WO2007146786A1 - Compositions pharmaceutiques et procédés pour restaurer la masse et la fonction de lymphocytes b - Google Patents

Compositions pharmaceutiques et procédés pour restaurer la masse et la fonction de lymphocytes b Download PDF

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WO2007146786A1
WO2007146786A1 PCT/US2007/070734 US2007070734W WO2007146786A1 WO 2007146786 A1 WO2007146786 A1 WO 2007146786A1 US 2007070734 W US2007070734 W US 2007070734W WO 2007146786 A1 WO2007146786 A1 WO 2007146786A1
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pharmaceutical composition
cells
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Jerry L. Nadler
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Diakine Therapeutics, Inc.
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A61K38/26—Glucagons

Definitions

  • the present invention relates to the use of pharmaceutical compositions and methods for using same for (1 ) restoring ⁇ -cell mass and function in an individual in need thereof; (2) preventing the development of, or reversing, Type 1 diabetes in an individual in need thereof; (3) for preventing the development of, or reversing, latent autoimmune diabetes of adults (LADA) in an individual in need thereof; and/or (4) for treating Type 2 diabetes by increasing the number of functional insulin-producing cells (e.g., ⁇ -cells) in an individual in need thereof.
  • functional insulin-producing cells e.g., ⁇ -cells
  • Insulin is a hormone produced in the pancreas by ⁇ -cells.
  • the function of insulin is to regulate the amount of glucose (sugar) in the blood, which enters cells through receptors that accept insulin and allow glucose to enter. Once inside, glucose can be used as fuel. Excess glucose is stored in the liver and muscles in a form called glycogen. When blood glucose levels are low, the liver releases glycogen to form glucose. Without insulin, glucose has difficulty entering cells.
  • DKA diabetic ketoacidotic coma
  • diabetes mellitus There are two forms of diabetes mellitus: (1 ) insulin dependent or Type 1 diabetes (a.k.a., Juvenile Diabetes, Brittle Diabetes, Insulin Dependent Diabetes Mellitus (IDDM)) and (2) non-insulin-dependent or Type Il diabetes (a.k.a., NIDDM).
  • Type 1 diabetes develops most often in young people but can appear in adults.
  • Type 2 diabetes develops most often in middle aged and older adults, but can appear in young people.
  • Diabetes is a disease derived from multiple causative factors and characterized by elevated levels of plasma glucose (hyperglycemia) in the fasting state or after administration of glucose during an oral glucose tolerance test.
  • Type 1 diabetes is an autoimmune disease condition characterized by high blood glucose levels caused by a total lack of insulin, i.e., a complete loss of pancreatic ⁇ -cell function and mass.
  • Type 1 diabetes occurs when a person's immune system attacks the insulin producing ⁇ -cells in the pancreas and destroys them.
  • IL-12 lnterleukin 12
  • STAT-4 Signal Transducers and Activators of Transcription family members
  • STAT-4 Signal Transducers and Activators of Transcription
  • Type 1 diabetes symptoms include excessive thirst (polydipsia), frequent urination (polyuria), extreme hunger (polyphagia), extreme fatigue, and weight loss. These symptoms are caused by hyperglycemia and a breakdown of body fats. Persons diagnosed with Type 1 diabetes typically exhibit blood sugar levels over 300 mg and ketones present in their urine. Restoration of ⁇ -cell mass and insulin production can fully reverse the diabetic state. Evidence suggests that people with long standing Type 1 diabetes have ⁇ -cells that continue to form but are undesirably destroyed by continued autoimmune destruction. Therefore, pharmaceutical compositions and methods for arresting autoimmune ⁇ -cell damage would provide an effective way to restore normal ⁇ -cell mass levels and reverse or cure Type 1 diabetes.
  • LADA is a newly recognized subset of Type 1 diabetes and is thought to account for up to 10%-20% of all cases of diabetes. LADA is often present in people initially diagnosed with Type 2 diabetes. Although it has characteristics similar to adult onset type 1 diabetes, the beta-cell destruction is considered to be less aggressive in its progression.
  • Type 2 diabetes results from a combination of insulin resistance and impaired insulin secretion but ultimately many people with Type 2 diabetes show markedly reduced pancreatic ⁇ -cell mass and function which, in turn, causes Type 2 diabetic persons to have a "relative" deficiency of insulin because pancreatic ⁇ -cells are producing some insulin, but the insulin is either too little or isn't working properly to adequately allow glucose into cells to produce energy.
  • Recent autopsy studies have shown clear evidence of ongoing ⁇ -cell death (apoptosis) in people with Type 2 diabetes. Therefore, therapeutic approaches to arrest ⁇ -cell death could provide a significant treatment for reversing or curing Type 2 diabetes.
  • Type 2 diabetes leads to excess glucose in the blood, resulting in hyperglycemia, or high blood sugar.
  • a person with Type 2 diabetes experiences fatigue, increased thirst, frequent urination, dry, itchy skin, blurred vision, slow healing cuts or sores, more infections than usual, numbness and tingling in feet. Without treatment, a person with Type 2 diabetes will become dehydrated and develop a dangerously low blood volume.
  • Type 2 diabetes remains uncontrolled for a long period of time, more serious symptoms may result, including severe hyperglycemia (blood sugar over 600 mg) lethargy, confusion, shock, and ultimately "hyperosmolar hyperglycemic non-ketotic coma.”
  • Persistent or uncontrolled hyperglycemia is associated with increased and premature morbidity and mortality.
  • therapeutic control of glucose homeostasis, lipid metabolism, obesity, and hypertension are critically important in the clinical management and treatment of diabetes mellitus.
  • the object of diabetes treatments is to prevent the occurrence of the above-mentioned chronic complications, slow disease progression by improving hyperglycemic status, or reversing/curing it.
  • Conventional methods for treating diabetes have included administration of fluids and insulin in the case of Type I diabetes and administration of various hypoglycemic agents in the case of Type Il diabetes.
  • Hypoglycemic agents such as insulin preparations, insulin secretagogues, insulin sensitizers and ⁇ -glucosidase inhibitors have been widely applied as the method for the clinical treatment.
  • Examples include acarbose (PrecoseJ), glimeprimide (AmarylJ), metformin (Glucophage7), nateglinide (Starlix7), pioglitazone (Actos7), repaglinide (PrandinJ), rosiglitazone (Avandia7), sulfonylureas, Orlistat (Xenical7), exenatide (Byetta), and the like.
  • Many of the known hypoglycemic agents exhibit undesirable side effects and are toxic in certain cases. For example, in the case of the diabetic patients with seriously lowered pancreatic insulin secretion, effectiveness of insulin secretagogues and insulin sensitizers is diminished.
  • diabetes mellitus could be "cured” by a successful transplant of the tissue containing cells that secrete or produce insulin, i.e., the islets of Langerhans. Transplantation of insulin producing cells (a.k.a., islets) has been tried as a method to reverse or cure Type 1 diabetes, but there are significant risks associated with the surgery and with the toxic immunosuppression type drugs that need to be taken to prevent or mitigate allograft rejection and autoimmune reoccurrence. Immunosuppression drugs act by reducing the activity of a recipient's immune system so that the transplanted insulin producing cells are not rejected.
  • combination therapy approach provided by a preferred embodiment of present invention would be a major improvement in cellular replacement therapy by reducing the amount of transplanted cells needed to reverse or cure Type 1 diabetes, facilitating the increase viability and growth of insulin producing cells, thereby improving success rates.
  • GLP-1 Glucagon-Like Peptide
  • GIP Gastric Inhibitory Polypeptide
  • lncretins are intestinal hormones released after meal ingestion that stimulate insulin secretion.
  • GLP-1 is a 300-amino-acid (peptide) incretin synthesized in the small and large intestine by the L-type cells of the gastroenteropancreatic endocrine system and is released in response to food ingestion.
  • GLP-1 enhances glucose-stimulated postprandial insulin secretion, stimulates insulin gene expression and proinsulin biosynthesis, inhibits pancreatic glucagons release, gastric emptying, and acid secretion.
  • GIP is another insulin releasing hormone secreted from endocrine cells in the intestinal tract in response to food intake. Together with autonomic nerves, GLP-1 and GIP play a vital supporting role to the pancreatic islets in the control of blood glucose homeostasis and nutrient metabolism.
  • GLP-1 shows potent insulinotropic action in both diabetic and nondiabetics. GLP-1 causes expansion of beta-cell mass via proliferation of insulin-producing cells. GLP-1 shows an ability to stimulate ⁇ -cell neogenesis in streptozotocin (STZ)-treated newborn rats, resulting in persistent improvement of glucose homeostasis to adult age. GLP-1 induces differentiation of islet duodenal homeobox-1 -positive pancreatic ductal cells into insulin-secreting cells by enhancing expression of transcription factors PDX-1 and HNF3. GLP-1 has been shown to promote functional maturation of fetal porcine ⁇ -cells and islet cell growth in a Type 2 diabetic rat model.
  • STZ streptozotocin
  • GLP-1 receptor signaling directly modifies the susceptibility of ⁇ -cells to apoptotic injury that may be the potential mechanism linking to preservation and enhancement of ⁇ -cell mass and function.
  • GLP-1 receptor signaling does not seem essential for glucose-stimulated insulin secretion, as shown in GPL-1 receptor knockout mice, which suggests that the functional signaling of GLP-1 in ⁇ -cells may be in addition to the one initiated by glucose.
  • GLP-1 has been studied as a potential drug for the management of diabetes for two reasons: (i) its effect on ⁇ -cell growth; and (ii) its insulin-stimulating effect with minimal risk of hypoglycemia and absence of effect on insulin action in non-diabetic humans. In limited clinical trails, GPL-1 is effective in treating Type 2 diabetic patients, showing a significant improvement in postprandial glycemic control and normalization of fasting hyperglycemia due to its ability of insulinotropic activity.
  • GIP is released from intestinal endocrine K-cells into the bloodstream following ingestion of carbohydrate, protein and particularly fat.
  • GIP's major physiological role is generally believed to be that of an incretin hormone that targets pancreatic islets to enhance insulin secretion and help reduce postprandial hyperglycemia.
  • GIP acts through binding to specific G-protein coupled GIP receptors located on pancreatic beta-cells (Wheeler, M. B. et al., 1995, Endocrinology 136:4629-4639).
  • GIP has been shown to stimulate ⁇ -cell proliferation synergistically with glucose in the islet INS-1 cell line, in association with induction of MAPK and Pl 3-kinase.
  • GIP exerts anti-apoptotic actions in studies using INS-1 ⁇ -cells.
  • GLP-1 glucagon-like peptide-1
  • the ability to stimulate insulin secretion plus other potentially beneficial actions on pancreatic beta-cell growth and differentiation have led to much interest in using GLP-1 or GIP and analogs thereof for the treatment of type 2 diabetes.
  • GLP-1 nor GIP appear suitable for therapeutic use in chronic disorders, such as Type 2 diabetes because GLP-1 and GIP are rapidly cleared from blood circulation (half life of about 1.5 min.) by the ubiquitous enzyme dipeptidyl peptidase-IV (DPP-IV). Exogenously administered GLP-1 is also rapidly degraded. This metabolic instability limits the therapeutic potential of native GLP-1 and GIP.
  • DPP-IV ubiquitous enzyme dipeptidyl peptidase-IV
  • Ex-4 As an analog of GLP-1 , Ex-4 was first isolated from the salivary secretions of a South American lizard known as the GiIa monster (Heloderma suspectum). Ex-4 consists 39-amino acids with 53% structural homology to mammalian GLP-1. Ex-4 is capable of binding to both human and rat GLP-1 receptors and shows similar pharmacological and biological properties of GLP-1. As a more potent agent than GLP-1 , Ex-4 is strongly capable of increasing ⁇ -cell mass by enhancing both cell replication and neogenesis, and by inhibiting the apoptosis of ⁇ -cells.
  • Ex-4 differs from GLP-1 : (i) Ex-4 is resistant to DPP-IV cleavage, resulting in a long-lasting biological function that is potentially suitable for therapeutic use; (ii) Ex-4 has greater insulinotropic efficacy; and (iii) although both GLP-1 and Ex-4 have similar effects to augment insulin-stimulated glucose uptake and metabolism in skeletal muscle, Ex-4 also increases glucose uptake in adipocytes. Ex-4 may also use different signaling pathways, possibly through a receptor other than the GLP-1 receptor. This may render Ex-4 more effective in reducing blood glucose by simultaneously stimulating ⁇ -cell insulin secretion and increasing glucose utilization in both skeletal muscle and fat tissue.
  • Ex-4 has also been studied for treatment of Type 2 diabetes, as an additive to existing treatments (such as metformin and/or sulfonylurea) to control hyperglycemia in Type 2 diabetic patients.
  • An injectable synthetic form of Ex-4 (Byetta® (exenatide) sold by Amylin Pharmaceuticals, Inc.) has been recently approved for use in treating Type 2 diabetes as an adjunctive therapy to improve blood sugar control.
  • ALS anti-lymphocyte serum
  • NOD Non-Obese Diabetic mice.
  • ALS is a potent immunosuppressant that causes general dysfunction in all types of lymphocytes. Long-term use of ALS has been known to lead to the risk of tumorigenesis and other severe infectious diseases due to general immune deficiency. Therefore, ALS and other immunosuppressant drugs have not been shown to be clinically useful in treating diabetes.
  • a biological/immune response modifier e.g., small molecule, antibody, peptide or gene therapy reagent
  • an anti-inflammatory agent e.g., small molecule, antibody, peptide or gene therapy reagent
  • LSF Lisofylline
  • any compound or agent e.g., small molecule or peptide
  • Ex-4, Byetta® any compound or agent that facilitates growth and/or differentiation of pancreatic ⁇ -cells or any insulin producing cell
  • the present invention provides for the use of compounds or agents that can block cytokine signaling or formation and thereby prevent autoimmune damage to regenerated/emerging new insulin producing cells.
  • ⁇ -cell differentiation and/or growth promoting agents will not be clinically effective because simultaneous regeneration of ⁇ -cells and prevention of autoimmune reactions would not be realized. This result is wholly unexpected.
  • the present invention provides a method for the prevention and treatment (including reversal and cure) of mammals (including humans and animals) suffering from diseases or conditions caused by, or associated with, diabetes mellitus (Type 1 , LADA and Type 2), hyperglycemia, dyslipidemia, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, hyperinsulinemia, diabetic complications, glucose intolerance, obesity or the like.
  • diabetes mellitus Type 1 , LADA and Type 2
  • hyperglycemia dyslipidemia
  • hyperlipidemia hyperlipidemia
  • hypercholesterolemia hypertriglyceridemia
  • hyperinsulinemia diabetic complications
  • glucose intolerance obesity or the like.
  • the method of the present invention comprises administering to a mammal, e.g., a human patient or animal, a preventative- or therapeutically-effective amount of a pharmaceutical composition
  • a pharmaceutical composition comprising, in admixture with a pharmaceutically acceptable carrier, diluent, excipient, adjuvant or vehicle: (1 ) a biological/immune response modifier (immunomodulating) or anti-inflammatory agent (e.g., small molecule, antibody, peptide or gene therapy reagent) that effectively blocks autoimmune response in a mammal by inhibiting the activity or expression of inflammatory cytokines such as, for example, IL-12, IL-23 or IL-27, or STAT-4 and (2) any compound or agent (small molecule or peptide) that facilitates growth and/or differentiation of pancreatic ⁇ -cells or any insulin producing cell, either alone or in admixture with a diluent or in the form of a medicament.
  • a biological/immune response modifier
  • a pharmaceutical composition useful in the treatment of Type I diabetes, LADA, and Type 2 diabetes which comprises (1) a therapeutically-effective amount of a biological/immune response modifier or anti-inflammatory agent and (2) a therapeutically-effective amount any compound or agent (small molecule or peptide) that facilitates growth and/or differentiation of pancreatic ⁇ -cells or any insulin producing cell, as described herein, in admixture with a pharmaceutically acceptable carrier, diluent, excipient, adjuvant or vehicle.
  • IL-12 overproduction or inhibiting the production of cytokines such as IL-23 and IL-27 which promote STAT-4 activation and autoimmune disorders such as Type 1 diabetes and LADA development is believed to be a viable approach.
  • cytokines such as IL-6, IL-1 , beta interferon gamma, TNF- ⁇ , etc. and the resultant excessive Th1 type responses can be suppressed by modulating IL-12, IL-23 and/or IL-27 production.
  • compounds e.g., small molecule, antibody, peptide or gene therapy reagent
  • down-regulate IL-12, IL-23 and/or IL-27 production can be used as biological response modifiers (immunomodulating agents) that block or inhibit inflammatory responses, inactivate STAT-4, reduce the gene expression of DPP-IV or otherwise increase the endogenous stability and levels of incretin hormones, such as GLP-1 , without the deleterious side effects experienced with immunosuppressants.
  • Preferred biological/immune response modifying (immunomodulating) or anti-inflammatory compounds or agents include, without limitation, members of the group consisting of: Lisofylline (LSF) and the LSF analogs described in WO/00/61583 (corresponding to U.S. Patent No. 6,774,130 (the entire disclosure of which is incorporated herein by reference) or any other small molecule or peptide or method capable of blocking interleukin 12, interleukin 23 or activation and/or expression of STAT-4, as further described below.
  • LSF Lisofylline
  • WO/00/61583 corresponding to U.S. Patent No. 6,774,130 (the entire disclosure of which is incorporated herein by reference) or any other small molecule or peptide or method capable of blocking interleukin 12, interleukin 23 or activation and/or expression of STAT-4, as further described below.
  • LSF (1-(5-R-hydroxyhexyl)-3,7-dimethylxanthine) is a synthetic, modified xanthine based compound have the following structural formula:
  • LSF and the LSF analogs described below exhibit anti-inflammatory function by reducing inflammatory cytokine production or downstream effects (including, without limitation, IL-12, IL-23, IL- 27, TNF- ⁇ , IFN- ⁇ , IL-6 and IL-1 ⁇ ), selectively suppressing neutrophil and leukocyte adhesion and phagocytic activity, and decreasing neutrophil migration and degranulation during sepsis. More significantly, LSF allows retention of beta-cell insulin secretory function after inflammatory cytokine insult and regulates immune cellular function to prevent autoimmunity.
  • LSF also exhibits the ability to ameliorate hemorrhage-induced tissue injury and to preserve tissue function during decreased blood flow or in poorly ventilated conditions. LSF also inhibits phosphatidic acid formation to prevent oxidant-mediated capillary leak, thus reducing capillary barrier damage caused by oxidative stress. All of these characteristics render LSF and the LSF analogs described below capable of improving biological function and reducing autoimmune damage in ⁇ -cells. LSF is also useful as monotherapy for the treatment of Type 2 diabetes and its associated complications due to an ability to enhance the in vivo action of GLP-1.
  • LSF is useful in conjunction with any compound or agent (small molecule, peptide, etc.) that facilitates growth and/or differentiation of pancreatic ⁇ -cells or any insulin producing cell, in accordance with the features of the present invention.
  • immunosuppressant therapy including ALS
  • LSF and its analogs represent a new class of immunomodulatory compounds that are capable of regulating cellular functions but retain host immune competence. Combining the effectiveness of ⁇ -cell regeneration by Ex-4 and autoimmune prevention by LSF may protect regenerated ⁇ -cells from autoimmune destruction while maintaining patient immunological competency.
  • compositions useful in the present invention may conveniently be provided, or is otherwise envisioned in the form of formulations suitable for parenteral (including intravenous, intramuscular and subcutaneous) nasal, oral administration or pulmonary via a inhalation device.
  • parenteral including intravenous, intramuscular and subcutaneous
  • a biological/immune response modifier or anti-inflammatory agent as described herein, and any compound or agent (small molecule or peptide) that facilitates growth and/or differentiation of pancreatic ⁇ -cells or any insulin producing cell, each in a single composition or solution for administration together.
  • a suitable administration format may best be determined by a medical practitioner for each patient individually.
  • Suitable pharmaceutically acceptable carriers and their formulation are described in standard formulation treatises, e.g., Remington's Pharmaceutial Sciences by E. W. Martin. See also Wang, Y. J. and Hanson, M. A. "Parenteral Formulations of Proteins and Peptides: Stability and Stabilizers," Journal of Parenteral Science and Technology, Technical Report No. 10, Supp. 42:2S (1998).
  • Preferred compounds or agents that may be used in accordance with the principles of the present invention for inducing pancreatic ⁇ -cell or insulin producing cell growth and/or differentiation include, but are not limited to, members of the group consisting of: glucagon-like peptide-1 (GLP-1 ) and long-acting, DPP-IV-resistant GLP-1 analogs thereof, GLP-1 receptor agonists, gastric inhibitory polypeptide (GIP) and analogs thereof (e.g., which are disclosed in U.S. Patent Publication No.
  • DPP-IV dipeptidyl peptidase IV
  • insulin preparations insulin derivatives, insulin-like agonists, insulin secretagogues, insulin sensitizers, biguanides, gluconeogenesis inhibitors, sugar absorption inhibitors, renal glucose re-uptake inhibitors, ⁇ 3 adrenergic receptor agonists, aldose reductase inhibitors, advanced glycation end products production inhibitors, glycogen synthase kinase-3 inhibitors, glycogen phosphorylase inhibitors, antilipemic agents, anorexic agents, lipase inhibitors, antihypertensive agents, peripheral circulation improving agents, antioxidants, diabetic neuropathy therapeutic agents, and the like.
  • DPP-IV dipeptidyl peptidase IV
  • the present invention provides use of the pharmaceutical compositions and agents described herein in conjunction with (1 ) methods for restoring ⁇ -cell mass and function in an individual in need thereof; (2) methods for preventing the development of, or reversing, Type 1 diabetes in an individual in need thereof; (3) methods for preventing the development of, or reversing, latent autoimmune diabetes of adults (LADA) in an individual in need thereof; and (4) methods for treating Type 2 diabetes by increasing the number of functional insulin producing cells (e.g., ⁇ -cells) in an individual in need thereof.
  • LADA latent autoimmune diabetes of adults
  • the above compounds and agents used in the pharmaceutical composition of the present invention may be purchased from conventional sources, may be readily isolated from and purified (isolated) from natural sources or may be synthesized using conventional techniques known to the skilled artisan using readily available starting materials.
  • FIGURE 1 depicts the amount of insulin in the supernate sample as determined by EIA after one-hour incubation with each of 3 mM and subsequent 28 mM glucose medium.
  • FIGURE 2 depicts the effect in apoptosis reduction in isolated mouse islets after individual and combined treatment of LSF and Ex-4 in vitro.
  • FIGURE 3 depicts the effect of mitochondrial metabolism (as reflected by level of MTT metabolite) observed in isolated mouse islets after individual and combined treatment with LSF and Ex-4.
  • FIGURE 4 depicts average levels of blood glucose in 4 NOD mice groups treated with saline (control), Ex-4 alone, LSF alone and LSF and Ex-4 combined, respectively.
  • FIGURE 5 depicts immunochemistry of insulin in NOD mouse pancreatic sections untreated and treated with LSF and Ex-4.
  • FIGURE 6 depicts results of Brdu staining of NOD mouse pancreatic sections treated with saline (control), Ex-4 alone, LSF alone and LSF and Ex-4 combined, respectively.
  • compositions and methods of the present invention comprise the combined use of: (1) a biological/immune response modifier or anti-inflammatory agent (e.g., small molecule, antibody, peptide or gene therapy reagent) that effectively blocks comprising a biological response modifier and a ⁇ -cell growth factor in admixture with a pharmaceutically acceptable carrier, adjuvant or vehicle, wherein the pharmaceutical composition blocks or prevents the autoimmune response in a mammal by inhibiting the activity or expression of cytokines such as interleukins 12, 23 or 27, or members of the family of Signal Transducers and Activators of Transcription (STAT), preferably STAT-4, which are believed to be regulators of T cell differentiation involved in immune responses, and (2) any compound or agent (small molecule or peptide) that induces growth and/or differentiation of pancreatic ⁇ -cells or any insulin producing cell.
  • a biological/immune response modifier or anti-inflammatory agent e.g., small molecule, antibody, peptide or gene therapy reagent
  • STAT Signal
  • Preferred agents that could be used to induce pancreatic ⁇ -cell or insulin producing cell growth and/or differentiation include, but are not limited to, one or more members of the group consisting of: • glucagon-like peptide 1 (GLP-1 );
  • inhibitors of GLP-1 degradation (a.k.a., DPP-IV inhibitors), which may be orally administered drugs that improve glycemic control by preventing DPP-IV degradation of GLP-1 and GIP and increasing incretin hormone levels to restore beta cell mass or function , including, without limitation, members of the group consisting of Sitagliptin (a.k.a. MK-0431 , Merck), Vildagliptin (a.k.a. LAF-237) and NVP DPP728 (both of Novartis), Saxagliptin (Bristol Myers Squibb), P32/98 (Probiodrug) and FE 999011 (a.k.a.
  • GIP gastric inhibitory polypeptide
  • peptides such as gastrin and/or epidermal growth factor 1 , including islet neogenesis therapy (Transition Therapeutics),
  • PTHrP Parathyroid hormone related peptide
  • Hepatocyte growth factor or islet neogenesis associated protein INGAP
  • ⁇ -cell differentiation or growth include, without limitation, providing one or any combination of transcription factors shown to be important for insulin gene transcription or ⁇ -cell growth or development, including, without limitation, members of the group consisting of Neurogen 3, PDX-1 , NKX6.1 and the like.
  • HDAC histone deacetylose inhibitors
  • NVP-LAQ824 TrichostatinA-O
  • hydroxamate hydroxamate
  • suberanihohydroxamic or cyclic tetrapeptides apicidin and trapoxin
  • synthetic inhibitors including CG1521 and others, scriptide and analogs.
  • HDAC inhibitors include: oxamflatin, pyroxamide, propenamides, chlamydocin, diheteropeptin, WF-3136, CyM and Cyl-2, FR 901228, cyclic-hydroxamic-acid-containing peptides, MS-275, CI-994 and depudecin.
  • preferred agents that induce pancreatic ⁇ -cell or insulin producing cell growth and/or differentiation include, but are not limited to, amino-terminal extended forms of GLP-1 selected from the group consisting of: (a) glucagon-like peptide 1(7-37); (b) glucagon-like peptide 1(7-36) amide; and (c) an effective fragment or analog of (a) or (b) (each of which are described in U.S. Pat. No. 6,899,883 and U.S. Pat. No. 6,989,148).
  • the present invention involves the use of inventive pharmaceutical composition comprising an autoimmune blocker and a ⁇ -cell growth or differentiating agent to create or grow insulin producing cells in a test tube to be transplanted in patients by any acceptable procedure to prevent, treat or reverse Type 1 diabetes or Type 2 diabetes.
  • inventive pharmaceutical composition comprising an autoimmune blocker and a ⁇ -cell growth or differentiating agent to create or grow insulin producing cells in a test tube to be transplanted in patients by any acceptable procedure to prevent, treat or reverse Type 1 diabetes or Type 2 diabetes.
  • this combined therapeutic approach can be given to a human to restore beta (insulin producing) cells in the body to prevent, treat or reverse Type 1 diabetes, LADA or Type 2 diabetes.
  • the present invention provides a method for improving the outcome or success of cellular (islet cell, isolated ⁇ -cells, genetically engineered or induced (e.g., via transcription factors) ⁇ -cells) transplantation in a mammal to reverse Type 1 diabetes, LADA and Type 2 diabetes, comprising administering to the mammal (or cells to be transplanted) an effective amount of a pharmaceutical composition of the present invention.
  • Preferred LSF analogs include, without limitation, compounds, pharmaceutically acceptable derivatives (e.g., racemic mixtures, resolved enantiomers, diastereomers, tautomers, salts and solvates thereof) or prodrugs thereof, having the following Formula I:
  • X, Y and Z are independently selected from a member of the group consisting of C(R3), N, N(R3) and S;
  • R1 is selected from a member of the group consisting of hydrogen, methyl, a substituted alkyl (as defined herein, which includes without limitation substituted C(5-9)alkyl), C(5-9)alkenyl, C(5-9)alkynyl, C(5-9)hydroxyalkyl, C(3-8)alkoxyl, C(5-9)alkoxyalkyl; and
  • R2 and R3 are independently selected from a member of the group consisting of hydrogen, halo, oxo, C(1-20)alkyl, C(1-20)hydroxyalkyl, C(1-20)thioalkyl, C(1-20)alkylamino, C(1-20)alkylaminoalkyl, C(1-20)aminoalkyl, C(1-20)aminoalkoxyalkenyl, C(1-20)aminoalkoxyalkynyl, C(1-20)diaminoalkyl, C(1-20)triaminoalkyl,
  • R1 is optionally substituted with a member selected from the group consisting of N-OH, acylamino, cyano (e.g., NC-), cyanamido (e.g., NCNH-), cyanato (e.g., NCO-), sulfo, sulfonyl, sulfinyl, sulfhydryl (mercapto), sulfeno, sulfanilyl, sulfamyl, sulfamino, and phosphino, phosphinyl, phospho, phosphono and -NRaRb , wherein each of Ra and Rb may be the same or different and each is independently selected from the group consisting of hydrogen, optionally substituted alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl and heterocyclic group.
  • Each R2 and R3 is optionally substituted with one or more members of the group consisting of hydroxyl, methyl, carboxyl, furyl, furfuryl, biotinyl, phenyl, naphthyl, amino group, amido group, carbamoyl group, cyano (e.g., NC-), cyanamido (e.g., NCNH-), cyanato (e.g., NCO-), sulfo, sulfonyl, sulfinyl, sulfhydryl (mercapto), sulfeno, sulfanilyl, sulfamyl, sulfamino, phosphino, phosphinyl, phospho, phosphono, N-OH, -Si(CH3)3 (a.k.a.
  • SiMe3 C(1-3)alkyl, C(1 -3)hydroxyalkyl, C(1 -3)thioalkyl, C(1-3)alkylamino, benzyldihydrocinnamoyl group, benzoyldihydrocinnamido group, heterocyclic group and carbocyclic group.
  • the heterocyclic group or carbocyclic group is optionally substituted with one or more members of the group consisting of halo, hydroxyl, nitro (e.g., -NO2), SO2NH2, C(1-6)alkyl, C(1-6)haloalkyl, C(1-8)alkoxyl, C(1-11 )alkoxyalkyl, C(1-6)alkylamino, and C(1 -6)aminoalkyl.
  • both X and Y are not N(R3) when Z is C(R3) and R3 is H or C(1-3)alkyl.
  • R1 is not an ⁇ -1 secondary alcohol substituted C(5-8) alkyl when both X and Y are N(R3), Z is C(R3) and R3 is H or C(1-3) alkyl.
  • R1 is an ⁇ -1 secondary alcohol substituted C(5-8) alkyl when both X and Y are N(R3), Z is C(R3) and R3 is H or C(1 -3) alkyi.
  • LSF analog compounds include the following compounds, pharmaceutically acceptable derivatives (e.g., racemic mixtures, resolved enantiomers, diastereomers, tautomers, salts and solvates thereof) or prodrugs thereof, having the following Formula II:
  • R 4 , R 5 and R 6 are independently selected from a member of the group consisting of hydrogen, halo, oxo, C (1 . 2 o ) alkyl, C (1 . 2 o ) hydroxyalkyl, C (1 . 2 o ) thioalkyl, C(i-20)alkylamino, C (1 . 20) alkylaminoalkyl, C (1 . 20) aminoalkyl, C ( i_ 2 o ) aminoalkoxyalkenyl, C(i_20)aminoalkoxyalkynyl, C(i. 20 )diaminoalkyl, C ( i.
  • Each R4, R5 and R6 is optionally substituted with one or more members of the group consisting of hydroxyl, methyl, carboxyl, furyl, furfuryl, biotinyl, phenyl, naphthyl, amino group, amido group, carbamoyl group, cyano (e.g., NC-), cyanamido (e.g., NCNH- ), cyanato (e.g., NCO-), sulfo, sulfonyl, sulfinyl, sulfhydryl (mercapto), sulfeno, sulfanilyl, sulfamyl, sulfamino, phosphino, phosphinyl, phospho, phosphono, N-OH, -Si(CH3)3, C(1-3)alkyl, C(1-3)hydroxyalkyl, C(1-3)thioalkyl, C(1-3)alkylamino,
  • the heterocyclic group or carbocyclic group is optionally substituted with one or more members of the group consisting of halo, hydroxyl, nitro (e.g., -NO2), SO2NH2, C(1-6) alkyl, C(1-6)haloalkyl, C(1-8)alkoxyl, C(1-11 )alkoxyalkyl, C(1-6)alkylamino, and C(1-6) aminoalkyl.
  • each R4, R5 and R6 are not simultaneously methyl.
  • both R4 and R5 are not methyl when R6 is H.
  • R6 is not methyl when R4 is methylfuryl and R5 is H.
  • R6 is not propyl or isopropyl when R4 is methyl and R5 is H.
  • R4 is not acetamidohexyl when R5 is methyl and R6 is H.
  • R2, and R3 groups of Formula I and R4, R5 and R6 groups of Formula Il include, without limitation, members selected from the group consisting of 1-adamantanemethyl, 1-phenylcyclopropyl, 1-phenylproply, 1-propenyl, 2-bromopropyl, 2-buten-2-yl, 2-butyl, 2-cyclohexylethyl, 2-cyclopentylethyl, 2-furyl, 2-hydroxyethyl, 2-hydroxystyryl, 2-methoxyethyl, 2-methoxystyryl, 2-methylbutyl, 2-methylcyclopropyl, 2-norboranemethyl, 2-phenylpropyl, 2-propenyl, 2-propyl, 2-thienyl, 2-trifluoromethylstyryl, 3,4,5-triethoxyphenyl, 3,4,5-trimethoxyphenyl, 3,4-dichlorobenzyl, 3,4-dichlorophenyl, 3,3
  • R2, R3, R4, R5 and R6 groups include, without limitation, members selected from the group consisting of methyl, ethyl, oxo, isopropyl, n-propyl, isobutyl, n-butyl, t-butyl, 2-hydroxyethyl, 3-hydroxypropyl, 3-hydroxy-n-butyl, 2methoxyethyl, 4-methoxy-n-butyl, 5-hydroxyhexyl, 2-bromopropyl, 3-dimethylaminobutyl, 4-chloropentyl, methylamino, aminomethyl, methylphenyl, and the like.
  • the LSF compounds, LSF analogs, salts, solvates and prodrugs thereof may exist in their tautomeric form (for example, as an amide or imino ether). All such tautomeric forms are contemplated herein as part of the present invention.
  • stereoisomers for example, geometric isomers, optical isomers and the like
  • the present compounds including those of the salts, solvates and prodrugs of the compounds as well as the salts and solvates of the prodrugs
  • those which may exist due to asymmetric carbons on various substituents including enantiomeric forms (which may exist even in the absence of asymmetric carbons), rotameric forms, atropisomers, and diastereomehc forms, are contemplated within the scope of this invention, as are positional isomers (such as, for example, 4-pyridyl and 3-pyridyl).
  • stereoisomers of the compounds described herein as suitable for use in the present invention may, for example, be substantially free of other isomers, or may be admixed, for example, as racemates or with all other, or other selected, stereoisomers.
  • the chiral centers of the present invention can have the S or R configuration as defined by the IUPAC 1974 Recommendations.
  • the use of the terms "salt”, “solvate” "prodrug” and the like, is intended to equally apply to the salt, solvate and prodrug of enantiomers, stereoisomers, rotamers, tautomers, positional isomers, racemates or prodrugs of compounds disclosed herein.
  • the LSF analogs described herein may contain one or more asymmetrically substituted carbon atoms and, thus, may occur as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers.
  • Each stereogenic carbon may be of the R or S configuration.
  • Many geometric isomers of olefins, C-N double bonds, and the like can also be present in the compounds described herein, and all such stable isomers are contemplated in the present invention. It is well known in the art how to prepare optically active forms, such as by resolution of racemic forms or by synthesis from optically active starting materials. All chiral, diastereomeric, racemic forms and all geometric forms of a structure are intended to be encompassed within the present invention unless a specific stereochemistry or isomer form is specifically indicated.
  • the compounds of the present invention may be modified by appending appropriate functionalites to enhance selective biological properties.
  • modifications are known in the art and include, without limitation, those which increase penetration into a given biological compartment (e.g., blood, lymphatic system, central nervous system), increase oral or intravenous bioavailability, increase solubility to allow administration by injection, alter metabolism, alter rate of excretion, etc.
  • Steps or “Optical isomer” mean a stable isomer that has at least one chiral atom or restricted rotation giving rise to perpendicular dissymmetric planes (e.g., certain biphenyls, allenes, and spiro compounds) and can rotate plane-polarized light. Because asymmetric centers and other chemical structure exist in the compounds described herein as suitable for use in the present invention which may give rise to stereoisomerism, the invention contemplates stereoisomers and mixtures thereof.
  • the compounds described herein and their salts include asymmetric carbon atoms and may therefore exist as single stereoisomers, racemates, and as mixtures of enantiomers and diastereomers.
  • such compounds will be prepared as a racemic mixture. If desired, however, such compounds can be prepared or isolated as pure stereoisomers, i.e., as individual enantiomers or diastereomers, or as stereoisomer-enriched mixtures. As discussed in more detail below, individual stereoisomers of compounds are prepared by synthesis from optically active starting materials containing the desired chiral centers or by preparation of mixtures of enantiomeric products followed by separation or resolution, such as conversion to a mixture of diastereomers followed by separation or recrystallization, chromatographic techniques, use of chiral resolving agents, or direct separation of the enantiomers on chiral chromatographic columns. Starting compounds of particular stereochemistry are either commercially available or are made by the methods described below and resolved by techniques well-known in the art.
  • Enantiomers means a pair of stereoisomers that are non-superimposable mirror images of each other.
  • Diastereoisomers or “Diastereomers” mean optical isomers which are not mirror images of each other.
  • Non-Racemic Mixture means a mixture containing unequal parts of individual enantiomers.
  • “Stable compound”, as used herein, is a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent, i.e., possesses stability that is sufficient to allow manufacture and that maintains the integrity of the compound for a sufficient period of time to be useful for the purposes detailed herein (e.g., therapeutic or prophylactic administration to a mammal or for use in affinity chromatography applications).
  • such compounds are stable at a temperature of 40° C or less, in the absence of moisture or other chemically reactive conditions, for at least a week.
  • “Metabolically stable compound” denotes a compound that remains bioavailable when orally ingested by a mammal.
  • the substituent is piperazinyl, piperidinyl, or tetrazolyl
  • said piperazinyl, piperidinyl, tetrazolyl group may be bonded to the rest of the compound of Formula I or II, as well as the R2, R3, R4, R5 and R6 groups substituted thereon, via any atom in such piperazinyl, piperidinyl, tetrazolyl group.
  • Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
  • the substituents may be either the same or different at every position.
  • 0-15 substitutions are preferred, 0-5 substitutions are more preferred, and 0-1 substitution is most preferred.
  • Optional or “optionally” means that the subsequently described event or circumstance may or may not occur, and that the description includes, without limitation, instances where said event or circumstance occurs and instances in which it does not.
  • optionally substituted alkyl means that alkyl may or may not be substituted by those groups enumerated in the definition of substituted alkyl.
  • Acyl denotes a radical provided by the residue after removal of hydroxyl from an organic acid.
  • acyl radicals include, without limitation, alkanoyl and aroyl radicals.
  • lower alkanoyl radicals include, without limitation, formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, trifluoroacetyl.
  • Acylamino denotes an N-substituted amide, i.e., RC(O)-NH and RC(O)-NR'-.
  • a non-limiting example is acetamido.
  • Acyloxy means 1 to about 4 carbon atoms. Preferred examples include, without limitation, alkanoyloxy, benzoyloxy and the like.
  • alkyl or “lower alkyl” is intended to include both branched and straight-chain saturated aliphatic hydrocarbon radicals/groups having the specified number of carbon atoms.
  • alkyl refers to a monoradical branched or unbranched saturated hydrocarbon chain, preferably having from 1 to 40 carbon atoms, more preferably 1 to 10 carbon atoms, even more preferably 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, secondary butyl, tert-butyl, n-hexyl, n-octyl, n-decyl, n-dodecyl, 2-ethyldodecyl, tetradecyl, and the like, unless otherwise indicated.
  • Substituted alkyl refers to an alkyl group as defined above having from 1 to 5 substituents selected, without limitation, from the group consisting of alkoxyl, substituted alkoxyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxyl, aminoacyl, aminoacyloxyl, oxyaminoacyl, azido, cyano, halogen, hydroxyl, keto, thioketo, carboxyl, carboxylalkyl, thioaryloxyl, thioheteroaryloxyl, thioheterocyclooxyl, thiol, thioalkoxyl, substituted thioalkoxyl, aryl, aryloxyl, heteroaryl, heteroaryloxyl, heterocyclic, heterocyclooxyl, hydroxyamino, alkoxyamino,
  • Alkylamino denotes amino groups which have been substituted with one or two alkyl radicals. Preferred are “lower N-alkylamino” radicals having alkyl portions having 1 to 6 carbon atoms. Preferred lower alkylamino may be mono or dialkylamino such as N-methylamino, N-ethylamino, N,N-dimethylamino, N,N-diethylamino or the like.
  • Alkylaminoalkyl embraces radicals having one or more alkyl radicals attached to an aminoalkyl radical.
  • Alkylaminocarbonyl denotes an aminocarbonyl group which has been substituted with one or two alkyl radicals on the amino nitrogen atom. Preferred are “N-alkylaminocarbonyl” “N,N-dialkylaminocarbonyl” radicals. More preferred are “lower N-alkylaminocarbonyl” “lower N,N-dialkylaminocarbonyl” radicals with lower alkyl portions as defined above.
  • Alkylcarbonyl examples include radicals having alkyl, aryl and aralkyl radicals, as defined above, attached via an oxygen atom to a carbonyl radical.
  • examples of such radicals include, without limitation, substituted or unsubstituted methylcarbonyl, ethylcarbonyl, phenylcarbonyl and benzylcarbonyl.
  • Alkylsulfonyl embraces alkyl radicals attached to a sulfonyl radical, where alkyl is defined as above. More preferred alkylsulfonyl radicals are "lower alkylsulfonyl” radicals having one to six carbon atoms. Examples of such lower alkylsulfonyl radicals include, without limitation, methylsulfonyl, ethylsulonyl and propylsulfonyl. The "alkylsulfonyl” radicals may be further substituted with one or more halo atoms, such as fluoro, chloro or bromo, to provide haloalkylsulfonyl radicals.
  • halo atoms such as fluoro, chloro or bromo
  • Alkylthio embraces radicals containing a linear or branched alkyl radical, of one to about ten carbon atoms attached to a divalent sulfur atom. More preferred alkylthio radicals are "lower alkylthio" radicals having alkyl radicals of one to six carbon atoms. Examples of such lower alkylthio radicals are methylthio, ethylthio, propylthio, butylthio and hexylthio.
  • Alkylthioalkyl embraces radicals containing an alkylthio radical attached through the divalent sulfur atom to an alkyl radical of one to about ten carbon atoms. More preferred alkylthioalkyl radicals are "lower alkylthioalkyl” radicals having alkyl radicals of one to six carbon atoms. Examples of such lower alkylthioalkyl radicals include, without limitation, methylthiomethyl.
  • Alkylene refers to a diradical of a branched or unbranched saturated hydrocarbon chain, preferably having from 1 to 40 carbon atoms, more preferably 1 to 10 carbon atoms, even more preferably 1 to 6 carbon atoms. This term is exemplified by groups such as methylene (-CH2-), ethylene (-CH2CH2-), the propylene isomers (e.g,- CH2CH2CH2- and -CH(CH3)CH2-), and the like.
  • Substituted alkylene refers to: (1 ) an alkylene group as defined above having from 1 to 5 substituents selected from a member of the group consisting of alkoxyl, substituted alkoxyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxyl, aminoacyl, aminoacyloxyl, oxyacylamino, azido, cyano, halogen, hydroxyl, keto, thioketo, carboxyl, carboxylalkyl, thiol, thioalkoxyl, substituted thioalkoxyl, aryl, aryloxyl, thioaryloxyl, heteroaryl, heteroaryloxyl, thioheteroaryloxyl, heterocyclic, heterocyclooxyl, thioheterocyclooxyl, nitro, and -NRaRb
  • substituted alkylene groups include, without limitation, those where 2 substituents on the alkylene group are fused to form one or more cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, heterocyclic or heteroaryl groups fused to the alkylene group; (2) an alkylene group as defined above that is interrupted by 1-20 atoms independently chosen from oxygen, sulfur and NRa, where Ra is chosen from hydrogen, optionally substituted alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl and heterocyclic, or groups selected from carbonyl, carboxyester, carboxyamide and sulfonyl; or (3) an alkylene group as defined above that has both from 1 to 5 substituents as defined above and is also interrupted by 1 to 20 atoms as defined above.
  • substituted alkylenes are chloromethylene (-CH(CI)-), aminoethylene (- CH(NH2)CH2-), 2-carboxypropylene isomers (-CH2CH(CO2H)CH2-), ethoxyethyl (- CH2CH2O-CH2CH2-), ethylmethylaminoethyl (-CH2CH2N(CH3)CH2CH2-),
  • alkynyl is intended to include hydrocarbon chains of either a straight or branched configuration and one or more triple carbon-carbon bonds which may occur in any stable point along the chain, such as ethynyl, propynyl and the like.
  • alkynyl refers to an unsaturated acyclic hydrocarbon radical in so much as it contains one or more triple bonds, such radicals containing about 2 to about 40 carbon atoms, preferably having from about 2 to about 10 carbon atoms and more preferably having 2 to about 6 carbon atoms.
  • Non-limiting examples of preferred alkynyl radicals include, ethynyl, propynyl, butyn-1-yl, butyn-2-yl, pentyn-1-yl, pentyn-2-yl, 3-methylbutyn-1-yl, hexyn-1-yl, hexyn-2-yl, hexyn-3-yl, 3,3-dimethylbutyn-1-yl radicals and the like.
  • Alicyclic hydrocarbon means a aliphatic radical in a ring with 3 to about 10 carbon atoms, and preferably from 3 to about 6 carbon atoms.
  • preferred alicyclic radicals include, without limitation, cyclopropyl, cyclopropylenyl, cyclobutyl, cyclopentyl, cyclohexyl, 2-cyclohexen-1-ylenyl, cyclohexenyl and the like.
  • Alkoxyalkyl embraces alkyl radicals having one or more alkoxy radicals attached to the alkyl radical, that is, to form monoalkoxyalkyl and dialkoxyalkyl radicals.
  • the "alkoxy” radicals may be further substituted with one or more halo atoms, such as fluoro, chloro or bromo, to provide haloalkoxy radicals.
  • More preferred haloalkoxy radicals are "lower haloalkoxy" radicals having one to six carbon atoms and one or more halo radicals.
  • alkoxycarbonyl means a radical containing an alkoxy radical, as defined above, attached via an oxygen atom to a carbonyl radical. More preferred are “lower alkoxycarbonyl” radicals with alkyl portions having 1 to 6 carbons. Examples of such lower alkoxycarbonyl (ester) radicals include, without limitation, substituted or unsubstituted methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl and hexyloxycarbonyl.
  • aminoalkyl embraces alkyl radicals substituted with amino radicals. More preferred are “lower aminoalkyl” radicals. Examples of such radicals include, without limitation, aminomethyl, aminoethyl, and the like.
  • Alkoxy embraces aralkyl radicals attached through an oxygen atom to other radicals.
  • Alkoxyalkyl embraces aralkoxy radicals attached through an oxygen atom to an alkyl radical.
  • Aralkyl embraces aryl-substituted alkyl radicals such as benzyl, diphenylmethyl, triphenylmethyl, phenylethyl, and diphenylethyl.
  • the aryl in said aralkyl may be additionally substituted with halo, alkyl, alkoxy, halkoalkyl and haloalkoxy.
  • Alkylamino embraces aralkyl radicals attached through an nitrogen atom to other radicals.
  • Alkylthio embraces aralkyl radicals attached to a sulfur atom.
  • Alkylthioalkyl embraces aralkylthio radicals attached through a sulfur atom to an alkyl radical.
  • Aromatic hydrocarbon radical means 4 to about 16 carbon atoms, preferably 6 to about 12 carbon atoms, more preferably 6 to about 10 carbon atoms.
  • aromatic hydrocarbon radicals include, without limitation, phenyl, naphthyl, and the like.
  • Aroyl embraces aryl radicals with a carbonyl radical as defined above. Examples of aroyl include, without limitation, benzoyl, naphthoyl, and the like and the aryl in said aroyl may be additionally substituted.
  • Arylamino denotes amino groups which have been substituted with one or two aryl radicals, such as N-phenylamino. Arylamino radicals may be further substituted on the aryl ring portion of the radical.
  • Aryloxyalkyl embraces radicals having an aryl radical attached to an alkyl radical through a divalent oxygen atom.
  • Arylthioalkyl embraces radicals having an aryl radical attached to an alkyl radical through a divalent sulfur atom.
  • Carboxy or “carboxyl”, whether used alone or with other terms, such as “carboxyalkyl”, denotes -CO2H.
  • Carboxyalkyl embraces alkyl radicals substituted with a carboxy radical. More preferred are “lower carboxyalkyl” which embrace lower alkyl radicals as defined above, and may be additionally substituted on the alkyl radical with halo. Examples of such lower carboxyalkyl radicals include, without limitation, carboxymethyl, carboxyethyl and carboxypropyl.
  • Cycloalkenyl embraces partially unsaturated carbocyclic radicals having three to twelve carbon atoms. More preferred cycloalkenyl radicals are "lower cycloalkenyl” radicals having four to about eight carbon atoms. Examples of such radicals include, without limitation, cyclobutenyl, cyclopentenyl and cyclohexenyl.
  • Cycloalkyl embraces saturated carbocyclic radicals having three to twelve carbon atoms. More preferred cycloalkyl radicals are "lower cycloalkyl” radicals having three to about eight carbon atoms. Examples of such radicals include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • Hydroxyalkyl embraces linear or branched alkyl radicals having one to about twenty carbon atoms any one of which may be substituted with one or more hydroxyl radicals.
  • Preferred hydroxyalkyl radicals are "lower hydroxyalkyl” radicals having one to six carbon atoms and one or more hydroxyl radicals.
  • Non-limiting examples of such radicals include hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl and hydroxyhexyl.
  • alkenyl is intended to include hydrocarbon chains of either a straight or branched configuration and one or more unsaturated carbon-carbon bonds which may occur in any stable point along the chain.
  • alkenyl refers to an unsaturated acyclic hydrocarbon radical in so much as it contains at least one double bond.
  • Such radicals containing from about 2 to about 40 carbon atoms, preferably from about 2 to about 10 carbon atoms and more preferably about 2 to about 6 carbon atoms.
  • Non-limiting examples of preferred alkenyl radicals include propylenyl, buten-1-yl, isobutenyl, penten-1-yl, 2-2-methylbuten-i-yl, 3-methylbuten-1-yl, hexen-1-yl, hepten-1-yl, and octen-1-yl, and the like
  • Alkoxyl represents an alkyl group of indicated number of carbon atoms attached through an oxygen bridge.
  • Alkoxy and alkyloxy embrace linear or branched oxy-containing radicals each having alkyl portions of one to about ten carbon atoms. More preferred alkoxy radicals are "lower alkoxy” radicals having one to six carbon atoms. Examples of such radicals include, without limitation, methoxy, ethoxy, propoxy, butoxy and tert-butoxy.
  • Aryl refers to an unsaturated aromatic carbocyclic group of from 6 to
  • aryl embraces aromatic radicals such as phenyl, naphthyl, tetrahydronaphthyl, indane and biphenyl.
  • such aryl groups can optionally be substituted with from 1 to 5 substituents selected from a member of the group consisting of acyloxyl, hydroxyl, thiol, acyl, alkyl, alkoxyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkoxyl, substituted alkenyl, substituted alkynyl, substituted cycloalkyl, substituted cycloalkenyl, aminoacyl, acylamino, alkaryl, aryl, aryloxyl, azido, carboxyl, carboxylalkyl, cyano, halo, nitro, heteroaryl, heteroaryloxyl, heterocyclic, heterocyclooxyl, aminoacyloxyl, oxyacylamino, thioalkoxyl, substituted thioalkoxyl, thioaryloxyl
  • N-arylaminoalkyl and "N-aryl-N-alkyl-aminoalkyl” denote amino groups which have been substituted with one aryl radical or one aryl and one alkyl radical, respectively, and having the amino group attached to an alkyl radical.
  • examples of such radicals include, without limitation, N-phenylaminomethyl and
  • Carbocycle or “carbocyclic group” is intended to mean any stable 3 to 7 membered monocyclic or bicyclic or 7 to 14 membered bicyclic or tricyclic or an up to 26 membered polycyclic carbon ring, any of which may be saturated, partially unsaturated, or aromatic.
  • Substituted carbocycle or “substituted carbocyclic group” refers to carbocyclic groups having from 1 to 5 substituents selected from a member of the group consisting of alkoxyl, substituted alkoxyl, cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxyl, amino, aminoacyl, aminoacyloxyl, oxyaminoacyl, azido, cyano, halogen, hydroxyl, keto, thioketo, carboxyl, carboxylalkyl, thioaryloxyl, thioheteroaryloxyl, thioheterocyclooxyl, thiol, thioalkoxyl, substituted thioalkoxyl, aryl, aryloxyl, heteroaryl, heteroaryloxyl, heterocyclic, heterocyclooxyl, hydroxyamino, alkoxya
  • carbocyclic groups include, without limitation, members selected from the group consisting of adamantyl, anthracenyl, benzamidyl, benzyl, bicyclo[2.2.1]heptanyl, bicyclo[2.2.1]hexanyl, bicyclo[2.2.2]octanyl, bicyclo[3.2.0]heptanyl, bicyclo[4.3.0]nonanyl, bicyclo[4.4.0]decanyl, biphenyl, biscyclooctyl, cyclobutanyl (cyclobutyl), cyclobutenyl, cycloheptanyl (cycloheptyl), cycloheptenyl, cyclohexanedionyl, cyclohexenyl, cyclohexyl, cyclooctanyl, cyclopentadienyl, cyclopentanedionyl, cyclopentenyl, cyclopentyl
  • Cycloalkyl is intended to include saturated ring groups, including mono-, bi- or poly-cyclic ring systems, such as, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and adamantyl.
  • “Bicycloalkyl” is intended to include saturated bicyclic ring groups such as, without limitation, [3.3.0]bicyclooctane, [4.3.0]bicyclononane, [4.4.0]bicyclodecane (decalin), [2.2.2]bicyclooctane, and so forth.
  • Halo or "halogen” as used herein refers to fluoro, chloro, bromo and iodo; and "counterion” is used to represent a small, negatively charged species such as chloride, bromide, hydroxide, acetate, sulfate and the like.
  • Haloalkyl is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, substituted with 1 or more halogen.
  • Haloalkyl embraces radicals wherein any one or more of the alkyl carbon atoms is substituted with halo as defined above.
  • monohaloalkyl, dihaloalkyl and polyhaloalkyl radicals may have either an iodo, bromo, chloro or fluoro atom within the radical.
  • Dihalo and polyhaloalkyl radicals may have two or more of the same halo atoms or a combination of different halo radicals.
  • “Lower haloalkyl” embraces radicals having 1-6 carbon atoms.
  • Non-limiting examples of haloalkyl radicals include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl and dichloropropyl.
  • Heterocycle or “heterocyclic group” refers to a saturated or unsaturated group having a single ring, multiple condensed rings or multiple covalently joined rings, from 1 to 40 carbon atoms and from 1 to 10 hetero ring atoms, preferably 1 to 4 hetero ring atoms, selected from nitrogen, sulfur, phosphorus, and/or oxygen.
  • heterocycle or “heterocyclic group” means a stable 5 to 7 membered monocyclic or bicyclic or 7 to 10 membered bicyclic heterocyclic ring that may be saturated, partially unsaturated, or aromatic, and that comprises carbon atoms and from 1 to 4 heteroatoms independently selected from a member of the group consisting of nitrogen, oxygen and sulfur and wherein the nitrogen and sulfur heteroatoms are optionally be oxidized and the nitrogen heteroatom may optionally be quaternized, and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring.
  • heterocyclic groups may be substituted on carbon or on a nitrogen, sulfur, phosphorus, and/or oxygen heteroatom so long as the resulting compound is stable. Unless otherwise constrained by the definition for the heterocyclic substituent, such heterocyclic groups can be optionally substituted with 1 to 5, and preferably 1 to 3 substituents.
  • substituents include members selected from the group consisting of alkoxyl, substituted alkoxyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxyl, aminoacyl, aminoacyloxyl, oxyaminoacyl, cyano, halogen, hydroxyl, keto, thioketo, carboxyl, carboxylalkyl, thioaryloxyl, thioheteroaryloxyl, thioheterocyclooxyl, thiol, thioalkoxyl, substituted thioalkoxyl, aryl, aryloxyl, heteroaryl, heteroaryloxyl, heterocyclic, heterocyclooxyl, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO-substituted alkyl,
  • heterocyclic groups include, without limitation, acridinyl, acridonyl, adeninyl, alkylpyridinyl, alloxanyl, alloxazinyl, anthracenyl, anthranilyl, anthraquinonyl, anthrenyl, ascorbyl, azaazulenyl, azabenzanthracenyl, azabenzanthrenyl, azabenzonaphthenyl, azabenzophenanthrenyl, azachrysenyl, azacyclazinyl, azaindolyl, azanaphthacenyl, azanaphthalenyl, azaphenoxazinyl, azapinyl, azapurinyl, azapyrenyl, azatriphenylenyl, azepinyl, azetidinedionyl, azetidinon
  • Preferred heterocyclic groups include, without limitation, members of the group consisting of acridinyl, aziridinyl, azocinyl, azepinyl, benzimidazolyl, benzodioxolanyl, benzofuranyl, benzothiophenyl, carbazole, 4a H-carbazole, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, dioxoindolyl, furazanyl, furyl, furfuryl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isobenzofuranyl, isochromanyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazo
  • “Pharmaceutically acceptable derivative” or “prodrug” means any pharmaceutically acceptable salt, ester, salt of an ester, or other derivative of a compound of the present invention which, upon administration to a recipient, is capable of providing (directly or indirectly) a compound of this invention.
  • the term "prodrug”, as employed herein, denotes a compound that is a drug precursor which, upon administration to a subject, undergoes chemical conversion by metabolic or chemical processes to yield a pharmaceutically active compound.
  • Particularly favored derivatives and prodrugs are those that increase the bioavailability of the compounds of this invention when such compounds are administered to a mammal (e.g., by allowing an orally administered compound to be more readily absorbed into the blood) or that enhance delivery of the parent compound to a biological compartment (e.g., the brain or lymphatic system) relative to the parent species.
  • Prodrugs are considered to be any covalently bonded carriers which release the active parent drug according to Formula I or Il in vivo when such prodrug is administered to a mammalian subject.
  • Preferred prodrugs include, without limitation, derivatives where a group that enhances aqueous solubility or active transport through the gut membrane is appended to the structure of Formula I or II.
  • Prodrugs of the compounds of Formula I or Il are prepared by modifying functional groups present in the compounds in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compounds.
  • Prodrugs include compounds of Formula I or Il wherein hydroxyl, amino, sulfhydryl, or carboxyl groups are bonded to any group that, when administered to a mammalian subject, cleaves to form a free hydroxyl, amino, sulfhydryl, or carboxyl group, respectively.
  • Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol and amine functional groups in the compounds of Formula I or II, and the like. A discussion of prodrugs is provided in T.
  • Solvate means a physical association of a compound described herein with one or more solvent molecules. This physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding. In certain instances the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid.
  • Solvate encompasses both solution-phase and isolatable solvates. Non-limiting examples of preferred solvates include ethanolates, methanolates, and the like.
  • “Hydrate” is a solvate wherein the solvent molecule is H 2 O.
  • “Pharmaceutically acceptable salts” refer to derivatives of the disclosed compounds wherein the parent compound of Formula I or Il is modified by making acid or base salts of the compound of Formula I or II.
  • pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like.
  • the pharmaceutically acceptable salts of the compounds of Formula I or Il include the conventional nontoxic salts or the quaternary ammonium salts of the compounds of Formula I or Il formed, for example, from nontoxic inorganic or organic acids.
  • such conventional non-toxic salts include, without limitation, those derived from inorganic acids such as acetic, 2-acetoxybenzoic, adipic, alginic, ascorbic, aspartic, benzoic, benzenesulfonic, bisulfic, butyric, citric, camphoric, camphorsulfonic, cyclopentanepropionic, digluconic, dodecylsulfanilic, ethane disulfonic, ethanesulfonilic, fumaric, glucoheptanoic, glutamic, glycerophosphic, glycolic, hemisulfanoic, heptanoic, hexanoic, hydrochloric, hydrobromic, hydroiodic, 2-hydroxyethanesulfonoic, hydroxymaleic, isethionic, lactic, malic, maleic, methanesulfonic, 2-naphthalenesulfonilic, nic
  • the pharmaceutically acceptable salts of the present invention can be synthesized from the compounds of Formula I or Il which contain a basic or acidic moiety by conventional chemical methods, for example, by reacting the free base or acid with stoichiometric amounts of the appropriate base or acid, respectively, in water or in an organic solvent, or in a mixture of the two (nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred) or by reacting the free base or acid with an excess of the desired salt-forming inorganic or organic acid or base in a suitable solvent or various combinations of solvents.
  • suitable salts are found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418, et al., the entire disclosure of which is incorporated herein by reference.
  • exemplary acid addition salts include acetates, ascorbates, benzoates, benzenesulfonates, bisulfates, borates, butyrates, citrates, camphorates, camphorsulfonates, fumarates, hydrochlorides, hydrobromides, hydroiodides, lactates, maleates, methanesulfonates, naphthalenesulfonates, nitrates, oxalates, phosphates, propionates, salicylates, succinates, sulfates, tartarates, thiocyanates, toluenesulfonates (also known as tosylates,) and the like.
  • Exemplary basic salts include ammonium salts, alkali metal salts such as sodium, lithium, and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases (for example, organic amines) such as dicyclohexylamines, t-butyl amines, and salts with amino acids such as arginine, lysine and the like.
  • Basic nitrogen-containing groups may be quarternized with agents such as lower alkyl halides (e.g. methyl, ethyl, and butyl chlorides, bromides and iodides), dialkyl sulfates (e.g.
  • dimethyl, diethyl, and dibutyl sulfates dimethyl, diethyl, and dibutyl sulfates
  • long chain halides e.g. decyl, lauryl, and stearyl chlorides, bromides and iodides
  • aralkyl halides e.g. benzyl and phenethyl bromides
  • “Pharmaceutically effective” or “therapeutically effective” amount of a compound of the present invention is an amount that is sufficient to effect the desired therapeutic, ameliorative, inhibitory or preventative effect, as defined herein, when administered to a mammal in need of such treatment.
  • the amount will vary depending upon the subject and disease condition being treated, the weight and age of the subject, the severity of the disease condition, the manner of administration and the like, which can be readily determined by one of skill in the art.
  • Treatment refers to any treatment of a disease (e.g., diabetes mellitus) or condition in a mammal, particularly a human, and includes, without limitation: (i) preventing the disease or condition from occurring in a subject which may be predisposed to the condition but has not yet been diagnosed with the condition and, accordingly, the treatment constitutes prophylactic treatment for the pathologic condition; (ii) inhibiting the disease or condition, i.e., arresting its development; (iii) relieving the disease or condition, i.e., causing regression of the disease or condition; or (iv) relieving the symptoms resulting from the disease or condition, e.g., relieving an inflammatory response without addressing the underlining disease or condition.
  • a disease e.g., diabetes mellitus
  • condition in a mammal, particularly a human, and includes, without limitation: (i) preventing the disease or condition from occurring in a subject which may be predisposed to the condition but has not yet been diagnosed with the condition and, accordingly, the
  • the present invention also envisions the quatemization of any basic nitrogen-containing groups of the compounds disclosed herein.
  • the basic nitrogen can be quatemized with any agents known to those of ordinary skill in the art including, without limitation, lower alkyl halides, such as methyl, ethyl, propyl and butyl chlorides, bromides and iodides; dialkyl sulfates including dimethyl, diethyl, dibutyl and diamyl sulfates; long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides; and aralkyl halides including benzyl and phenethyl bromides. Water or oil-soluble or dispersible products may be obtained by such quatemization.
  • preferred compounds suitable as biological/immune response modifiers or anti-inflammatory agents that effectively block autoimmune response or cytokine formation in a mammal include, but are not limited to the following compounds. It will be appreciated, as noted above, that where an R or S enantiomer is exemplified for each particular compound, the corresponding S or R enantiomer, respectively, is also intended even though it may not be specifically shown below.
  • More preferred compounds of the present invention having utility for inhibiting IL-12 signaling include without limitation, the following:
  • compositions comprising, a pharmaceutically acceptable carrier and an active ingredient comprising: (1 ) a biological/immune response modifier or anti-inflammatory agent (e.g., small molecule, antibody, peptide or gene therapy reagent) that effectively blocks autoimmune response in a mammal by inhibiting the activity or expression of inflammatory cytokines such as, for example, IL-12, IL-23 or IL-27, or members of the Signal Transducers and Activators of Transcription (STAT) family, preferably STAT-4, which are believed to be regulators of T cell differentiation involved in immune responses, alone or in combination with (2) a compound or agent (small molecule or peptide) that facilitates growth and/or differentiation of pancreatic ⁇ -cells or any insulin producing cell, either alone or in admixture with a diluent or in the form of a medicament.
  • a biological/immune response modifier or anti-inflammatory agent e.g., small molecule, antibody, peptide or gene therapy reagent
  • LSF analogs include, without limitation, members of the group consisting of the compounds (LSF analogs) described in the following U.S. Patents, the entire disclosures or which are incorporated herein by reference:
  • additional biological/immune response modifying (immunomodulating) or anti-inflammatory compounds or agents that may be for used in accordance with the principles of the present invention include, without limitation, members of the group consisting of the following cytokine formation blocking agents or methods: SiRNA (small interfering RNA); mTOR (mammalian target of Rapamycin); Leflunomide and active metabolites (e.g., A77 1726, LEF M); blockers of formation of advance glycation end products or small molecule or antibodies that inhibit the receptor for advance glycation end products (RAGE); Lipoxins or analogs thereof (e.g., LXA4); small molecule inhibitors of IL-12 (e.g., apilimod mesylate (a.k.a.
  • the dosage of active ingredient in the pharmaceutical compositions of this invention may be varied; however, it is necessary that the amount of the active ingredient be such that a suitable dosage form is obtained.
  • the selected dosage depends upon the desired therapeutic effect, on the route of administration, and on the duration of the treatment.
  • an effective dosage for the activities of this invention is in the range of 1 x 10 "7 to 200 mg/kg/day, preferably 1 x 10 "4 to 100 mg/kg/day, which can be administered as a single dose or divided into multiple doses.
  • the therapeutic amount is between about 0.5 mg to about 12 mg, and more preferably between about 2 mg to about 8 mg, with the most preferred dosage being between about 2 mg and about 6 mg.
  • Unit dosage forms are preferred.
  • a therapeutically effective daily dose is from about 0.001 mg to about 15 mg/kg of body weight per day of a compound of the invention; preferably, from about 0.1 mg to about 10 mg/kg of body weight per day; and most preferably, from about 0.1 mg to about 1.5 mg/kg of body weight per day.
  • the dosage range would be from about 0.07 mg to about 1050 mg per day of a compound of the invention, preferably from about 7.0 mg to about 700 mg per day, and most preferably from about 7.0 mg to about 105 mg per day.
  • Some degree of routine dose optimization may be required to determine an optimal dosing level and pattern. Suitable dosages are well known or readily determinable by the skilled artisan.
  • the pharmaceutical compositions of the present invention can be administered by oral, parenteral (e.g., intramuscular, intraperitoneal, intravenous or subcutaneous injection, or implant), by inhalation spray, nasal, buccal, vaginal, rectal, implanted reservoir, sublingual or topical routes of administration and can be formulated with pharmaceutically acceptable carriers to provide dosage forms appropriate for each route of administration.
  • parenteral as used herein includes subcutaneous, intracutaneous, intravenous, intramuscular, intraarticular, intraarterial, intrasynovial, intrastemal, intrathecal, intralesional and intracranial injection or infusion techniques.
  • Any method of the present invention can comprise administering an effective amount of a composition or pharmaceutical composition comprising (1 ) a biological/immune response modifier or anti-inflammatory agent (e.g., small molecule, antibody, peptide or gene therapy reagent) that effectively blocks autoimmune response or cytokine formation in a mammal (e.g., Lisofylline (LSF) and structurally related LSF analogs, as further described below), alone or in combination with (2) any compound or agent (e.g., small molecule or peptide) (e.g., Ex-4) that facilitates growth and/or differentiation of pancreatic ⁇ -cells or any insulin producing cell.
  • a biological/immune response modifier or anti-inflammatory agent e.g., small molecule, antibody, peptide or gene therapy reagent
  • LSF Lisofylline
  • Ex-4 any compound or agent that facilitates growth and/or differentiation of pancreatic ⁇ -cells or any insulin producing cell.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules.
  • the active compound is admixed with at least one inert pharmaceutically acceptable carrier such as sucrose, lactose, or starch.
  • Such dosage forms can also comprise, as is normal practice, additional substances other than such inert diluents, e.g., lubricating agents such as magnesium stearate.
  • the dosage forms may also comprise buffering agents. Tablets and pills can additionally be prepared with enteric coatings.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, the elixirs containing inert diluents commonly used in the art, such as water. Besides such inert diluents, compositions can also include adjuvants, such as wetting agents, emulsifying and suspending agents, and sweetening, flavoring and perfuming agents.
  • Preparations according to this invention for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions, or emulsions.
  • non-aqueous solvents or vehicles are propylene glycol, polyethylene glycol, vegetable oils, such as olive oil and corn oil, gelatin, and injectable organic esters such as ethyl oleate.
  • Such dosage forms may also contain adjuvants such as preserving, wetting, emulsifying, and dispersing agents. They may be sterilized by, for example, filtration through a bacteria-retaining filter, by incorporating sterilizing agents into the compositions, by irradiating the compositions, or by heating the compositions. They can also be manufactured in the form of sterile solid compositions which can be dissolved in sterile water, or some other sterile injectable medium immediately before use.
  • compositions for rectal or vaginal administration are preferably suppositories which may contain, in addition to the active substance, excipients such as coca butter or a suppository wax.
  • compositions for nasal or sublingual administration are also prepared with standard excipients well known in the art.
  • composition of the present invention may include also conventional excipients of the type used in pharmaceutical compositions.
  • the composition may include pharmaceutically acceptable organic or inorganic carriers suitable for oral administration.
  • examples of such carriers include; sugar spheres, diluents, hydrophilic polymers, lubricants, glidants (or anti-adherents), plasticizers, binders, disintegrants, surfactants and pH modifiers.
  • Suitable diluents include microcrystalline cellulose, lactose, sucrose, fructose, glucose dextrose, or other sugars, dibasic calcium phosphate, calcium sulphate, cellulose, ethylcellulose, cellulose derivatives, kaolin, mannitol, lactitol, maltitol, xylitol, sorbitol, or other sugar alcohols, dry starch, dextrin, maltodextrin or other polysaccharides, inositol or mixtures thereof.
  • Suitable hydrophilic polymers include hydroxypropylmethyl cellulose, carbomers, polyethylene oxides, hydroxypropyl cellulose, hydroxyethyl cellulose, carboxymethylcellulose, sodium carboxymethylcellulose, carboxyvinylpolymers, polyvinyl alcohols, glucans, scleroglucans, mannans, xanthans, carboxymethylcellulose and its derivatives, methylcellulose and, in general, cellulose, crosslinked polyvinylpyrrolidone, carboxymethyl starch, potassium methacrylate-divinylbenzene copolymer, hydroxypropylcyclodextrin, alpha, beta, gamma cyclodextrin or derivatives and other dextran derivatives, natural gums, seaweed extract, plant exudate, agar, agarose, algin, sodium alginate, potassium alginate, carrageenan, kappa-carrageenan, lambda-carrageenan, fucoidan,
  • Suitable glidants include colloidal silica, fumed silicon dioxide, silica hydrogel, talc, fumed silica, gypsum, kaolin and glyceryl monostearate.
  • Suitable plasticizers include acetylated monoglycerides; butyl phthalyl butyl glycolate; dibutyl tartrate; diethyl phthalate; dimethyl phthalate; ethyl phthalyl ethyl glycolate; glycerin; propylene glycol; triacetin; citrate; tripropioin; diacetin; dibutyl phthalate; acetyl monoglyceride; polyethylene glycols; castor oil; Methyl citrate; polyhydric alcohols, glycerol, acetate esters, gylcerol triacetate, acetyl triethyl citrate, dibenzyl phthalate, dihexyl phthalate, butyl octyl phthalate, diisononyl phthalate, butyl octyl phthalate, dioctyl azelate, epoxidised tallate, triis
  • Suitable binders include starches, hydroxypropylmethyl cellulose, hydroxypropyl cellulose, ethyl cellulose, polyvinyl pyrrolidone, acacia, guar gum, hydroxyethylcellulose, agar, calcium carrageenan, sodium alginate, gelatin, saccharides (including glucose, sucrose, dextrose and lactose), molasses, extract of Irish moss, panwar gum, ghatti gum, mucilage of isapol husk, carboxymethylcellulose, methylcellulose, veegum, larch arbolactan, polyethylene glycols, waxes and mixtures thereof.
  • Suitable disintegrants include starches, sodium starch glycollate, crospovidone, croscarmellose, microcrystalline cellulose, low substituted hydroxypropyl cellulose, pectins, potassium methacrylate-divinylbenzene copolymer, polyvinylalcohol, thylamide, sodium bicarbonate, sodium carbonate, starch derivatives, dextrin, beta cyclodextrin, dextrin derivatives, magnesium oxide, clays, bentonite and mixtures thereof.
  • Suitable surfactants include nonionic surfactants such as sorbitan sesquioleate, polyoxyethylene sorbitan monooleate, polyoxyethylene monostearate, glycerol monostearate, propylene glycol monolaurate, polyoxyethylene lauryl ether, polyoxyethylene cetyl ether or polyoxyethylene hydrogenated castor oil; and ionic surfactants such as sodium dodecyl sulfate or benzalkonium chloride; and the like.
  • nonionic surfactants such as sorbitan sesquioleate, polyoxyethylene sorbitan monooleate, polyoxyethylene monostearate, glycerol monostearate, propylene glycol monolaurate, polyoxyethylene lauryl ether, polyoxyethylene cetyl ether or polyoxyethylene hydrogenated castor oil
  • ionic surfactants such as sodium dodecyl sulfate or benzalkonium chloride
  • Suitable pH modifiers include organic acids such as citric acid, fumaric acid, tartaric acid, succinic acid, ascorbic acid, acetic acid, malic acid, glutaric acid and adipic acid; salts of these acids; salts of inorganic acids and magnesium hydroxide.
  • the present invention provides an article of manufacture in accordance with the present invention comprises a means for holding an pharmaceutical composition, as previously described, suitable for administration to a patient in combination with printed labeling instructions providing a discussion of when or how a particular dosage form should be administered to the patient.
  • the pharmaceutical composition will be contained in any suitable means or container capable of holding and dispensing the dosage form and which will not significantly interact with the composition and will further be in physical relation with the appropriate labeling advising that the dosage form exhibits an ability, or may be used, to restore ⁇ -cell mass and function in a mammal in need thereof.
  • the labeling instructions will be consistent with the methods of treatment as described hereinbefore.
  • the labeling may be associated with a container by any means that maintain a physical proximity of the two. Further, by way of non-limiting example, they may both be contained in a packaging means such as a box or plastic shrink wrap or may be associated with the instructions being bonded to container such as with glue or adhesive that does not obscure the labeling instructions or other bonding or holding means.
  • Figure 2 shows that both LSF and Ex-4 alone could protect isolated islet cells from pro-inflammatory cytokines (e.g. IL-1 ⁇ , TNF- ⁇ and IFN- ⁇ ).
  • pro-inflammatory cytokines e.g. IL-1 ⁇ , TNF- ⁇ and IFN- ⁇ .
  • a synergism in apoptosis reduction in ⁇ -cells was observed after combined treatment with Ex-4 and LSF in vitro (P ⁇ 0.005) (40 percent reduction)
  • LSF showed an ability to enhance metabolism in ⁇ -cells.
  • both ATP production and mitochondrial metabolism are increased by LSF treatment.
  • Ex-4 and LSF alone exhibited an ability to increase mitochondrial metabolism in mouse islets, but the combination of LSF and Ex-4 produced a significant increase in mitochondrial metabolism compared to either drug alone.
  • Ex-4/LSF treatment enhanced ⁇ -cell metabolism (about 2.2 to 2.5 fold).
  • mice Blood glucose levels in the mice were monitored, and a small dose of insulin was administered to hyperglycemic mice to maintain euglycemia for the first few days. The pump was removed after 28 days, thereby discontinuing treatment with the drug; however, blood glucose levels were continually monitored for several more weeks. These mice were then sacrificed, and slide sections were prepared from their pancreases to evaluate histology and insulin staining (Example 5) and evidence for growth of new beta cells (Example 6).
  • Pancreata were fixed and stained with an anti-insulin antibody.
  • Figure 5 shows very little insulin remaining in the control diabetic pancreas and many inflammatory cells destroying the islets.
  • the Ex-4/LSF animal with diabetes reversed showed many insulin positive cells and those insulin-positive cell clusters seem ductal in origin.
  • Ex-4/LSF-associated cell proliferation in vivo was evaluated. Diabetic NOD mice that were treated with Ex-4 alone, Ex-4 plus LSF, LSF alone and normal saline for 28 days via mini-pumps were injected with Brdu (50mg/kg) LP. 24 hours later, pancreatic tissues were collected and stained with an anti-Brdu antibody. Figure 6 shows Brdu-positive cells were detected in those mice that had LSF alone, Ex-4 alone and Ex-4 plus LSF therapies, but not seen in mice treated with saline. Significantly, most Brdu-positive cells were found in islet-like clusters in the Ex-4/LSF combined animals that also were positive for insulin.
  • the pancreas begins as a dorsal and a ventral bud, both of which form from the embryonic endodermal layer through the regulation of activin and fibroblast growth factor (FGF) from the notochord.
  • FGF fibroblast growth factor
  • the two buds fuse into the single organ that is present in adult mammals, and the endocrine portion of the pancreas is clearly differentiated into ⁇ , ⁇ , ⁇ , and PP cells that secrete glucagon, insulin, somatostatin, and pancreatic polypeptide, respectively.
  • This process of differentiation requires many transcriptional signals from the mesenchyme, the tissue surrounding the notochord and pancreas. Before differentiation can occur, the endoderm needs to be patterned properly.
  • the forkhead box factors Foxal and Foxa2 are found in the early endodermal tissue, and are believed to be involved in this patterning. Foxa2, specifically, is believed to be essential to this process, as its deletion in mice results in sever disruption of the endodermal formation.
  • morphogenesis begins and the two pancreatic buds are formed.
  • the two transcriptions factors that seem to regulate this process are both in the homeobox class - they share a highly conserved 60-amino acid sequence called the homeobox or homeodomain that acts as the DNA-binding domain (DBD).
  • DBD DNA-binding domain
  • the first, pancreatic and duodenal homeobox factor 1 (Pdx1 ) is synthesized in the entire mass that later develops into the two pancreatic buds.
  • Pdx1 plays a key role in the very early development of the pancreatic tissue: its deletion in mice causes the complete lack of a pancreas in the adult.
  • Pre-B-cell leukemia transcription factor 1 (Pbx1 ) interacts with a specific amino acid sequence in the middle of Pdx1 , and this interaction is believed to be important in triggering Pdxi 's morphogenetic effect.
  • Neurogenin 3 Neurogenin 3
  • Hes1 hairy and enhancer of split 1
  • NeuroDI transcription factor neurogenic differentiation 1
  • the differentiation between ⁇ - and ⁇ -cells is directed by a pair of homeobox transcription factors called Pax4 and Pax6.
  • Pax4 expression is believed to commit cells towards the ⁇ - and ⁇ -cell paths, as the deficiency of Pax4 in mice results in the failure of development of those two cell types; Pax ⁇ deficiency causes the absence of ⁇ -cells, leading researchers to believe that Pax6-expressing cells develop into ⁇ -cells.
  • the final differentiation of the ⁇ -cells is directed by the NK homeobox factors Nkx2.2 and Nkx6.1. Disruption of Nkx6.1 in mice results in a scarcity of ⁇ -cells while other cell types are present in usual numbers; the deficiency of Nkx2.2 in mice leads to a complete lack of insulin-producing ⁇ -cells.
  • mice treated with the combination of Ex4 and LSF should feature higher levels of expression of the transcription factors involved in the differentiation of pancreatic ⁇ -cells than control mice and mice treated with Ex4 or LSF individually.
  • mice displayed an increase in blood glucose levels before the pump was removed.
  • LSF's moderate ability to control blood glucose levels when used alone, hyperglycemia returned immediately following the removal of the pump.
  • the mice treated with a combination of Ex-4 and LSF maintained a euglycemic state, and they remained non-diabetic for as long as 20 weeks after the removal of the pump.
  • LSF and Ex-4 increased mitochondrial metabolism and protected islets and ⁇ -cells from pro-inflammatory cytokine damage more effectively than either treatment LSF alone or Ex-4 alone. Further, the combination of LSF and Ex-4 reversed diabetes within first week of implantation of pump, over long-term, mice maintained euglycemia after withdrawing treatment. A near-normal glucose stimulation response was observed along with an increase in cell proliferation in pancreata and evidence of new beta cell formation.
  • ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇
  • LSF (about 20 to 60 mg/kg/day) and (a) Glucagon-Like Peptide 1 (7-37); (b) Glucagon-Like Peptide 1(7-36) Amide; or (c) a fragment or analog of (a) or (b) (about 10 to 40 nM/day).
  • Control groups can include normal saline, LSF alone (e.g., about 27 mg/kg/day) and/or either (a) Glucagon-Like Peptide 1(7-37); (b) Glucagon-Like Peptide 1 (7- 36) Amide; or (c) a fragment or analog of (a) or (b) (e.g., about 18 nM/day) alone.
  • Blood glucose levels in these mice are monitored, and small doses of insulin may be administered to the hyperglycemic mice to maintain euglycemia.
  • the pump can then be removed after about 20 to 90 days or longer, to discontinue treatment with one of the above formulations; and the blood glucose levels can be continually monitored for several more weeks thereafter.
  • mice are then sacrificed, and slide sections prepared from their pancreases to evaluate histology and insulin staining and evidence for the growth of new beta cells.
  • mice The blood glucose levels in mice (four in each group) can be monitored daily, and the levels in each group can be charted to show average levels of blood glucose in each mouse group. Diabetes reversal can be seen within 2-3 days after implantation of pumps containing LSF and (a) Glucagon-Like Peptide 1 (7-37); (b) Glucagon-Like Peptide 1(7-36) Amide; or (c) an effective fragment or analog of (a) or (b), while hyperglycemia can be controlled 10-12 days after LSF alone pump therapy.
  • Administering only (a) Glucagon-Like Peptide 1 (7-37); (b) Glucagon-Like Peptide 1(7-36) Amide; or (c) an effective fragment or analog of (a) or (b) alone may show no or much less effective diabetes control in NOD mice.
  • euglycemia can remain in NOD mice treated with LSF plus (a) Glucagon-Like Peptide 1(7-37); (b) Glucagon-Like Peptide 1(7-36) Amide; or (c) an effective fragment or analog of (a) or (b).
  • pancreata can be fixed and stained with an anti-insulin antibody to observe insulin positive cells and those insulin-positive cell clusters that are ductal in origin.
  • Cell proliferation in vivo can be evaluated 24 hours after treatment by collecting pancreatic tissues and staining them with an anti-Brdu antibody to observe Brdu-positive cells in islet-like clusters animals that also are positive for insulin.
  • mice treated with the combination of LSF and should feature higher levels of expression of the transcription factors involved in the differentiation of pancreatic ⁇ -cells than control mice and mice treated with LSF alone.

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Abstract

La présente invention concerne des compositions pharmaceutiques et des procédés les employant pour restaurer la masse et la fonction de lymphocytes B chez un mammifère nécessitant ceci. Les compositions pharmaceutiques comprennent un modificateur de réponse biologique et un facteur de croissance de lymphocytes B en mélange avec un support, adjuvant ou véhicule pharmaceutiquement acceptable.
PCT/US2007/070734 2006-06-08 2007-06-08 Compositions pharmaceutiques et procédés pour restaurer la masse et la fonction de lymphocytes b WO2007146786A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009099582A2 (fr) * 2008-01-31 2009-08-13 Diakine Therapeutics, Inc. Compositions et procédés de traitement du diabète utilisant des analogues de la lisofylline et le peptide associé à la néogenèse des îlots

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6774130B2 (en) * 1998-01-16 2004-08-10 Cell Therapeutics, Inc. Therapeutic compounds for inhibiting interleukin-12 signaling and methods for using same
US20060079541A1 (en) * 2004-09-14 2006-04-13 Boehringer Ingelheim International Gmbh 3-methyl-7-butinyl-xanthines, the preparation thereof and their use as pharmaceutical compositions

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6774130B2 (en) * 1998-01-16 2004-08-10 Cell Therapeutics, Inc. Therapeutic compounds for inhibiting interleukin-12 signaling and methods for using same
US20060079541A1 (en) * 2004-09-14 2006-04-13 Boehringer Ingelheim International Gmbh 3-methyl-7-butinyl-xanthines, the preparation thereof and their use as pharmaceutical compositions

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
YANG ET AL.: "Inflammatory Blockade Improves Human Pancreatic Islet Function and Viability", AMERICAN JOURNAL OF TRANSPLANTATION, vol. 5, no. 3, March 2005 (2005-03-01), pages 475 - 483 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009099582A2 (fr) * 2008-01-31 2009-08-13 Diakine Therapeutics, Inc. Compositions et procédés de traitement du diabète utilisant des analogues de la lisofylline et le peptide associé à la néogenèse des îlots
WO2009099582A3 (fr) * 2008-01-31 2010-01-07 Diakine Therapeutics, Inc. Compositions et procédés de traitement du diabète utilisant des analogues de la lisofylline et le peptide associé à la néogenèse des îlots

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