Boehringer Ingelheim Pharma Gmbh & Co. Kg 8-[3-amino-piperidin-1-yl]-xanthines, leur production et leur utilisation comme medicament
WO2004018469A1 (fr) 2002-08-22 2004-03-04 Boehringer Ingelheim Pharma Gmbh & Co. Kg Nouveaux derives de purine, leur procede de production et leur utilisation en tant que medicament
WO2004018467A2 (fr) 2002-08-22 2004-03-04 Boehringer Ingelheim Pharma Gmbh & Co. Kg Derives de xanthine, leur production et leur utilisation comme medicaments
DE10238477A1 (de) 2002-08-22 2004-03-04 Boehringer Ingelheim Pharma Gmbh & Co. Kg Neue Purinderivate, deren Herstellung und deren Verwendung als Arzneimittel
DE10238470A1 (de) 2002-08-22 2004-03-04 Boehringer Ingelheim Pharma Gmbh & Co. Kg Neue Xanthinderivate, deren Herstellung und deren Verwendung als Arzneimittel
WO2004020407A1 (fr) 2002-08-29 2004-03-11 Taisho Pharmaceutical Co.,Ltd. Benzenesulfonate d'un derive de 4-fluoro-2-cyanopyrrolidine
WO2004026822A2 (fr) 2002-09-19 2004-04-01 Abbott Laboratories Compositions pharmaceutiques utiles comme inhibiteurs de la peptidase-iv dipeptidyl (dpp-iv)
WO2004032836A2 (fr) 2002-10-07 2004-04-22 Merck & Co., Inc. Inhibiteurs de la dipeptidyl peptidase heterocyclique beta-amino utiles pour le traitement ou la prevention du diabete
WO2004033455A2 (fr) 2002-10-08 2004-04-22 Novo Nordisk A/S Sels succiniques d'inhibiteurs heterocycliques de dpp-iv
WO2004037169A2 (fr) 2002-10-18 2004-05-06 Merck & Co., Inc. Inhibiteurs de dipeptidylpeptidase heterocyclique beta-amino destines au traitement ou a la prevention de diabetes
WO2004037181A2 (fr) 2002-10-23 2004-05-06 Bristol-Myers Squibb Company Inhibiteurs de dipeptidyl peptidase iv a base de glycinenitrile et procedes correspondants
WO2004041795A1 (fr) 2002-10-30 2004-05-21 Guilford Pharmaceuticals Inc. Nouveaux inhibiteurs de dipeptidyl peptidase iv
WO2004048379A1 (fr) 2002-11-01 2004-06-10 Sumitomo Pharmaceuticals Co., Ltd. Compose de xanthine
WO2004043940A1 (fr) 2002-11-07 2004-05-27 Merck & Co., Inc. Derives de phenylalanine utilises comme inhibiteurs de la dipeptidyl peptidase dans le traitement ou la prevention du diabete
WO2004041820A1 (fr) 2002-11-08 2004-05-21 Boehringer Ingelheim Pharma Gmbh & Co. Kg Nouveaux derives de xanthine, leur production et leur utilisation comme medicaments
DE10251927A1 (de) 2002-11-08 2004-05-19 Boehringer Ingelheim Pharma Gmbh & Co. Kg Neue Xanthinderivate, deren Herstellung und deren Verwendung als Arzneimittel
US20040138214A1 (en) 2002-11-08 2004-07-15 Boehringer Ingelheim Pharma Gmbh & Co. Kg Xanthine derivatives, the preparation thereof and their use as pharmaceutical compositions
US20040110817A1 (en) 2002-11-18 2004-06-10 Pfizer Inc Dipeptidyl peptidase IV inhibiting fluorinated cyclic amides
WO2004046106A1 (fr) 2002-11-18 2004-06-03 Pfizer Products Inc. Amides cycliques fluorés inhibant la dipeptidyl peptidase iv
DE10256264A1 (de) 2002-12-03 2004-06-24 Boehringer Ingelheim Pharma Gmbh & Co. Kg Neue substituierte Imidazo-pyridinone und Imidazo-pyridazinone, ihre Herstellung und ihre Verwendung als Arzneimittel
WO2004050658A1 (fr) 2002-12-03 2004-06-17 Boehringer Ingelheim Pharma Gmbh & Co. Kg Nouvelles imidazo-pyridinones et imidazo-pyridazinones substituees, leur production et leur utilisation en tant que medicaments
WO2004050022A2 (fr) 2002-12-04 2004-06-17 Merck & Co., Inc. Derives de phenylalanine utilises comme inhibiteurs de la dipeptidylpeptisase pour le traitement ou la prevention de diabetes
WO2004052850A2 (fr) 2002-12-09 2004-06-24 Bristol-Myers Squibb Company Procedes et composes pour produire des inhibiteurs de la dipeptidyle-peptidase et leurs intermediaires
WO2004052362A1 (fr) 2002-12-10 2004-06-24 Novartis Ag Combinaision d'un inhibiteur de dpp-iv et d'un compose ppar-alpha
WO2004058266A1 (fr) 2002-12-20 2004-07-15 Merck & Co., Inc. Derives de 3-amino-4-phenylbutanoique acide utilises en tant qu'inhibiteurs de dipeptidyl peptidase pour le traitement ou la prevention du diabete
WO2004065380A1 (fr) 2003-01-14 2004-08-05 Arena Pharmaceuticals Inc. Derives aryles et heteroaryles tri-substitues en position 1,2,3 en tant que modulateurs de metabolisme et prophylaxie et traitement de troubles lies au metabolisme
WO2004064778A2 (fr) 2003-01-17 2004-08-05 Merck & Co. Inc. Derives d'acide 3-amino-4-phenylbutanoique utilises comme inhibiteurs de la dipeptidyl peptidase pour le traitement ou la prevention du diabete
JP2004244412A (ja) 2003-01-20 2004-09-02 Kotobuki Seiyaku Kk ４位に置換基を有する２−シアノピロリジン誘導体及びその製造方法並びにそれを含有する薬剤
WO2004067509A1 (fr) 2003-01-31 2004-08-12 Sanwa Kagaku Kenkyusho Co., Ltd. Composé inhibant la dipeptidyl peptidase iv
WO2004069162A2 (fr) 2003-01-31 2004-08-19 Merck & Co., Inc. Derives d'acide 3-amino-4-phenylbutanoique utilises comme inhibiteurs de dipeptidyle peptidase pour le traitement ou la prevention du diabete
WO2004071454A2 (fr) 2003-02-13 2004-08-26 Guilford Pharmaceuticals Inc. Composes d'azetidine substitues servant d'inhibiteurs de dipeptidyl peptidase iv
WO2004076413A2 (fr) 2003-02-24 2004-09-10 Arena Pharmaceuticals, Inc. Derives d'aryle et heteroaryle susbtitues tenant lieu de modulateurs du metabolisme du glucose et prophylaxie et traitement de troubles associes
WO2004076433A1 (fr) 2003-02-28 2004-09-10 Aic Inhibiteurs de dipeptidyle peptidase
WO2004076434A1 (fr) 2003-02-28 2004-09-10 Aic Inhibiteurs de dipeptidyl peptidases
WO2004085378A1 (fr) 2003-03-19 2004-10-07 Merck & Co. Inc. Procede pour preparer des derives d'acide amine beta chiraux par hydrogenation asymetrique
WO2004085661A2 (fr) 2003-03-24 2004-10-07 Merck & Co., Inc Procede de synthese de derives d'acides amines beta chiraux
WO2004087053A2 (fr) 2003-03-25 2004-10-14 Syrrx, Inc. Inhibiteurs de dipeptidyle peptidase
WO2004087650A2 (fr) 2003-03-27 2004-10-14 Merck & Co. Inc. Procede et intermediaires pour la preparation d'inhibiteurs d'amide d'acide beta-amino de dipeptidyle peptidase-iv
WO2004092128A1 (fr) 2003-04-10 2004-10-28 Smithkline Beecham Corporation Formes cristallines anhydres de (2s, 4s)-1-{(2r)-2-amino-3-'4-methoxybenzyl)sulfonyl!-3-methylbutanoyl}-4-fluoropyrrolindine-2-carbonitrile
WO2004096806A1 (fr) 2003-04-30 2004-11-11 Sumitomo Pharmaceuticals Co. Ltd. Derive d'imidazole condense
WO2004099134A2 (fr) 2003-05-05 2004-11-18 Prosidion Ltd. Inhibiteurs de la dp iv a base de glutaminyle
WO2004103276A2 (fr) 2003-05-14 2004-12-02 Merck & Co., Inc. Derives d'acide 3-amino-4-phenylbutanoique en tant qu'inhibiteurs de dipeptidyl peptidase dans le cadre du traitement ou de la prevention du diabete
WO2004103993A1 (fr) 2003-05-14 2004-12-02 Syrrx, Inc. Inhibiteurs de dipeptidyl peptidase
US20040254226A1 (en) 2003-05-14 2004-12-16 Syrrx, Inc. Dipeptidyl peptidase inhibitors
WO2004104216A2 (fr) 2003-05-21 2004-12-02 Bayer Healthcare Ag Diagnostics et agents therapeutiques destines a des maladies liees a une dipeptidylpeptidase iv (dpp4)
WO2004104215A2 (fr) 2003-05-21 2004-12-02 Bayer Healthcare Ag Approches diagnostiques et therapeutiques des maladies associees a la dipeptidylpeptidase 7 (dpp7)
WO2004108730A1 (fr) 2003-06-05 2004-12-16 Fujisawa Pharmaceutical Co., Ltd. Inhibiteur de l'enzyme dpp-iv
WO2004110375A2 (fr) 2003-06-06 2004-12-23 Merck & Co., Inc. Polytherapie permettant de traiter le diabete
WO2004110436A1 (fr) 2003-06-06 2004-12-23 Merck & Co., Inc. Indoles fusionnes en tant qu'inhibiteurs de dipeptidyle peptidase destines au traitement ou a la prevention des diabetes
WO2004111041A1 (fr) 2003-06-12 2004-12-23 Fujisawa Pharmaceutical Co., Ltd. Compose de pyrrolidine, de thiazolidine et d'oxazolidine inhibant la dipeptidyl-peptidase-iv (dpp-iv)
WO2004112701A2 (fr) 2003-06-17 2004-12-29 Merck & Co., Inc. Derives de cyclohexylglycine servant d'inhibiteurs de la dipeptidyl peptidase pour le traitement ou la prevention du diabete
WO2004111051A1 (fr) 2003-06-18 2004-12-23 Boehringer Ingelheim International Gmbh Derives d'imidazopyridazinones et d'imidazopyridones, leur preparation et leur utilisation comme medicaments
DE10327439A1 (de) 2003-06-18 2005-01-05 Boehringer Ingelheim Pharma Gmbh & Co. Kg Neue Imidazopyridazinon- und Imidazopyridonderivate, deren Herstellung und deren Verwendung als Arzneimittel
WO2005000846A1 (fr) 2003-06-20 2005-01-06 F.Hoffmann-La Roche Ag Hexahydropyrido-isoquinolines utilises comme inhibiteurs de dpp-iv
WO2005000848A1 (fr) 2003-06-20 2005-01-06 F. Hoffmann-La Roche Ag Derives de pyrido[2,1-a]isoquinoline utilises comme inhibiteurs de dpp-iv
US20040259902A1 (en) 2003-06-20 2004-12-23 Markus Boehringer Pyrido [2,1-a] isoquinoline derivatives
US20040259903A1 (en) 2003-06-20 2004-12-23 Markus Boehringer Pyrido [2,1-a] isoquinoline derivatives
US20050032804A1 (en) 2003-06-24 2005-02-10 Cypes Stephen Howard Phosphoric acid salt of a dipeptidyl peptidase-IV inhibitor
WO2005003135A1 (fr) 2003-06-24 2005-01-13 Merck & Co., Inc. Sel d'acide phosphorique d'un inhibiteur de la dipeptidyl peptidase iv
JP2005023038A (ja) 2003-07-04 2005-01-27 Taisho Pharmaceut Co Ltd 慢性腎疾患治療薬
WO2005007647A1 (fr) 2003-07-11 2005-01-27 Arena Pharmaceuticals, Inc. Derives aryles et heteroaryles trisubstitues utilises en tant que modulateurs du metabolisme et prophylaxie et traitement de troubles afferents
WO2005009956A1 (fr) 2003-07-21 2005-02-03 Smithkline Beecham Corporation Sel d'acide (2s,4s)-4-fluoro-1-[4-fluoro-beta-(4-fluorophenyl)-1-phenylalanyl]-2-pyrrolidinecarbonitrile p-toluenesulfonique, et certaines de ses formes crristallines anhydres
DE10333935A1 (de) 2003-07-25 2005-02-24 Aventis Pharma Deutschland Gmbh Neue bicyclische Cyanoheterocyclen, Verfahren zu ihrer Herstellung und ihre Verwendung als Arzneimittel
US20050059724A1 (en) 2003-07-25 2005-03-17 Aventis Pharma Deutschland Gmbh Novel cyanopyrrolidides, process for their preparation and their use as medicaments
WO2005012308A1 (fr) 2003-07-25 2005-02-10 Sanofi-Aventis Deutschland Gmbh Nouveaux cyanopyrrolidides, procedes pour leur production et leur utilisation comme medicament
WO2005012312A1 (fr) 2003-07-25 2005-02-10 Sanofi-Aventis Deutschland Gmbh Nouvelles cyanothiazolides, leur procede de production et leur utilisation comme medicament
US20050059716A1 (en) 2003-07-25 2005-03-17 Aventis Pharma Deutschland Gmbh Novel bicyclic cyanoheterocycles, process for their preparation and their use as medicaments
WO2005011581A2 (fr) 2003-07-31 2005-02-10 Merck & Co., Inc. Hexahydrodiazepinones utilises en tant qu'inhibiteurs de la dipeptidyl peptidase iv pour le traitement ou la prevention du diabete
US20050038020A1 (en) 2003-08-01 2005-02-17 Hamann Lawrence G. Adamantylglycine-based inhibitors of dipeptidyl peptidase IV and methods
WO2005012249A2 (fr) 2003-08-01 2005-02-10 Bristol-Myers Squibb Company Inhibiteurs a base d'adamantyglycine de la dipeptidyl peptidase iv et procedes associes
WO2005019168A2 (fr) 2003-08-20 2005-03-03 Pfizer Products Inc. Derives fluores de lysine en tant qu'inhibiteurs de la dipeptidylpeptidase iv
US20050043292A1 (en) 2003-08-20 2005-02-24 Pfizer Inc Fluorinated lysine derivatives as dipeptidyl peptidase IV inhibitors
WO2005020920A2 (fr) 2003-09-02 2005-03-10 Merck & Co., Inc. Nouvelles formes cristallines d'un sel d'acide phosphorique d'un inhibiteur de dipeptidyl peptidase-iv
WO2005023762A1 (fr) 2003-09-04 2005-03-17 Abbott Laboratories Derives de pyrrolidine-2-carbonitrile et leur utilisation comme inhibiteurs de la dipeptidyle peptidase-iv (dpp-iv)
WO2005026148A1 (fr) 2003-09-08 2005-03-24 Takeda San Diego, Inc. Inhibiteurs de la dipeptidylpeptidase
WO2005030751A2 (fr) 2003-09-08 2005-04-07 Takeda Pharmaceutical Company Limited Inhibiteurs de dipeptidyle peptidase
WO2005025554A2 (fr) 2003-09-09 2005-03-24 Japan Tobacco Inc. Inhibiteur de la dipeptidylpeptidase iv
WO2005030127A2 (fr) 2003-09-23 2005-04-07 Merck & Co., Inc. Nouvelle forme cristalline d'un sel d'acide phosphorique d'un inhibiteur de dipeptidyle peptase-iv
WO2005032590A1 (fr) 2003-10-03 2005-04-14 Takeda Pharmaceutical Company Limited Remede contre le diabete
WO2005033099A2 (fr) 2003-10-03 2005-04-14 Glenmark Pharmaceuticals Ltd. Nouveaux inhibiteurs de dipeptidylpeptidase iv, leurs procedes de preparation et compositions les contenant
WO2005037779A2 (fr) 2003-10-15 2005-04-28 Imtm Gmbh Nouveaux inhibiteurs de dipeptidylpeptidases iv destines a influencer le fonctionnement de diverses cellules et a traiter des maladies immunologiques, inflammatoires, neuronales et autres
WO2005034940A2 (fr) 2003-10-15 2005-04-21 Imtm Gmbh Inhibiteurs doubles d'alanyl-aminopeptidase et de dipeptidylpeptidase iv utilises pour influer de maniere fonctionnelle sur differentes cellules et pour traiter des affections immunologiques, inflammatoires, neuronales et autres
WO2005040095A1 (fr) 2003-10-16 2005-05-06 Astrazeneca Ab Inhibiteurs de la dipeptidyl-peptidase iv
WO2005037828A1 (fr) 2003-10-20 2005-04-28 Lg Life Sciences Ltd. Inhibiteurs de dpp-iv, procedes d'elaboration correspondants, et compositions pharmaceutiques renfermant ces inhibiteurs comme principe actif
WO2005042488A1 (fr) 2003-10-31 2005-05-12 Takeda Pharmaceutical Company Limited Composes pyridines utilises comme inhibiteurs de dipeptidyle peptidase iv
WO2005044195A2 (fr) 2003-11-04 2005-05-19 Merck & Co., Inc. Derives de phenylalanine fusionnes utilises comme inhibiteurs de la dipeptidyl peptidase-iv dans le traitement ou la prevention du diabete
WO2005047297A1 (fr) 2003-11-12 2005-05-26 Phenomix Corporation Composés heterocycliques d'acide boronique
WO2005049022A2 (fr) 2003-11-17 2005-06-02 Novartis Ag Utilisation de composes organiques
WO2005058849A1 (fr) 2003-12-15 2005-06-30 Glenmark Pharmaceuticals Ltd. Nouveaux inhibiteurs de dipeptidyle peptidase iv, leur procede de preparation et compositions les contenant
WO2005063750A1 (fr) 2003-12-23 2005-07-14 Boehringer Ingelheim International Gmbh Composes imidazol bicycliques, leur fabrication et leur utilisation comme medicaments
WO2005072530A1 (fr) 2004-01-16 2005-08-11 Merck & Co., Inc. Nouveau sel cristallin d'un inhibiteur de dipeptidyle peptidase-iv
WO2005075426A1 (fr) 2004-02-03 2005-08-18 Glenmark Pharmaceuticals Ltd. Nouveaux inhibiteurs de dipeptidyle peptidase iv, leur procedes de preparation et compositions en comportant
US20080146818A1 (en) 2004-02-05 2008-06-19 Yasumichi Fukuda Bicycloester Derivative
WO2005079795A2 (fr) 2004-02-20 2005-09-01 Novartis Ag Utilisation de composes organiques
WO2005082849A1 (fr) 2004-02-23 2005-09-09 Trustees Of Tufts College Lactames utilisees comme inhibiteurs peptidomimetiques a contrainte conformationnelle
WO2005082348A2 (fr) 2004-02-23 2005-09-09 Trustees Of Tufts College Inhibiteurs de la dipeptidylpeptidase iv
WO2005087235A1 (fr) 2004-03-09 2005-09-22 National Health Research Institutes Composes de pyrrolidine
WO2005095381A1 (fr) 2004-03-15 2005-10-13 Takeda Pharmaceutical Company Limited Inhibiteurs de la dipeptidyle peptidase
WO2005116014A1 (fr) 2004-05-12 2005-12-08 Pfizer Products Inc. Derives de proline et leur utilisation en tant qu'inhibiteurs de la dipeptidyl-peptidase iv
US20070167468A1 (en) 2004-08-06 2007-07-19 Sanofi-Aventis Deutschland Gmbh Substituted bicyclic 8-pyrr0lidinoxanthines, methods for their production, pharmaceutical formulations and their use
WO2006040625A1 (fr) 2004-10-12 2006-04-20 Glenmark Pharmaceuticals S.A. Nouveaux inhibiteurs de dipeptidyle peptidase iv, compositions pharmaceutiques en contenant, et leur procede de preparation
US20090192129A1 (en) 2004-12-12 2009-07-30 Dainippon Sumitomo Pharma Co., Ltd. Bicyclic pyrrole derivatives
WO2006068163A1 (fr) 2004-12-24 2006-06-29 Dainippon Sumitomo Pharma Co., Ltd. Dérivés bicycliques de pyrrole
WO2006076231A2 (fr) 2005-01-10 2006-07-20 Arena Pharmaceuticals, Inc. Polytherapie destinee au traitement du diabete et de troubles lies au diabete et au traitement de troubles pouvant etre soignes par une augmentation du taux de glp-1 dans le sang
WO2006088129A1 (fr) 2005-02-18 2006-08-24 Mitsubishi Pharma Corporation Sel d'un dérivé de proline, solvate dudit sel, et méthode de production dudit sel
US20090216016A1 (en) 2005-02-18 2009-08-27 Mitsubishi Pharma Corporation Salt of proline derivative, solvate thereof, and production method thereof
WO2006100181A2 (fr) 2005-03-22 2006-09-28 F. Hoffmann-La Roche Ag Nouveau sel et polymorphes de l'inhibiteur de dpp-iv
WO2006116157A2 (fr) 2005-04-22 2006-11-02 Alantos Pharmaceuticals Holding, Inc. Inhibiteurs de la dipeptidyl peptidase iv
EP1902730A1 (fr) 2005-06-09 2008-03-26 Banyu Pharmaceutical Co., Ltd. Agoniste de npy y2 pour une utilisation en tant qu agent thérapeutique contre une maladie s accompagnant de diarrhée
WO2007019255A2 (fr) 2005-08-04 2007-02-15 Novartis Ag Nouveaux composes
WO2007027651A2 (fr) 2005-08-30 2007-03-08 Abbott Laboratories Compositions pharmaceutiques utilisees comme inhibiteurs de la dipeptidyl peptidase iv (dpp-iv)
WO2007035372A2 (fr) 2005-09-16 2007-03-29 Takeda Pharmaceutical Company Limited Formes polymorphes de sel benzoate de 2-[[6-[(3r)-3-amino-1-piperidinyl]-3,4-dihydro-3-methyl-2,4-dioxo-1(2h)-pyrimidinyl]methyl]-benzonitrile, et leurs procedes d'utilisation
WO2007071576A1 (fr) 2005-12-21 2007-06-28 F. Hoffmann-La Roche Ag Nouveau sel et polymorphe d’un inhibiteur de dpp-iv
WO2007120689A2 (fr) 2006-04-11 2007-10-25 Arena Pharmaceuticals, Inc. Procédés d'utilisation du récepteur gpr119 pour identifier des composés utiles pour augmenter la masse osseuse chez un individu
WO2007120702A2 (fr) 2006-04-11 2007-10-25 Arena Pharmaceuticals, Inc. Agonistes du récepteur de gpr119 dans des procédés d'augmentation de la masse osseuse et de traitement de l'ostéoporose et autres états se caractérisant par une masse osseuse faible, et thérapie de combinaison associée
WO2007128721A1 (fr) 2006-05-04 2007-11-15 Boehringer Ingelheim Internationalgmbh Polymorphes
WO2007148185A2 (fr) 2006-06-21 2007-12-27 Pfizer Products Inc. 3-amino-pyrrolidino-4-lactames substitués
WO2008027273A2 (fr) 2006-08-30 2008-03-06 Phenomix Corporation Sels citrates et tartrates solides d'inhibiteurs de la dpp-iv
WO2008070692A2 (fr) * 2006-12-06 2008-06-12 Smithkline Beecham Corporation Composés chimiques et leurs utilisations
WO2008114857A1 (fr) 2007-03-22 2008-09-25 Kyorin Pharmaceutical Co., Ltd. Procédé de préparation d'un dérivé d'aminoacétylpyrrolidinecarbonitrile
WO2009084497A1 (fr) 2007-12-28 2009-07-09 Dainippon Sumitomo Pharma Co., Ltd. Dérivé de pipéridine substituée par un méthyle
WO2009126245A1 (fr) 2008-04-07 2009-10-15 Arena Pharmaceuticals, Inc. Procédés d'utilisation d'un récepteur couplé à la protéine g pour identifier des sécrétagogues du peptide yy (pyy) et composés utiles dans le traitement de pathologies modulées par le pyy

Non-Patent Citations (109)

* Cited by examiner, † Cited by third party
Title
ABBOTT ET AL., BRAIN RES, vol. 1043, 2005, pages 139 - 144
ABE ET AL., J NAT PROD, vol. 67, 2004, pages 999 - 1004
ADRIAN ET AL., GASTROENTEROL, vol. 89, 1985, pages 1070 - 1077
AHREN ET AL., DIABETES CARE, vol. 25, 2002, pages 869 - 875
AHREN ET AL., ENDOCRINOLOGY, vol. 146, 2005, pages 2055 - 2059
AHREN ET AL., J CLIN ENDOCRINOL METAB, vol. 89, 2004, pages 2078 - 2084
AREHART ET AL., CIRC RES, CIRC. RES., vol. 102, 2008, pages 986 - 993
ATIK ET AL., CLIN ORTHOP RELAT RES, vol. 443, 2006, pages 19 - 24
BALASUBRAMANIAM ET AL., J. MED. CHEM., vol. 43, 2000, pages 3420 - 3427
BALASUBRAMANIAM ET AL., PEPTIDES, vol. 28, 2007, pages 235 - 240
BATTERHAM ET AL., NATURE, vol. 418, 2002, pages 650 - 654
BEHRE, SCAND J CLIN LAB INVEST, vol. 67, 2007, pages 449 - 458
BILCHIK ET AL., GASTROENTEROL, vol. 105, 1993, pages 1441 - 1448
BOEY ET AL., DIABETOLOGIA, vol. 49, 2006, pages 1360 - 1370
BOEY ET AL., NEUROPEPTIDES, vol. 42, 2008, pages 19 - 30
BOLLAG ET AL., ENDOCRINOLOGY, vol. 141, 2000, pages 1228 - 1235
BOLLAG ET AL., MOL CELL ENDOCRINOL, vol. 177, 2001, pages 35 - 41
BOSE ET AL., DIABETES, vol. 54, 2005, pages 146 - 151
BRADLEY, JPATHOL, vol. 214, 2008, pages 149 - 160
BRANCATI, F. L. ET AL., ARCH. INTERN. MED., vol. 159, 1999, pages 957 - 963
CALDWELL ET AL., BIOORG MED CHEM LETT, vol. 14, 2004, pages 1265 - 1268
COX, PEPTIDES, vol. 28, 2007, pages 345 - 351
CRUZE ET AL., PEPTIDES, vol. 28, 2007, pages 269 - 280
DEACON ET AL., J CLIN ENDOCRINOL METAB, vol. 85, 2000, pages 3575 - 3581
DEACON, REGUL PEPT, vol. 128, 2005, pages 117 - 124
DRUCKER, CELL METAB, vol. 3, 2006, pages 153 - 165
DURING ET AL., NAT. MED., vol. 9, 2003, pages 1173 - 1179
EBERLEIN ET AL., PEPTIDES, vol. 10, 1989, pages 797 - 803
EDMONDSON ET AL., BIOORG MED CHEM LETT, vol. 14, 2004, pages 5151 - 5155
EKBLAD ET AL., PEPTIDES, vol. 23, 2002, pages 251 - 261
EKSTRAND ET AL., PNAS USA, vol. 100, 2003, pages 6033 - 6038
EL BAHH ET AL., EUR. J. NEUROSCI., vol. 22, 2005, pages 1417 - 1430
G. P. STAHLY, CRYSTAL GROWTH & DESIGN, vol. 7, no. 6, 2007, pages 1007 - 1026
GONON ET AL., CARDIOVASC RES., vol. 78, 2008, pages 116 - 122
GRANDT ET AL., REGUL. PEPT., vol. 51, 1994, pages 151 - 159
GREIG ET AL., ANN N YACAD SCI, vol. 1035, 2004, pages 290 - 315
GRISE ET AL., J. SURG. RES., vol. 82, 1999, pages 151 - 155
GUERRE-MILLO, DIABETES & METABOLISM, vol. 34, 2008, pages 12 - 18
H.-U. DEMUTH ET AL.: "Type 2 diabetes-Therapy with dipeptidyl peptidase IV inhibitors", BIOCHIM. BIOPHYS. ACTA, vol. 1751, 2005, pages 33 - 44
HANSMANN ET AL., CIRCULATION, vol. 115, 2007, pages 1275 - 1284
HARA ET AL., DIABETES CARE, vol. 29, 2006, pages 1357 - 1362
HAY ET AL., J CLIN GASTROENTEROL, vol. 14, 1992, pages 309 - 317
HILL, J. 0. ET AL., SCIENCE, vol. 280, 1998, pages 1371 - 1374
JONES ET AL., ANN. REP. MED. CHEM., vol. 44, 2009, pages 149 - 170
JONES, EXPERT OPIN. THER. PATENTS, vol. 19, no. 10, 2009, pages 1339 - 1359
K. AUGUSTYNS ET AL.: "Inhibitors of proline-specific dipeptidyl peptidases: DPP-IV inhibitors as a novel approach for the treatment of Type 2 diabetes", EXPERT OPIN. THER. PATENTS, vol. 15, 2005, pages 1387 - 1407
KEIGHLEY ET AL., AILMENT PHARMACOL THER, vol. 18, 2003, pages 66 - 70
KEIRE ET AL., AM. J. PHYSIOL. GASTROINTEST. LIVER PHYSIOL., vol. 279, 2000, pages G126 - G131
KUBOTA ET AL., J. BIOL. CHEM., vol. 277, 2002, pages 25863 - 25866
LAMB ET AL., J. MED. CHEM., vol. 50, 2007, pages 2264 - 2268
LE STUNFF ET AL., DIABETES, vol. 43, 1989, pages 696 - 702
LEE ET AL., J. CLIN. INVEST., vol. 111, 2003, pages 1853 - 1862
LEE ET AL., PEPTIDES, vol. 24, 2003, pages 99 - 106
LIU ET AL., AM SURG, vol. 62, 1996, pages 232 - 236
LIU ET AL., J. SURG. RES., vol. 58, 1995, pages 6 - 11
LIU ET AL., J. SURG. RES., vol. 58, 1995, pages 707 - 712
LIU ET AL., SURGERY, vol. 118, 1995, pages 229 - 236
LUNDBERG ET AL., PNAS USA, vol. 79, 1982, pages 4471 - 4475
MAEDA ET AL., NAT. MED., vol. 8, 2002, pages 731 - 737
MATSUDA ET AL., JBIOL CHEM, vol. 277, 2002, pages 37487 - 37491
MCFADDEN ET AL., AM. J. SURG., vol. 188, 2004, pages 516 - 519
MCINTOSH ET AL., REGUL PEPT, vol. 128, 2005, pages 159 - 165
MENTLEIN, EXPERT OPIN INVESTIG DRUGS, vol. 14, 2005, pages 57 - 64
MORLEY ET AL., LIJE SCIENCES, vol. 41, 1987, pages 2157 - 2165
NAUCK ET AL., DIABETES, vol. 53, no. 3, 2004, pages 190 - 196
NAUCK ET AL., DRUG NEWS PERSPECT, vol. 16, 2003, pages 413 - 422
NIGHTINGALE ET AL., GUT, vol. 39, 1996, pages 267 - 272
NISHIMURA ET AL., CIRCULATION, vol. 117, 2008, pages 216 - 223
O'BRIEN, M.; DAILY, B.; SCHURRIA, M.: "Assay for DPPIV activity using a homogeneous, luminescent method", CELL NOTE, 2005
OHASHI ET AL., HYPERTENSION, vol. 47, 2006, pages 1108 - 1116
OKU ET AL., FEBS LETTERS, vol. 581, 2007, pages 5029 - 5033
ORTIZ ET AL., JPET, vol. 323, 2007, pages 692 - 700
OUCHI ET AL., CIRCULATION, vol. 100, 1999, pages 2473 - 2476
OUCHI ET AL., CLIN CHIM ACTA, vol. 380, 2007, pages 24 - 30
PARKER ET AL., BR. J. PHARMACOL., vol. 153, 2008, pages 420 - 431
PEARSON, NURSING TIMES, vol. 100, 2004, pages 86 - 90
PEDERSON, P., DIAB. METAB. REV., vol. 5, 1989, pages 505 - 509
PERRY, I. J. ET AL., BMJ, vol. 310, 1995, pages 560 - 564
PETERS ET AL., BIOORG MED CHEM LETT, vol. 14, 2004, pages 1491 - 1493
PITTNER ET AL., INT. J. OBES. RELAT. METAB. DISORD., vol. 28, 2004, pages 963 - 971
RAISZ, J CLIN INVEST, vol. 115, 2005, pages 3318 - 3325
REED; SCRIBNER, DIABETES, OBESITY AND METABOLISM, vol. 1, 1999, pages 75 - 86
RENSHAW ET AL., CURRENT DRUG TARGETS, vol. 6, 2005, pages 171 - 179
ROTWEIN, R. ET AL., N. ENGL. J. MED., vol. 308, 1983, pages 65 - 71
RUGGERI, NAT MED, vol. 8, 2002, pages 1227 - 1234
SCHWARTZ, CELL METABOLISM, vol. 11, 2010, pages 445 - 447
SHAH, CURRENT OPINION IN DRUG DISCOVERY & DEVELOPMENT, vol. 12, 2009, pages 519 - 532
SHIBATA ET AL., J. BIOL. CHEM., vol. 279, 2004, pages 28670 - 28674
SHIBATA ET AL., J. MOL. CELL CARDIOL., vol. 42, 2007, pages 1065 - 1074
SHIBATA ET AL., NAT MED, vol. 11, 2005, pages 1096 - 1103
SHORE ET AL., J. ALLERGY CLIN. IMMUNOL, vol. 118, 2006, pages 389 - 395
SUMMER ET AL., AM J. PHYSIOL. LUNG CELL MOL. PHYSIOL, 7 March 2008 (2008-03-07)
TAO ET AL., CIRCULATION, vol. 115, 2007, pages 1408 - 1416
TATEMOTO ET AL., NATURE, vol. 285, 1980, pages 417 - 418
TILG ET AL., NAT. REV. IMMUNOL., vol. 6, 2006, pages 772 - 783
TSENG ET AL., PEPTIDES, vol. 23, 2002, pages 389 - 395
TSUKIYAMA ET AL., MOL ENDOCRINOL, vol. 20, 2006, pages 1644 - 1651
UENO ET AL., REGUL PEPT, vol. 145, 2008, pages 12 - 16
VILLHAUER ET AL., J MED CHEM, vol. 45, 2002, pages 2362 - 2365
VILLHAUER ET AL., J MED CHEM, vol. 46, 2003, pages 2774 - 2789
VONA-DAVIS ET AL., PEPTIDES, vol. 28, 2007, pages 334 - 338
WOLDBYE ET AL., NEUROBIOLOGY OFDISEASE, vol. 20, 2005, pages 760 - 772
WORLD HEALTH ORGANIZATION TECHNICAL REPORT SERIES 921, 2003
WORTLEY ET AL., GASTROENTEROL, vol. 133, 2007, pages 1534 - 1543
XIE ET AL., BONE, vol. 37, 2005, pages 759 - 769
YAMAMOTO ET AL., CLINICAL SCIENCE, vol. 103, 2002, pages 137 - 142
YOKOTA ET AL., BLOOD, vol. 96, 2000, pages 1723 - 1732
ZANDER ET AL., LANCET, vol. 359, 2002, pages 824 - 830
ZHONG ET AL., AM JPHYSIOL ENDOCRINOL METAB, vol. 292, 2007, pages E543 - E548

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8933083B2 (en) 2003-01-14 2015-01-13 Arena Pharmaceuticals, Inc. 1,2,3-trisubstituted aryl and heteroaryl derivatives as modulators of metabolism and the prophylaxis and treatment of disorders related thereto such as diabetes and hyperglycemia
US10894787B2 (en) 2010-09-22 2021-01-19 Arena Pharmaceuticals, Inc. Modulators of the GPR119 receptor and the treatment of disorders related thereto
WO2012099915A1 (fr) * 2011-01-19 2012-07-26 Hongwen Zhu Dérivés de thiazolidine et leur utilisation thérapeutique
WO2012170867A1 (fr) 2011-06-09 2012-12-13 Rhizen Pharmaceuticals Sa Nouveaux composes utilises comme modulateurs de gpr-119
US9944600B2 (en) 2012-06-12 2018-04-17 Chong Kun Dang Pharmaceutical Corp. Piperidine derivatives for GPR119 agonist
WO2014011926A1 (fr) 2012-07-11 2014-01-16 Elcelyx Therapeutics, Inc. Compositions comportant des statines, des biguanides et d'autres agents pour réduire un risque cardiométabolique
US9096641B2 (en) 2013-06-05 2015-08-04 Evestra, Inc. Imidazolyl progesterone antagonists
US9776987B2 (en) 2013-11-26 2017-10-03 Chong Kun Dang Pharmaceutical Corp Amide derivatives for GPR119 agonist
US11007175B2 (en) 2015-01-06 2021-05-18 Arena Pharmaceuticals, Inc. Methods of treating conditions related to the S1P1 receptor
US11884626B2 (en) 2015-06-22 2024-01-30 Arena Pharmaceuticals, Inc. Crystalline L-arginine salt of (R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclo-penta [b]indol-3-yl)acetic acid(Compound1) for use in S1P1 receptor-associated disorders
US11534424B2 (en) 2017-02-16 2022-12-27 Arena Pharmaceuticals, Inc. Compounds and methods for treatment of primary biliary cholangitis

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