Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
  • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
  • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
  • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
  • A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
  • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
  • A61K31/351—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom not condensed with another ring
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
  • A61K31/382—Heterocyclic compounds having sulfur as a ring hetero atom having six-membered rings, e.g. thioxanthenes
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/397—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having four-membered rings, e.g. azetidine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
  • A61K31/4025—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil not condensed and containing further heterocyclic rings, e.g. cromakalim
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
  • A61K31/415—1,2-Diazoles
  • A61K31/4155—1,2-Diazoles non condensed and containing further heterocyclic rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
  • A61K31/4164—1,3-Diazoles
  • A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
  • A61K31/4196—1,2,4-Triazoles
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
  • A61K31/42—Oxazoles
  • A61K31/422—Oxazoles not condensed and containing further heterocyclic rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
  • A61K31/4245—Oxadiazoles
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
  • A61K31/425—Thiazoles
  • A61K31/427—Thiazoles not condensed and containing further heterocyclic rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
  • A61K31/443—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with oxygen as a ring hetero atom
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/4965—Non-condensed pyrazines
  • A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/50—Pyridazines; Hydrogenated pyridazines
  • A61K31/501—Pyridazines; Hydrogenated pyridazines not condensed and containing further heterocyclic rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
  • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
  • A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
  • A61K31/5375—1,4-Oxazines, e.g. morpholine
  • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
  • A61K31/541—Non-condensed thiazines containing further heterocyclic rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
  • A61K31/553—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one oxygen as ring hetero atoms, e.g. loxapine, staurosporine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
  • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/04—Anorexiants; Antiobesity agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/06—Antihyperlipidemics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
  • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/12—Antihypertensives
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
  • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
  • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
  • C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
  • C07D307/80—Radicals substituted by oxygen atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
  • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
  • C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
  • C07D407/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
  • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
  • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
  • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
  • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
  • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
  • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
  • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

• the present invention relates to novel indanyloxydihydrobenzofuranylacetic acids, that are agonists of the G-protein coupled receptor 40 (GPR40, also known as free fatty acid receptor FFAR 1 ), to processes for their preparation, to pharmaceutical compositions conta in ing these com pou nds and to their med ical use for the prophylaxis and/or treatment of diseases which can be influenced by the modulation of the function of GPR40.
• the pharmaceutical compositions of the invention are suitable for the prophylaxis and/or therapy of metabolic diseases, such as diabetes, more specifically type 2 diabetes mellitus, and conditions associated with the disease, including insulin resistance, obesity, cardiovascular disease and dyslipidemia.
• Metabolic diseases are diseases caused by an abnormal metabolic process and may either be congenital due to an inherited enzyme abnormality or acquired due to a disease of an endocrine organ or failure of a metabolically important organ such as the liver or the pancreas.
• Diabetes mellitus is a disease state or process derived from multiple causative factors and is defined as a chronic hyperglycemia associated with resulting damages to organs and dysfunctions of metabolic processes. Depending on its etiology, one differentiates between several forms of diabetes, which are either due to an absolute (lacking or decreased insulin secretion) or to a relative lack of insulin. Diabetes mellitus Type I (IDDM, insulin-dependent diabetes mellitus) generally occurs in adolescents under 20 years of age. It is assumed to be of auto-immune etiology, leading to an insulitis with the subsequent destruction of the beta cells of the islets of Langerhans which are responsible for the insulin synthesis. In addition, in latent autoimmune diabetes in adults (LADA; Diabetes Care.
• LADA latent autoimmune diabetes in adults
• beta cells are being destroyed due to autoimmune attack.
• the amount of insulin produced by the remaining pancreatic islet cells is too low, resulting in elevated blood glucose levels (hyperglycemia).
• Diabetes mellitus Type II generally occurs at an older age. It is above all associated with a resistance to insulin in the l iver and the skeletal muscles, but also with a defect of the islets of Langerhans. High blood glucose levels (and also high blood lipid levels) in turn lead to an impairment of beta cell function and to an increase in beta cell apoptosis. Persistent or inadequately controlled hyperglycemia is associated with a wide range of pathologies.
• Diabetes is a very disabling disease, because today's common antidiabetic drugs do not control blood sugar levels well enough to completely prevent the occurrence of high and low blood sugar levels. Out of range blood sugar levels are toxic and cause long-term complications for example retinopathy, Tenopathy, neuropathy and peripheral vascular disease. There is also a host of related conditions, such as obesity, hypertension, stroke, heart disease and hyperlipidemia, for which persons with diabetes are substantially at risk.
• Obesity is associated with an increased risk of follow-up diseases such as cardiovascular diseases, hypertension, diabetes, hyperlipidemia and an increased mortality.
• Diabetes (insulin resistance) and obesity are part of the "metabolic syndrome” which is defined as the linkage between several diseases (also referred to as syndrome X, insulin-resistance syndrome, or deadly quartet). These often occur in the same patients and are major risk factors for development of diabetes type II and cardiovascular disease. It has been suggested that the control of lipid levels and glucose levels is requ ired to treat d iabetes type I I , heart d isease, and other occurrences of metabolic syndrome (see e.g., Diabetes 48: 1836-1841 , 1999; JAMA 288: 2209-2716, 2002).
• the free fatty acid receptor GPR40 (also referred to as either FFAR, FFAR1 , or FFA1 ) is a cell-surface receptor and a member of the gene superfamily of G-protein coupled receptors, which was first identified as a so-called orphan receptor, i.e. a receptor without a known ligand, based on the predicted presence of seven putative transmembrane regions in the corresponding protein (Sawzdargo et al. (1997) Biochem. Biophys. Res. Commun. 239: 543-547).
• GPR40 is found to be highly expressed in several particular cell types: the pancreatic ⁇ cells and insulin-secreting cell lines, as well as in enteroendocrine cells, taste cells, and is reported to be expressed in immune cells, splenocytes, and in the human and mon key brain . Meanwhile, fatty acids of varying chain lengths are thought to represent the endogenous ligands for GPR40, activation of which is linked primarily to the modulation of the Gq family of intra-cellular signaling G proteins and concomitant induction of elevated calcium levels, although activation of Gs- and Gi-proteins to modulate intracellular levels of cAMP have also been reported. GPR40 is activated especially by long-chain FFA, particularly oleate, as well as the PPAR-gamma agonist rosiglitazone.
• GPR40 agonists may have the potential to restore or preserve islet function, therefore, GPR40 agonists may be beneficial also in that that they may delay or prevent the diminution and loss of islet function in a Type 2 diabetic patient.
• GLP-1 glucagon-like peptide- 1
• GIP glycose-dependent insulinotropic peptide; also known as gastric inhibitory peptide
• GLP-1 glucagon-like peptide- 1
• GIP glycose-dependent insulinotropic peptide; also known as gastric inhibitory peptide
• endocrine cells that are located in the epithelium of the small intestine. When these endocrine cells sense an increase in the concentration of glucose in the lumen of the digestive tract, they act as the trigger for incretin release. Incretins are carried through the circulation to beta cells in the pancreas and cause the beta cells to secrete more insulin in anticipation of an increase of blood glucose resulting from the d igesting meal .
• GPR40 modulators may contribute to enhanced insulin release from the pancreatic beta cells also indirectly by e.g. a synergistic effect of GLP-1 and possibly GIP on the insulin release, and the other release incretins may also contribute to an overall beneficial contribution of GPR40 modulation on metabolic diseases.
• the indirect contributions of GPR40 modulation on insulin release through the elevation of plasma levels of incretins may be further augmented by the coadministration of inhibitors of the enzymes responsible for the incretin degradation, such as inhibitors of DPP-4.
• GPR40 in modulating insulin secretion indicates the therapeutic agents capable of modulating GPR40 function could be useful for the treatment of disorders such as diabetes and conditions associated with the disease, including insulin resistance, obesity, cardiovascular disease and dyslipidemia.
• the object of the present invention is to provide new compounds, hereinafter described as compounds of formula (I), in particular new 2,3- indanyloxydihydrobenzofuranylacetic acids, which are active with regard to the G- protein-coupled receptor GPR40, notably are agonists of the G-protein-coupled receptor GPR40.
• a further object of the present invention is to provide new compounds, in particular new indanyloxydihydrobenzofuranylacetic acids, which have an activating effect on the G-protein-coupled receptor GPR40 in vitro and/or in vivo and possess suitable pharmacological and pharmacokinetic properties to use them as medicaments.
• a further object of the present invention is to provide effective GPR40 agonists, in particular for the treatment of metabolic disorders, for example diabetes, dyslipidemia and/or obesity.
• a further object of the present invention is to provide methods for treating a disease or condition mediated by the activation the G-protein-coupled receptor GPR40 in a patient.
• a further object of the present invention is to provide a pharmaceutical composition comprising at least one compound according to the invention.
• a further object of the present invention is to provide a combination of at least one compound according to the invention with one or more additional therapeutic agents.
• GPR40 modulators are known in the art, for example, the compounds disclosed in WO 2004041266 (EP 1559422), WO 2007033002 and WO 2009157418.
• the indanyloxydihydrobenzofuranylacetic acids of the present invention may provide several advantages, such as enhanced potency, high metabolic and/or chemical stability, high selectivity and tolerability, enhanced solubility, and the possibility to form stable salts.
• the invention relates to a compound of formula I
• a second ring is annulated to said phenyl or heteroaromatic ring
• each of the phenyl ring, tetrazolyl ring, heteroaromatic ring, annulated phenyl ring, and annulated heteroaromatic ring is optionally additionally substituted with 1 to 4 groups independently selected from R 4 ;
• any alkyi and cydoalkyi group or sub-group within the groups mentioned is optionally substituted with one or more F atoms, and wherein multiple R 2 may be identical or different, if m is 2 or 3; is selected from the group R 3 -G1 consisting of
• heterocydyl is selected from
• heteroaryl is selected from
• R 4 is selected from the group R 4 -G1 consisting of F, CI, Br, I, CN, -OH, Ci -4 -alkyl, C 3- 6-cycloalkyl-, HO-
• any alkyl and cydoalkyi group or sub-group within the groups mentioned is optionally substituted with 1 or more F atoms;
• heterocydyl is selected from
• heteroaryl is selected from
• any alkyl and cycloalkyl group or sub-group within the groups mentioned is optionally substituted with one or more F atoms;
• the expression "optionally substituted with 1 or more F atoms” means that none or one up to successively all H atoms bound to carbon atoms of the respective group or submoiety may be replaced by F atoms, preferably 1 to 5 H atoms or, more preferred, 1 to 3 H atoms may be replaced by F atoms.
• the extension -Gn used within the definitions is meant to identify genus n of the respective substituent. For example, R 1 -G1 defines genus 1 of the substituent R 1 .
• this invention relates to a pharmaceutical composition, comprising one or more compounds of general formula I or one or more pharmaceutically acceptable salts thereof according to the invention, optionally together with one or more inert carriers and/or diluents.
• th is invention relates to a method for treating d iseases or conditions which are mediated by activating the G-protein-coupled receptor GPR40 in a patient in need thereof characterized in that a compound of general formula I or a pharmaceutically acceptable salt thereof is administered to the patient.
• a method for treating a metabolic disease or disorder such as diabetes, dyslipidemia and/or obesity, in a patient in need thereof characterized in that a therapeutically effective amount of a compound of general formula I or a pharmaceutically acceptable salt thereof is administered to the patient.
• a compound of the general formula I or a pharmaceutically acceptable salt thereof for use in a therapeutic method as described hereinbefore and hereinafter.
• invention relates to a method for treating a disease or condition mediated by the activation of the G-protein-coupled receptor GPR40 in a patient that includes the step of administering to the patient in need of such treatment a therapeutically effective amount of a compound of the general formula I or a pharmaceutically acceptable salt thereof in combination with a therapeutically effective amount of one or more additional therapeutic agents.
• this invention relates to the use of a compound of the general formula I or a pharmaceutically acceptable salt thereof in combination with one or more additional therapeutic agents for the treatment of diseases or conditions which are mediated by the activation of the G-protein-coupled receptor GPR40.
• this invention relates to a pharmaceutical composition which comprises a compound according to general formula I or a pharmaceutically acceptable salt thereof and one or more additional therapeutic agents, optionally together with one or more inert carriers and/or diluents.
• R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R N , and m are defined as above and hereinafter. If residues, substituents, or groups occur several times in a compound, as for example R N , they may have the same or different meanings. Some preferred meanings of individual groups and substituents of the compounds according to the invention will be given hereinafter. Any and each of these definitions may be combined with each other.
• R 1 is preferably selected from the group R 1 -G1 as defined hereinbefore.
• R 1 -G2 is preferably selected from the group R 1 -G1 as defined hereinbefore.
• each of said phenyl ring, tetrazolyl ring, heteroaromatic rings, annulated phenyl ring, and annulated heteroaromatic rings is substituted with one group R 3 and optionally additionally substituted with 1 or 2 substituents independently selected from R 4 .
• each annulated phenyl ring and annulated heteroaromatic ring is substituted with one group R 3 and optionally additionally substituted with 1 or 2 substituents independently selected from R 4 .
• the group R 1 is selected from the group R 1 -G3 consistin of:
• each group is substituted with one group R and optionally additionally substituted with 1 or 2 groups independently selected from R 4 ;
• the group R 1 is selected from the group R 1 -G3a consisting of
• each group is substituted with one group R 3 and optionally additionally substituted with 1 or 2 groups independently selected from R 4 .
• the group R 1 is selected from the group R 1 -G3b
• group R 1 is selected from the group R 1 -G4 consisting of
• group R 1 is selected from the group R 1 -G4 consisting of ,
• each group is substituted with one group R 3 and optionally additionally substituted with 1 or 2 groups independently selected from R 4 .
• R 1 -G4a
• the group R 1 is selected from the group R 1 -G4a consisting of which is substituted with one group R 3 and optionally additionally substituted with 1 or 2 groups independently selected from R 4 .
• R 1 -G4b In another embodiment the group R 1 is selected from the group R 1 -G4b consisting of
• group R 1 is selected from the group R 1 -G5 consisting of
• group R 1 is selected from the group R 1 -G5a consisting of
• R 2 is preferably selected from the group R 2 -G1 as defined hereinbefore.
• R 2 -G2 is preferably selected from the group R 2 -G1 as defined hereinbefore.
• the group R 2 is selected from the group R 2 -G3 consisting of F, CI, Br, H2FC-, F 3 C-, NC-, and F3C-O-.
• R 2 -G4 :
• the group R 2 is selected from the group R 2 -G4 consisting of F, CI, and NC-.
• R 2 -G4a In another embodiment the group R 2 is selected from the group R 2 -G4a consisting of F, CI, F 3 C-, and NC-.
• the group R 2 is selected from the group R 2 -G4b consisting of F.
• the group R 2 is selected from the group R 2 -G4c consisting of F 3 C-.
• the group R 3 is preferably selected from the group R 3 -G1 as defined hereinbefore.
• each phenyl and heteroaryl group is optionally substituted with 1 to 3 substituents independently selected from R 6 ;
• heterocyclyl is selected from
• heteroaryl is selected from
• each alkyi and cydoalkyi group and each alkyi and cydoalkyi sub-group within the groups mentioned is substituted with 1 to 3 groups independently selected from R 5 and optionally substituted with 1 or more F atoms; or from
• each alkyl, cydoalkyi, and heterocydyl group or sub-group within the groups mentioned is optionally substituted with 1 to 3 groups independently selected from R 5 and optionally substituted with 1 or more F atoms;
• each phenyl and heteroaryl group is optionally substituted with 1 to 3 substituents independently selected from R 6 ;
• heterocydyl is selected from
• heteroaryl is selected from
• group R 3 is selected from the group R 3 -G3 consisting of
• each alkyi, cydoalkyi, and heterocyclyl group or sub-group within the groups mentioned is optionally substituted with 1 or 2 groups independently selected from R 5 and optionally substituted with 1 or more F atoms;
• each phenyl and heteroaryl group is optionally substituted with 1 to 3 substituents independently selected from R 6 ;
• heterocyclyl is selected from
• heteroaryl is selected from
• R 3 in total cannot be Ci -4 -alkyl-, Ci -4 -alkyl-O-Ci -4 -alkyl, HO-Ci -4 - alkyl, and Ci -4 -alkyl-O-.
• group R 3 is selected from the group R 3 -G3a consisting of
• each alkyi and cydoalkyi group and each alkyi and cydoalkyi sub-group within the groups mentioned is substituted with 1 to 3 groups independently selected from R 5 and optionally substituted with 1 to 3 F atoms; or from
• each alkyi, cydoalkyi, and heterocyclyl group or sub-group within the groups mentioned is optionally substituted with 1 or 2 groups independently selected from R 5 and optionally substituted with 1 to 3 F atoms;
• each phenyl and heteroaryl group is optionally substituted with 1 to 3 substituents independently selected from R 6 ;
• heterocyclyl is selected from
• heteroaryl is selected from
• group R 3 is selected from the group R 3 -G4 consisting of Ci -4 -alkyl, C3-6-cycloalkyl-, Ci -4 -alkyl-O-, and C3-6-cycloalkyl-O-,
• each alkyi and cydoalkyi group and each alkyi and cydoalkyi sub-group within the groups mentioned is substituted with 1 group selected from R 5 and optionally substituted with 1 or 2 H 3 C- group;
• each phenyl and heteroaryl group is optionally substituted with 1 or 2 substituents independently selected from R 6 ;
• heterocydyl is selected from
• heteroaryl is selected from
• group R 3 is selected from the group R 3 -G4a consisting of Ci -4 -alkyl, C3-6-cycloalkyl-, Ci -4 -alkyl-O-, and C3-6-cycloalkyl-O-,
• each alkyi and cydoalkyi group and each alkyi and cydoalkyi sub-group within the groups mentioned is substituted with 1 group selected from R 5 and optionally substituted with 1 or 2 H 3 C- groups; or from
• each phenyl and heteroaryl group is optionally substituted with 1 or 2 substituents independently selected from R 6 ;
• heterocydyl is selected from
• heteroaryl is selected from
• the group R 3 is selected from the group R 3 -G5 consisting of
• R 3 -G5a According to another embodiment the group R 3 is selected from the group R 3 -G5a consisting of
• cyclopropyl-CH 2 -O- and cyclohexyl-CH 2 -O-, each of both cycloalkyl groups is substituted with 1 HO- group and optionally substituted with 1 or 2 F atoms;
• azetidinyloxy, pyrrolidinyloxy, pyrrolidin-2-onyloxy, piperidinyloxy and 1 ,1 -dioxo- [1 ,2]thiazinanyloxy, in each of which the NH group is optionally replaced by N-CH 3 or N-S( O) 2 -CH 3 ;
• phenyl furanyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, triazolyl, oxadiazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyridin-2-onyl, pyrimidin-2-onyl, pyhmidin-4-onyl and pyridazin-3-onyl, wherein a NH group, if present, optionally is replaced by N-CH 3 , N-CH 2 -C(CH 3 ) 2 -OH or N-C(CH 3 ) 2 -CH 2 -OH, and which are optionally substituted with 1 H 3 C- group and optionally substituted with 1 group selected from -CH 3 , -CH 2 -CH 3 , -CH(CH 3 ) 2 , cyclopropyl, -CF 3
• the group R 3 is selected from the group R 3 -G6 consisting of
• the group R 3 is selected from the group R 3 -G6a consisting of
• R 4 is preferably selected from the group R 4 -G1 as defined hereinbefore.
• R 4 -G2 is preferably selected from the group R 4 -G1 as defined hereinbefore.
• R 4 -G3 consisting of F, CI, Br, CN, Ci -3 -alkyl, C 3- -cycloalkyl-, HO-Ci -3 -alkyl, Ci -3 -alkyl-O-Ci -3 -alkyl, -NR N H, Ci -4 -alky
• the group R 4 is selected from the group R 4 -G3 consisting of F, CI, CN, -CH 3 , -CF 3 , isopropyl, cyclopropyl, H 3 C-O-CH 2 -, H 3 C-O-, and F 3 C-O-.
• the group R 4 is selected from the group R 4 -G4 consisting of CH 3 .
• the group R 4 is selected from the group R 4 -G4a consisting of F and CH 3 .
• the group R 5 is preferably selected from the group R 5 -G1 as defined hereinbefore.
• heterocydyl is selected from
• heterocydyl is selected from
• any alkyl, cydoalkyi, and heterocydyl group or sub-group within the groups mentioned is optionally substituted with 1 or more F atoms and optionally substituted with 1 or 2 groups independently selected from H 3 C-, H3C-O-, and -CN,
• heterocydyl is selected from
• R 5 -G3a
• any alkyl, cydoalkyi, and heterocydyl group or sub-group within the groups mentioned is optionally substituted with 1 or more F atoms and optionally substituted with 1 or 2 groups independently selected from H 3 C-, HO-, H 3 C-O- and -CN,
• heterocydyl is selected from
• heterocyclyl is selected from
• an azetidinyl, oxetanyl, a pyrrolidinyl, pyrrolidin-2-onyl, tetrahydrofuranyl, sulfolanyl, piperidinyl, tetrahydropyranyl, 1 ,1 -dioxo-tetrahydrothiopyranyl, morpholinyl, and an oxazolidin-2-onyl ring, wherein each of these rings optionally is substituted with 1 CH 3 group and wherein an NH group, if present, optionally is replaced with NS( O) 2 -Ci -3 -alkyl;
• heteroaryl is selected from
• a pyridin-2-onyl, imidazolyl, pyrazolyl, and oxazolyl ring wherein in a heteroaryl group with a NH group this unit optionally is replaced by a N-CH 3 group.
• heterocyclyl is selected from
• pyridin-2-onyl pyridinyl, imidazolyl, pyrazolyl, and oxazolyl ring, each of which is optionally substituted with a H 3 C-O- group and wherein a heteroaryl group with a NH group this unit optionally is replaced by a N-CH 3 group.
• the group R 5 is selected from the group R 5 -G5 consisting of
• the group R 5 is selected from the group R 5 -G5a consisting of
• R 6 is preferably selected from the group R 6 -G1 as defined hereinbefore.
• R 6 -G2 is preferably selected from the group R 6 -G1 as defined hereinbefore.
• the group R 6 is selected from the group R 6 -G2a consisting of F, CI, -CN, Ci -3 -alkyl, cyclopropyl, HO-Ci -4 -alkyl-, H 3 C-O-Ci -4 -alkyl-, H 3 C-O-,
• the group R 6 is selected from the group R 6 -G4 consisting of F, -CH 3 , CN, and -OCH 3 .
• R 6 -G4a is selected from the group R 6 -G4 consisting of F, -CH 3 , CN, and -OCH 3 .
• the group R 6 is selected from the group R 6 -G4a consisting of F, -CH 3 , -CH 2 -CH 3 , -CH(CH 3 ) 2 , cyclopropyl, HO-C(CH 3 ) 2 -, HO-CH 2 -C(CH 3 ) 2 -, HO- C(CH 3 ) 2 -CH 2 -, -CF 3 , CN, and -OCH 3 .
• R N is preferably selected from the group R N -G1 as defined hereinbefore.
• R N -G2 is preferably selected from the group R N -G1 as defined hereinbefore.
• the index m is an integer selected from 0, 1 , 2, or 3. According to one embodiment the index m is 0, 1 , or 2. According to another embodiment the index m is 1 or 2. According to another embodiment the index m is 1 . According to another embodiment the index m is 2.
• R 3 is substituted with one group R 3 and optionally additionally substituted with 1 or 2 groups independently selected from R 4 ;
• R 2 is selected from the group consisting of F, CI, Br, H 2 FC-, F 3 C-, NC-, and F 3 C-O-;
• R 3 is selected from the group consisting of Ci -4 -alkyl, C3-6-cycloalkyl-, Ci -4 -alkyl-O-, and C3-6-cycloalkyl-O-,
• each alkyi and cydoalkyi group and each alkyi and cydoalkyi sub-group within the groups mentioned is substituted with 1 to 3 groups independently selected from R 5 and optionally substituted with 1 or more F atoms;
• each alkyi, cydoalkyi, and heterocyclyl group or sub-group within the groups mentioned is optionally substituted with 1 or 2 groups independently selected from R 5 and optionally substituted with 1 or more F atoms;
• each phenyl and heteroaryl group is optionally substituted with 1 to 3 substituents independently selected from R 6 ;
• R 4 is selected from the group consisting of F , CI , C N , -CH 3 , -CF 3 , isopropyl, cyclopropyl, H 3 C-O-CH 2 -, H 3 C-O-, and F3C-O-;
• any alkyl, cydoalkyi, and heterocydyl group or sub-group within the groups mentioned is optionally substituted with 1 or more F atoms and optionally substituted with 1 or 2 groups independently selected from H 3 C-, H3C-O-, and -CN,
• heterocydyl is selected from
• R 2 is selected from the group consisting of F, CI, and NC-;
• R 3 is selected from the group consisting of Ci -4 -alkyl, C 3- 6-cycloalkyl-, Ci -4 -alkyl-O-, and C 3- 6-cycloalkyl-O-, wherein each alkyi and cydoalkyi group and each alkyi and cydoalkyi sub-group within the groups mentioned is substituted with 1 group selected from R 5 and optionally substituted with 1 or 2 H 3 C- group;
• each phenyl and heteroaryl group is optionally substituted with 1 or 2 substituents independently selected from R 6 ;
• heterocydyl is selected from
• any alkyi, cydoalkyi, and heterocydyl group or sub-group within the groups mentioned is optionally substituted with 1 or more F atoms and optionally substituted with 1 or 2 groups independently selected from H 3 C-, H 3 C-O-, and -CN,
• heterocyclyl is selected from
• R 3 is selected from the group consisting of Ci -4 -alkyl, C 3- 6-cycloalkyl-, Ci -4 -alkyl-O-, and C 3- 6-cycloalkyl-O-, wherein each alkyi and cydoalkyi group and each alkyi and cydoalkyi sub-group within the groups mentioned is substituted with 1 to 3 groups independently selected from R 5 and optionally substituted with 1 to 3 F atoms;
• each alkyi, cydoalkyi, and heterocydyl group or sub-group within the groups mentioned is optionally substituted with 1 or 2 groups independently selected from R 5 and optionally substituted with 1 to 3 F atoms;
• each phenyl and heteroaryl group is optionally substituted with 1 to 3 substituents independently selected from R 6 ;
• heterocydyl is selected from
• heteroaryl is selected from
• any alkyl, cydoalkyi, and heterocydyl group or sub-group within the groups mentioned is optionally substituted with 1 or more F atoms and optionally substituted with 1 or 2 groups independently selected from H 3 C-, HO-, H 3 C-O- and -CN,
• heterocydyl is selected from
• R 3 is selected from the group consisting of Ci -4 -alkyl, C3-6-cycloalkyl-, Ci -4 -alkyl-O-, and C3-6-cycloalkyl-O-,
• each alkyi and cydoalkyi group and each alkyi and cydoalkyi sub-group within the groups mentioned is substituted with 1 to 3 groups independently selected from R 5 and optionally substituted with 1 to 3 F atoms;
• each alkyi, cydoalkyi, and heterocydyl group or sub-group within the groups mentioned is optionally substituted with 1 or 2 groups independently selected from R 5 and optionally substituted with 1 to 3 F atoms;
• each phenyl and heteroaryl group is optionally substituted with 1 to 3 substituents independently selected from R 6 ;
• heterocydyl is selected from
• heteroaryl is selected from
• any alkyl, cydoalkyi, and heterocydyl group or sub-group within the groups mentioned is optionally substituted with 1 or more F atoms and optionally substituted with 1 or 2 groups independently selected from H 3 C-, HO-, H 3 C-O- and -CN,
• heterocydyl is selected from
• the compounds of the invention I are preferably accessed from a precursor 1 that bears the carboxylic acid function in a protected or masked form as sketched in Scheme 1 ;
• R 1 , R 2 , and m have the meanings as defined hereinbefore and hereinafter.
• Suited precursor groups for the carboxylic acid may be, e.g., a carboxylic ester, a carboxylic amide, cyano, an olefin, oxazole, or a thiazole. All these groups have been transformed into the carboxylic acid function by different means which are described in the organic chemistry literature and are known to the one skilled in the art.
• the preferred precursor group is a Ci -4 -alkyl or benzyl carboxylate, each of which may be additionally mono- or polysubstituted with fluorine, methyl, and/or methoxy.
• These ester groups may be hydrolysed with an acid, such as hydrochloric acid or sulfuric acid, or an alkali metal hydroxide, such as lithium hydroxide, sodium hydroxide, or potassium hydroxide, to yield the carboxylic acid function; the hydrolysis is preferably conducted in aqueous solvents, such as water and tetrahydrofuran, 1 ,4- dioxane, alcohol, e.g.
• a tert-butyl ester is preferably cleaved under acidic conditions, e.g. trifluoroacetic acid or hydrochloric acid, in a solvent such as dichloromethane, 1 ,4- dioxane, isopropanol, or ethyl acetate.
• a benzyl ester is advantageously cleaved using hydrogen in the presence of a transition metal, preferably palladium on carbon.
• CP masked or protected form of COOH, e.g., C0 2 C.,_ 4 -alkyl, C0 2 CH 2 aryl,
• Compound 1 may be obtained from indane 2, which bears a leaving group, and phenol 3, which is decorated with the carboxylic acid precursor group (Scheme 2); R 1 , R 2 , and m in Scheme 2 have the meanings as defined hereinbefore and hereinafter.
• the leaving group LG in 2 is replaced with the O in 3 via a nucleophilic substitution; suited LG may be CI, Br, I, methylsulfonyloxy, phenylsulfonyloxy, p-tolylsulfonyloxy, and trifluoromethylsulfonyloxy.
• the reaction is usually carried out in the presence of a base, such as triethylamine, ethyldiisopropylamine, 1 ,8- diazabicyclo[5.4.0]undecene, carbonates, e.g. L12CO3, Na2CO3, K2CO3, and CS2CO3, hydroxides, e.g. LiOH, NaOH, and KOH, alcoholates, e.g. NaOMe, NaOEt, and KOtBu, hydrides, e.g. NaH and KH, amides, e.g. NaNH 2 , KN(SiMe 3 )2, and LiN(iPr) 2 , and oxides, e .g .
• a base such as triethylamine, ethyldiisopropylamine, 1 ,8- diazabicyclo[5.4.0]undecene
• carbonates e.g. L12CO3, Na2CO3, K2CO3,
• Additives such as silver salts, e.g. AgNO3, AgOSO 2 CF 3 , and Ag 2 CO3, crown ethers, e.g. 12-crown-4, 15-crown-5, and 18-crown- 6, hexamethylphosphorus t amide (HMPT), and 1 ,3-dimethyl-3,4,5,6-dihydro-2- pyrimidinone (DMPU), may be beneficial or even essential for the reaction to proceed.
• silver salts e.g. AgNO3, AgOSO 2 CF 3
• Ag 2 CO3 hexamethylphosphorus t amide
• HMPT hexamethylphosphorus t amide
• DMPU 1 ,3-dimethyl-3,4,5,6-dihydro-2- pyrimidinone
• Preferred solvents are dimethylsulfoxide, ⁇ , ⁇ -dimethylformamide, N,N- dimethylacetamide, N-methylpyrrolidinone, acetonitrile, acetone, 1 ,4-dioxane, tetrahydrofuran, alcohol, e.g. ethanol or isopropanol, water, or mixtures thereof, while not all of the solvents can be combined with each additive and base mentioned above. Suited reaction temperatures range from -20 to 140 °C.
• LG leaving group, e.g., CI, Br, I, OS0 2 Me, OS0 2 Ph, OS0 2 Tol, OS0 2 CF 3
• CP masked or protected form of COOH, e.g., C0 2 C 1.4 -alkyl, C0 2 CH 2 aryl,
• Phosphines often used are triphenylphosphine and tributylphosphine which are commonly combined with dimethyl azodicarboxylate, diethyl azodicarboxylate, diisopropyl azodicarboxylate, di-(4-chlorobenzyl) azodicarboxylate, dibenzyl azodicarboxylate, di-tert-butyl azodicarboxylate, azodicarboxylic acid bis- (dimethylamide), azodicarboxylic acid dipiperidide, or azodicarboxylic acid dimorpholide.
• CP masked or protected form of COOH, e.g., C0 2 C 1.4 -alkyl, C0 2 CH 2 aryl,
• Lewis acids are some of the more often used ones: hydrobromic acid, hydroiodic acid, hydrochloric acid, sulfuric acid, p h o s p h o r i c a c i d , P 4 Oio, trifluoroacetic acid, methanesulfonic acid, toluenesulfonic acid, trifluoromethanesulfonic acid, CISO3H, Sc(OSO2CF 3 )3, Tb(OSO 2 CF 3 ) 3 , SnCI 4 , FeCI 3 , AIBr 3 , AICI 3 , SbCI 5 , BCI 3 , BF 3 , ZnCI 2 , montmorillonites, POCI 3 , and PCI 5 .
• the reaction may be conducted, e.g., in dichloromethane, 1 ,2- dichloroethane, nitrobenzene, chlorobenzene, carbon disulfide, mixtures thereof, or without an additional solvent in an excess of the Lewis acid , at 0 to 1 80 °C.
• Carboxylic acids are preferably reacted in polyphosphoric acid at 0 to 120 °C, while carboxylic chlorides are preferably reacted with AICI3 in dichloromethane or 1 ,2- dichloroethane at 0 to 80 °C.
• Th e su bseq uent red u ction of th e keto g rou p i n Sch eme 4 is a sta nda rd transformation in organic synthesis, which may be accomplished with lithium borohydride, sodium borohydride, lithium aluminum hydride, or diisobutylaluminum hydride. While sodium borohydride is employed in aqueous or alcoholic solution at 0 to 60 °C, the other reducing agents mentioned are preferably used in inert solvents, such as tetrahydrofuran, diethyl ether, dichloromethane, and toluene, at -80 to 60 °C.
• the reduction of the keto group may also be conducted in a stereoselective fashion providing the alcohol in enantiomerically enriched or pure form.
• Suited chiral reducing agents are boranes combined with an enantiomerically pure [1 ,3,2]oxazaborol (Corey-Bakshi-Shibata reaction or Corey-ltsuno reaction) or formic acid, formates, hydrogen, or silanes in the presence of an enantiomerically pure transition metal catalyst.
• Typical reaction conditions for the former approach are borane (complexed with, e.g., dimethyl sulfide) and (R)- or (S)-3,3-diphenyl-1 -methyltetrahydro-1 H,3H- pyrrolo[1 ,2-c] [1 ,3,2]oxazaborol in , e .g . , d ichloromethane, tol uene, methanol , tetrahydrofuran, or mixtures thereof, at 0 to 60 °C.
• a chiral transition metal cata lyst such as a ruth en i u m com pl ex, e .g .
• chloro ⁇ [(1 S,2S)-(-)-2-amino-1 ,2- diphenylethyl](4-toluenesulfonyl)-amido ⁇ -(mesitylene)ruthenium(ll) may deliver the hydroxy compound with high enantiomeric excess using, e.g., formic acid in the presence of a base, e.g. triethylamine, in dichloromethane, at -20 to 60 °C.
• a base e.g. triethylamine
• indanone 4 can be synthesized as described in Scheme 5; R 1 , R 2 , and m have the meanings as defined hereinbefore and hereinafter. Starting with benzene 6 and 3-halo-propionic acid or a derivative thereof or acrylic acid or a derivative thereof the required indanone 4 may be obtained via the combination of a Friedel- Crafts alkylation and acylation reaction in one pot or two separate reactions (eq. 1 .)).
• a Lewis acid such as triflic acid, sulfuric acid, phosphoric acid, AICI3, ZnC , and phosphorus pentoxide
• a Lewis acid such as triflic acid, sulfuric acid, phosphoric acid, AICI3, ZnC , and phosphorus pentoxide
• a preferred combination comprises compound 6, 3-chloro-propionyl chloride, and AICI3 in dichloromethane or 1 ,2-dichlorethane at 20 to 80 °C.
• Rhodium is a preferred catalyst basis which is combined with a phosphine, e.g. triphenylphosphine, and a base, e.g. triethylamine, and used in a solvent, preferably tetrahydrofuran, at high carbon monoxide pressure, preferably 50 to 150 bar, at 150 to 200 °C (see e.g. J. Org. Chem. 1993, 58, 5386-92).
• a phosphine e.g. triphenylphosphine
• a base e.g. triethylamine
• 2-lodo or bromo ether 9 can be transformed into indane 3 via addition of an in situ generated carbon anion or radical to the double bond and subsequent trapping of the cyclic anion by a proton and the cyclic radical by a hydride source (eq. 1 .)).
• the reactions with lithium and magnesium reagents are preferably conducted in hexanes, tetrahydrofuran, diethyl ether, 1 ,2- dimethoxyethane, toluene, or mixtures thereof, at -100 to 60 °C.
• Zn is preferably used in tetrahydrofuran, d imethyl sulfoxide, N-methylpyrrolidinone, or mixtures thereof, at 0 to 100 °C.
• Frequently employed reaction conditions for the radical pathway are, e.g., tributyltin hydride, azobisisobutyronitrile, in benzene, at 60 to 100 °C (see e.g. J. Org. Chem. 1987, 52, 4072-8); and NaH 3 B(CN) in N,N- dimethylformamide under UV irradiation at 20 to 120 °C (see e.g. Synlett 2005, 2248- 50).
• indane 3 (equation 2.)
• the reaction is preferably conducted with a palladium catalyst in the presence of carbon monoxide or molybdenum hexacarbonyl as carbon monoxide source (see e.g. Tetrahedron Lett. 2010, 51, 2102-5).
• Hydrogen is the preferred reducing agent which is mainly employed in combination with a transition metal catalyst, such as palladium on carbon, Raney nickel, and PtO2.
• a transition metal catalyst such as palladium on carbon, Raney nickel, and PtO2.
• ⁇ , ⁇ -dimethylformamide, tetrahydrofuran, ethyl acetate, alcohol, e.g. methanol and ethanol, acetic acid, water, or mixtures thereof are preferably used as solvent, at hyd rogen pressures of 1 to 1 00 bar, and temperatures of 20 to 120 °C.
• This reaction may also be carried out stereoselectively providing compound 3 in enantiomerically enriched or pure form.
• PG protective group, e.g., Me, Bn, allyl, tBuMe 2 Si
• CP masked or protected form of COOH, e.g., C0 2 C 1.4 -alkyl, C0 2 CH 2 aryl,
• the syntheses of the starting compounds in Scheme 6 comprise standard procedures used in organic synthesis.
• Intermediate 11 can, for example, be prepared as described in Scheme 7.
• Compound 11 may thus be obtained from compound 13 which, in turn, may be assembled from phenol 14 and ester 15.
• the latter transformation may be achieved in the presence of a Lewis acid, e.g. sulfuric acid, ZrCI 4 , InCb, methanesulfonic acid, p-toluenesulfonic acid , H I, or amberlyst, in toluene, dichloromethane, acetic acid, ethanol , water, or without a solvent in an excess of the Lewis acid, at 0 to 120 °C.
• Transformation of compound 13 into intermediate 11 is preferably accomplished under basic conditions with sodium hydroxide in an aqueous solution at 0 to 100 °C.
• the synthetic routes presented may rely on the use of protecting groups.
• protecting groups such as hydroxy, carbonyl, carboxy, amino, alkylamino, or imino
• potentially reactive groups present such as hydroxy, carbonyl, carboxy, amino, alkylamino, or imino
• Suitable protecting groups for the respective functionalities and their removal are well known to the one skilled in the art and are described in the literature of organic synthesis.
• the compounds of general formula I may be resolved into their enantiomers and/or diastereomers as mentioned below.
• cis/trans mixtures may be resolved into their cis and trans isomers and racemic compounds may be separated into their enantiomers.
• the cis/trans mixtures may be resolved, for example, by chromatography into the cis and trans isomers thereof.
• the compounds of general formula I which occur as racemates may be separated by methods known per se into their optical antipodes and diastereomeric mixtures of compounds of general formula I may be resolved into their diastereomers by taking advantage of their different physico-chemical properties using methods known per se, e.g. chromatography and/or fractional crystallization; if the compounds obtained thereafter are racemates, they may be resolved into the enantiomers as mentioned below.
• racemates are preferably resolved by column chromatography on chiral phases or by crystallization from an optically active solvent or by reacting with an optically active substance which forms salts or derivatives such as esters or amides with the racemic compound.
• Salts may be formed with enantiomerically pure acids for basic compounds and with enantiomerically pure bases for acidic compounds.
• Diastereomeric derivatives are formed with enantiomerically pure auxiliary compounds, e.g. acids, their activated derivatives, or alcohols. Separation of the diastereomeric mixture of salts or derivatives thus obtained may be achieved by taking advantage of their different physico-chemical properties, e.g.
• the free antipodes may be released from the pure diastereomeric salts or derivatives by the action of suitable agents.
• Optically active acids commonly used for such a purpose as well as optically active alcohols applicable as auxiliary residues are known to those skilled in the art.
• the compounds of formula I may be converted into salts, particularly for pharmaceutical use into the pharmaceutically acceptable salts.
• pharmaceutically acceptable salts refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof.
• compound(s) according to this invention denote the compounds of the formula (I) according to the present invention including their tautomers, stereoisomers and mixtures thereof and the salts thereof, in particular the pharmaceutically acceptable salts thereof, and the solvates and hydrates of such compounds, including the solvates and hydrates of such tautomers, stereoisomers and salts thereof.
• treatment and “treating” embrace both preventative, i.e. prophylactic, or therapeutic, i.e. curative and/or palliative, treatment.
• treatment and “treating” comprise therapeutic treatment of patients having already developed said condition, in particular in manifest form.
• Therapeutic treatment may be symptomatic treatment in order to relieve the symptoms of the specific indication or causal treatment in order to reverse or partially reverse the conditions of the indication or to stop or slow down progression of the disease.
• compositions and methods of the present invention may be used for instance as therapeutic treatment over a period of time as well as for chronic therapy.
• treatment and “treating” comprise prophylactic treatment, i.e. a treatment of patients at risk to develop a condition mentioned hereinbefore, thus reducing said risk.
• this invention refers to patients requiring treatment, it relates primarily to treatment in mammals, in particular humans.
• terapéuticaally effective amount means an amount of a compound of the present invention that (i) treats or prevents the particular disease or condition, (ii) attenuates, ameliorates, or eliminates one or more symptoms of the particular disease or condition, or (iii) prevents or delays the onset of one or more symptoms of the particular disease or condition described herein.
• modulated or “modulating”, or “modulate(s)", as used herein, unless otherwise indicated, refer to the activation of the G-protein-coupled receptor GPR40 with one or more compounds of the present invention.
• mediated refers to the (i) treatment, including prevention of the particular disease or condition, (ii) attenuation, amelioration, or elimination of one or more symptoms of the particular disease or condition, or (iii) prevention or delay of the onset of one or more symptoms of the particular disease or condition described herein.
• substituted means that any one or more hydrogens on the designated atom, radical or moiety is replaced with a selection from the indicated group, provided that the atom's normal valence is not exceeded, and that the substitution results in an acceptably stable compound.
• Ci-6-alkyl means an alkyl group or radical having 1 to 6 carbon atoms.
• the last named subgroup is the radical attachment point, for example, the substituent "aryl-Ci-3-alkyl-" means an aryl group which is bound to a Ci-3-alkyl- group, the latter of which is bound to the core or to the group to which the substituent is attached.
• the numeration of the atoms of a substituent starts with the atom which is closest to the core or to the group to which the substituent is attached.
• 3-carboxypropyl-group represents the following substituent:
• each X, Y and Z group is optionally substituted with
• each group X, each group Y and each group Z either each as a separate group or each as part of a composed group may be substituted as defined.
• R ex denotes H, Ci-3-alkyl, C3-6- cycloalkyl, C3-6-cycloalkyl-Ci-3-alkyl or Ci-3-alkyl-O-, wherein each alkyl group is optionally substituted with one or more L ex .” or the like means that in each of the beforementioned groups which comprise the term alkyl, i.e. in each of the groups Ci- 3-alkyl, C3-6-cycloalkyl-Ci-3-alkyl and Ci-3-alkyl-O-, the alkyl moiety may be substituted with L ex as defined.
• a given chemical formula or name shall encompass tautomers and all stereo-, optical and geometrical isomers (e.g. enantiomers, diastereomers, E/Z isomers etc ..) and racemates thereof as well as mixtures in different proportions of the separate enantiomers, mixtures of diastereomers, or mixtures of any of the foregoing forms wh ere su ch isom ers and en a ntiom ers exist, as wel l as sa lts , i n cl ud i ng pharmaceutically acceptable salts thereof and solvates thereof such as for instance hydrates including solvates of the free compounds or solvates of a salt of the compound.
• phrases "pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, and commensurate with a reasonable benefit/risk ratio.
• pharmaceutically acceptable salts refer to derivatives of the disclosed compounds wherein the parent compound is modified by making pharmaceutically acceptable acid or base salts thereof.
• Salts of other acids than those mentioned above which for example are useful for purifying or isolating the compounds of the present invention also comprise a part of the invention.
• halogen generally denotes fluorine, chlorine, bromine and iodine.
• n is an integer from 1 to n, either alone or in combination with another radical denotes an acyclic, saturated, branched or linear hydrocarbon radical with 1 to n C atoms.
• Ci -5 -alkyl embraces the rad icals H 3 C-, H 3 C-CH 2 -, H 3 C-CH 2 -CH 2 -, H 3 C-CH(CH 3 )-, H 3 C-CH2-CH 2 -CH 2 -, H 3 C-CH 2 -CH(CH 3 )-, H 3 C-CH(CH 3 )-CH 2 -, H 3 C-C(CH 3 ) 2 -, H 3 C-CH 2 -CH 2 -CH 2 -CH 2 -, H 3 C-CH 2 -CH 2 -CH(CH 3 )-, H 3 C-CH 2 -CH(CH 3 )-, H 3 C-CH 2 -CH(CH 3 )-CH 2 -, H 3 C-CH(CH 3 )-CH 2 -, H 3 C-CH(CH 3 )-CH 2 -, H 3 C- CH 2 -C(CH 3 ) 2 -, H 3 C-C(CH 3 ) 2
• Ci -n -alkylene wherein n is an integer 1 to n, either alone or in combination with another radical, denotes an acyclic, straight or branched chain divalent alkyl radical containing from 1 to n carbon atoms.
• Ci -4 -alkylene includes -(CH 2 )-, -(CH 2 -CH 2 )-, -(CH(CH 3 ))-, -(CH 2 -CH 2 -CH 2 )-, -(C(CH 3 ) 2 )-,
• C 2-n -alkenyl is used for a group as defined in the definition for "Ci -n -alkyl” with at least two carbon atoms, if at least two of those carbon atoms of said group are bonded to each other by a double bond.
• C 2-n -alkenylene is used for a group as defined in the definition for "Ci-n-alkylene” with at least two carbon atoms, if at least two of those carbon atoms of said group are bonded to each other by a double bond.
• C 2-n -alkynyl is used for a group as defined in the definition for "Ci -n -alkyl” with at least two carbon atoms, if at least two of those carbon atoms of said group are bonded to each other by a triple bond.
• C 2-3 -alkynyl includes -C ⁇ CH, -C ⁇ C-CH 3 , -CH 2 -C ⁇ CH.
• C2 -n -alkynylene is used for a group as defined in the definition for "Ci-n-alkylene” with at least two carbon atoms, if at least two of those carbon atoms of said group are bonded to each other by a triple bond.
• C2-3- alkynylene includes -C ⁇ C-, -C ⁇ C-CH 2 -, -CH 2 -C ⁇ C-.
• C 3-n -carbocyclyl denotes a monocyclic, bicyclic or tricyclic, saturated or unsaturated hydrocarbon radical with 3 to n C atoms.
• the hydrocarbon radical is preferably nonaromatic.
• the 3 to n C atoms form one or two rings.
• the rings may be attached to each other via a single bond or may be fused or may form a spirocydic or bridged ring system.
• C3-io-carbocyclyl includes C3-io-cylcoalkyl, C3-io-cycloalkenyl, octahydropentalenyl, octahydroindenyl, decahydronaphthyl, indanyl, tetrahydronaphthyl.
• C3 -n -carbocyclyl denotes C3 -n -cylcoalkyl, in particular C3-7-cycloalkyl.
• C 3-n -cycloalkyl wherein n is an integer 4 to n, either alone or in combination with another radical denotes a cyclic, saturated, unbranched hydrocarbon radical with 3 to n C atoms.
• the cyclic group may be mono-, bi-, tri- or spirocydic, most preferably monocyclic.
• cycloalkyi groups examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclododecyl, bicyclo[3.2.1 .]octyl, spiro[4.5]decyl, norpinyl, norbonyl, norcaryl, adamantyl, etc.
• C 3-n -cycloalkenyl wherein n is an integer 3 to n, either alone or in combination with another radical, denotes a cyclic, unsaturated but nonaromatic, unbranched hydrocarbon radical with 3 to n C atoms, at least two of which are bonded to each other by a double bond.
• C3 -7 -cycloalkenyl includes cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl and cycloheptatrienyl.
• aryl as used herein, either alone or in combination with another radical, unless specified otherwise, denotes a carbocyclic aromatic monocyclic group containing 6 carbon atoms which may be further fused to a second 5- or 6-membered carbocydic group which may be aromatic, saturated or unsaturated.
• Aryl includes, but is not limited to, phenyl, indanyl, indenyl, naphthyl, anthracenyl, phenanthrenyl, tetrahydronaphthyl and dihydronaphthyl. More preferably the term "aryl” as used herein, either alone or in combination with another radical, denotes phenyl or naphthyl, most preferably phenyl.
• heterocyclyl is intended to include all the possible isomeric forms.
• Examples of such groups include aziridinyl, oxiranyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, tetrahydropyranyl , azepanyl, piperazinyl, morpholinyl, tetrahydrofuranonyl, tetrahydropyranonyl, pyrrolidinonyl, piperidinonyl, piperazinonyl, morpholinonyl.
• heterocyclyl includes the following exemplary structures which are not depicted as radicals as each form may be attached through a covalent bond to any atom so long as appropriate valences are maintained:
• heteroaryl is intended to include all the possible isomeric forms.
• the term “heteroaryl” includes the following exemplary structures which are not depicted as radicals as each form may be attached through a covalent bond to any atom so long as appropriate valences are maintained:
• IPi accumulation measurements using the IPOne assay system - 1321 N1 cells stably expressing human GPR40 receptor (Euroscreen, Belgium) are seeded 24 h before the assay in black clear-bottom collagen-coated 384-well plates in culture medium containing 10% FCS, 1 % Na-Pyruvate and 400 pg/m L G41 8.
• I Pi is assayed according to the Manufacturer's description (Cisbio Bioassays, France). In brief, the assay is started by substitution of the culture medium by stimulation buffer (Hepes 10 mM, CaCI 2 1 mM, MgCI 2 0.5 mM, KCI 4.2 mM, NaCI 146 mM and glucose 5.5 mM, pH 7.4) without LiCI.
• stimulation buffer Hepes 10 mM, CaCI 2 1 mM, MgCI 2 0.5 mM, KCI 4.2 mM, NaCI 146 mM and glucose 5.5 mM, pH 7.4
• Cells are stimulated for 1 hour at 37 °C, 10% CO 2 by addition of the compounds that are diluted in stimulation buffer containing LiCI yielding a final LiCI concentration of 50 mM.
• Assays are stopped by adding HTRF-conjugates (IP1 - d2 and Anti-IP1 cryptate Tb) and lysis buffer, provided by the manufacturer. After an incubation time of 1 hour at room temperature plates are measured using an EnVisionTM, Perkin Elmer. The obtained fluorescence ratios at 665/615 nM are then used to calculate the pEC 5 o values using GraphPad Prism 5 (Graphpad Software Inc, USA) by interpolation using an IPi reference curve and subsequent sigmoidal curve fitting allowing for a variable hill slope.
• the compounds according to the invention typically have EC 5 o values in the range from about 1 nM to about 10 ⁇ , preferably less than 1 ⁇ , more preferably less than 100 nM.
• EC 5 o values for compounds according to the invention determined in Assay I are shown in the following table. The number of the compound corresponds to the number of the Example in the experimental section.
• IPi accumulation measurements using the IPOne assay system - 1321 N1 cells stably expressing human GPR40 receptor (Euroscreen, Belgium) are seeded 24 h before the assay in white 384-well plates in culture medium containing 10% FCS, 1 % Na- Pyruvate and 400 g/mL G418. IPi is assayed according to the manufacturer's description (Cisbio Bioassays, France). In brief, the assay is started by substitution of the culture medium by stimulation buffer (Hepes 10 mM, CaC 1 mM, MgC 0.5 mM, KCI 4.2 mM, NaCI 146 mM, glucose 5.5 mM and LiCI 50 mM, pH 7.4).
• stimulation buffer Hepes 10 mM, CaC 1 mM, MgC 0.5 mM, KCI 4.2 mM, NaCI 146 mM, glucose 5.5 mM and LiCI 50 mM, pH 7.4
• Cells are stimulated for 1 h at 37 °C, 5% CO2 by addition of the compounds that are diluted in stimulation buffer containing LiCI. Assays are stopped by adding HTRF-conjugates (IP1 -d2 and Anti-IP1 cryptate Tb) and lysis buffer, provided by the manufacturer. After an incubation time of 1 h at room temperature plates are measured using an EnVisionTM, Perkin Elmer. The obtained fluorescence ratios at 665/615 nM are then used to calculate the pEC 5 o values using Assay Explorer 3.3 Software (Accelrys, Inc.) by interpolation using an IPi reference curve and subsequent sigmoidal curve fitting allowing for a variable hill slope.
• the compounds according to the invention typically have EC 5 0 values in the range from about 1 nM to about 10 ⁇ , preferably less than 1 ⁇ , more preferably less than 100 nM.
• the compounds of general formula I according to the invention are theoretically suitable for the treatment of all those diseases or conditions which may be affected or which are mediated by the activation of the G-protein-coupled receptor GPR40.
• the present invention relates to a compound of general formula I as a medicament. Furthermore, the present invention relates to the use of a compound of general formula I or a pharmaceutical composition according to this invention for the treatment and/or prevention of diseases or conditions which are mediated by the activation of the G-protein-coupled receptor GPR40 in a patient, preferably in a human.
• the present invention relates to a method for treating a disease or condition mediated by the activation of the G-protein-coupled receptor GPR40 in a mammal that includes the step of administering to a patient, preferably a human, in need of such treatment a therapeutically effective amount of a compound or a pharmaceutical composition of the present invention.
• Diseases and conditions mediated by agonists of the G-protein-coupled receptor GPR40 embrace metabolic diseases or conditions.
• the compounds and pharmaceutical compositions of the present invention are particularly suitable for treating diabetes mellitus, in particular Type 2 diabetes, Type 1 diabetes, complications of diabetes (such as e.g.
• retinopathy retinopathy, nephropathy or neuropathies, diabetic foot, ulcers or macroangiopathies
• metabolic acidosis or ketosis reactive hypoglycaemia, hyperinsulinaemia, glucose metabolic disorder, insul in resistance, metabol ic syndrome, dysl ipidaem ias of d ifferent orig ins, atherosclerosis and related diseases, obesity, high blood pressure, chronic heart failure, oedema and hyperuricaemia.
• the compounds and pharmaceutical compositions of the present invention are also suitable for preventing beta-cell degeneration such as e.g. apoptosis or necrosis of pancreatic beta cells.
• the compounds and pharmaceutical compositions of the present invention are also suitable for improving or restoring the functionality of pancreatic cells, and also for increasing the number and size of pancreatic beta cells. Therefore according to another aspect the invention relates to compounds of formula I and pharmaceutical compositions according to the invention for use in preventing, delaying, slowing the progression of and/or treating metabolic diseases, particularly in improving the glycaemic control and/or beta cell function in the patient. In another aspect the invention relates to compounds of formula I and pharmaceutical compositions according to the invention for use in preventing, delaying, slowing the progression of and/or treating type 2 diabetes, overweight, obesity, complications of diabetes and associated pathological conditions.
• compositions according to the invention are suitable for use in one or more of the following therapeutic processes:
• metabolic diseases such as for example type 1 diabetes, type 2 diabetes, insufficient glucose tolerance, insulin resistance, hyperglycaemia, hyperl ipidaemia, hypercholesterolemia, dyslipidaemia, syndrome X, metabolic syndrome, obesity, high blood pressure, chronic systemic inflammation, retinopathy, neuropathy, nephropathy, atherosclerosis, endothelial dysfunction or bone-related diseases (such as osteoporosis, rheumatoid arthritis or osteoarthritis);
• metabolic diseases such as for example type 1 diabetes, type 2 diabetes, insufficient glucose tolerance, insulin resistance, hyperglycaemia, hyperl ipidaemia, hypercholesterolemia, dyslipidaemia, syndrome X, metabolic syndrome, obesity, high blood pressure, chronic systemic inflammation, retinopathy, neuropathy, nephropathy, atherosclerosis, endothelial dysfunction or bone-related diseases (such as osteoporosis, rheumatoid arthritis or osteoarthritis);
• a condition or a disease selected from among the complications of diabetes, such as for example retinopathy, nephropathy or neuropathies, diabetic foot, ulcers or macroangiopathies;
• pancreatic beta cells for preventing or treating the degradation of pancreatic beta cells and/or improving and/or restoring the functionality of pancreatic beta cells and/or restoring the functionality of pancreatic insulin secretion;
• the compounds and pharmaceutical compositions according to the invention are suitable for the treatment of obesity, diabetes (comprising type 1 and type 2 diabetes, preferably type 2 diabetes mellitus) and/or complications of diabetes (such as for example retinopathy, nephropathy or neuropathies, diabetic foot, ulcers or macroangiopathies).
• diabetes comprising type 1 and type 2 diabetes, preferably type 2 diabetes mellitus
• complications of diabetes such as for example retinopathy, nephropathy or neuropathies, diabetic foot, ulcers or macroangiopathies.
• the compounds according to the invention are most particularly suitable for treating type 2 diabetes mellitus.
• the dose range of the compounds of general formula I applicable per day is usually from 0.001 to 10 mg per kg body weight, for example from 0.01 to 8 mg per kg body weight of the patient.
• Each dosage unit may conveniently contain from 0.1 to 1000 mg, for example 0.5 to 500 mg.
• the actual therapeutically effective amount or therapeutic dosage will of course depend on factors known by those skilled in the art such as age and weight of the patient, route of administration and severity of disease. In any case the compound or composition will be administered at dosages and in a manner which allows a therapeutically effective amount to be delivered based upon patient's unique condition.
• compositions, including any combinations with one or more additional therapeutic agents, according to the invention may be administered by oral, transdermal, inhalative, parenteral or sublingual route.
• oral or intravenous administration is preferred.
• Suitable preparations for administering the compounds of formula I, optionally in combination with one or more further therapeutic agents will be apparent to those with ordinary skill in the art and include for example tablets, pills, capsules, suppositories, lozenges, troches, solutions, syrups, elixirs, sachets, injectables, inhalatives and powders etc. Oral formulations, particularly solid forms such as e.g. tablets or capsules are preferred.
• the content of the pharmaceutically active compound(s) is advantageously in the range from 0.1 to 90 wt.-%, for example from 1 to 70 wt.-% of the composition as a whole.
• Suitable tablets may be obtained, for example, by mixing one or more compounds according to formula I with known excipients, for example inert diluents, carriers, disintegrants, adjuvants, surfactants, binders and/or lubricants.
• excipients for example inert diluents, carriers, disintegrants, adjuvants, surfactants, binders and/or lubricants.
• the tablets may also consist of several layers.
• the particular excipients, carriers and/or diluents that are suitable for the desired preparations will be familiar to the skilled man on the basis of his specialist knowledge.
• the preferred ones are those that are suitable for the particular formulation and method of administration that are desired.
• preparations or formulations according to the invention may be prepared using methods known per se that are familiar to the skilled man, such as for example by mixing or combining at least one compound of formula I according to the invention, or a pharmaceutically acceptable salt of such a compound, and one or more excipients, carriers and/or diluents.
• the compounds of the invention may further be combined with one or more, preferably one additional therapeutic agent.
• the additional therapeutic agent is selected from the group of therapeutic agents useful in the treatment of diseases or conditions described hereinbefore, in particular associated with metabolic diseases or conditions such as for example diabetes mellitus, obesity, diabetic complications, hypertension, hyperlipidemia.
• Additional therapeutic agents which are suitable for such combinations include in particular those which for example potentiate the therapeutic effect of one or more active substances with respect to one of the indications mentioned and/or which allow the dosage of one or more active substances to be reduced.
• a compound of the invention may be combined with one or more additional therapeutic agents selected from the group consisting of antidiabetic agents, agents for the treatment of overweight and/or obesity and agents for the treatment of high blood pressure, heart failure and/or atherosclerosis.
• Antidiabetic agents are for example metformin, sulphonylureas, nateglinide, repaglinide, thiazolidinediones, PPAR-(alpha, gamma or alpha/gamma) agonists or modulators, alpha-glucosidase inhibitors, DPPIV inhibitors, SGLT2-inhibitors, insulin and insulin analogues, GLP-1 and GLP-1 analogues or amylin and amylin analogues, cycloset, ⁇ ⁇ ⁇ -HSD inhibitors.
• Other suitable combination partners are inhibitors of protein tyrosinephosphatase 1 , substances that affect deregulated glucose production in the liver, such as e.g.
• glucose-6-phosphatase or fructose- 1 ,6-bisphosphatase
• glycogen phosphorylase glycogen phosphorylase
• glucagon receptor antagonists and inhibitors of phosphoenol pyruvate carboxykinase, glycogen synthase kinase or pyruvate dehydrokinase, alpha2-antagonists, CCR-2 antagonists or glucokinase activators.
• One or more lipid lowering agents are also suitable as combination partners, such as for example HMG-CoA-reductase inhibitors, fibrates, nicotinic acid and the derivatives thereof, PPAR-(alpha, gamma or alpha/gamma) agonists or modulators, PPAR-delta agonists, ACAT inhibitors or cholesterol absorption inhibitors such as, bile acid-binding substances such as, inhibitors of ileac bile acid transport, MTP inhibitors, or HDL-raising compounds such as CETP inhibitors or ABC1 regulators.
• HMG-CoA-reductase inhibitors such as for example HMG-CoA-reductase inhibitors, fibrates, nicotinic acid and the derivatives thereof, PPAR-(alpha, gamma or alpha/gamma) agonists or modulators, PPAR-delta agonists, ACAT inhibitors or cholesterol absorption inhibitors such as, bile acid-binding substances such
• Therapeutic agents for the treatment of overweight and/or obesity are for example antagonists of the cannabinoidl receptor, MCH-1 receptor antagonists, MC4 receptor agonists, NPY5 or NPY2 antagonists, 3-agonists, leptin or leptin mimetics, agonists of the 5HT2c receptor.
• Therapeutic agents for the treatment of high blood pressure, chronic heart failure and/or atherosclerosis are for example A-ll antagonists or ACE inhibitors, ECE inhibitors, diuretics, ⁇ -blockers, Ca-antagonists, centrally acting antihypertensives, antagonists of the alpha-2-adrenergic receptor, inhibitors of neutral endopeptidase, thrombocyte aggregation inhibitors and others or combinations thereof are suitable.
• Angiotensin II receptor antagonists are preferably used for the treatment or prevention of high blood pressure and complications of diabetes, often combined with a diuretic such as hydrochlorothiazide.
• the dosage for the combination partners mentioned above is usually 1 /5 of the lowest dose normally recommended up to 1/1 of the normally recommended dose.
• compounds of the present invention and/or pharmaceutical compositions comprising a compound of the present invention optionally in combination with one or more additional therapeutic agents are administered in conjunction with exercise and/or a diet.
• this invention relates to the use of a compound according to the invention in combination with one or more additional therapeutic agents described hereinbefore and hereinafter for the treatment of diseases or conditions which may be affected or which are mediated by the activation of the G- protein-coupled receptor GPR40, in particular diseases or conditions as described hereinbefore and hereinafter.
• the present invention relates a method for treating a disease or condition mediated by the activation of the G-protein-coupled receptor GPR40 in a patient that includes the step of administering to the patient, preferably a human, in need of such treatment a therapeutically effective amount of a compound of the present invention in combination with a therapeutically effective amount of one or more additional therapeutic agents described in hereinbefore and hereinafter,
• the compound according to the invention and the one or more additional therapeutic agents may both be present together in one formulation, for example a tablet or capsule, or separately in two identical or different formulations, for example as a so- called kit-of-parts.
• this invention relates to a pharmaceutical composition which comprises a compound according to the invention and one or more additional therapeutic agents described hereinbefore and hereinafter, optionally together with one or more inert carriers and/or diluents.
• ambient temperature and “room temperature” are used interchangeably and designate a temperature of about 20 °C.
• Carrier gas Helium, 1 mL/min costant flow
• Oven Program 50°C to 100°C in 10°C/min, to 200°C in
• Step 1 (S)-4-Bromo-2,3-dihydro-1 H-inden-1 -ol
• Chloro ⁇ [(1 S,2S)-(-)-2- amino-1 ,2-diphenylethyl](4-toluenesulfonyl)amido ⁇ -(mesitylene)ruthenium(l l) 700 mg; alternatively, the catalyst is formed in situ from N-[(1 S,2S)-2-amino-1 ,2- diphenylethyl]-4-methylbenzenesulfonamide and dichloro(p-cymene)-ruthenium(ll) dimer) is added and the mixture is stirred at room temperature for 16 hours. Water is added and the resulting mixture is extracted with dichloromethane.
• the enantiomers are separated by SFC on chiral phase (column: Daicel ADH, 5 ⁇ , 250 m m x 20 m m ; el uent : scCO 2 /(isopropanol+0.2% diethylamine) 80:20, 70 mL/min):
• Step 6 Methyl 2-((S)-6-((R)-4-bromo-2,3-dihydro-1 H-inden-1 -yloxy)-2,3- dihydrobenzofuran-3-yl)acetate
• Step 7 Methyl 2-((S)-6-((R)-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-2,3- dihydro-1 H-inden-1 -yloxy)-2,3-dihydrobenzofuran-3-yl)acetate
• Step 8 Methyl 2-((3S)-6-((1 R)-4-(2-methyl-5-(3-(methylsulfonyl)propoxy)phenyl)-2,3- dihydro-1 H-inden-1 -yloxy)-2,3-dihydrobenzofuran-3-yl)acetate
• Step 1 4-(4,4,5,5-Tetramethyl-1 ,3,2-dioxaborolan-2-yl)-2,3-dihydro-1 H-inden-1 -
• the title compound is prepared from 4-bromo-2,3-dihydro-1 H-inden-1 -one following a procedure analogous to that described in Step 7 of Intermediate 1 .
• Step 2 4-(4-Hydroxy-2,6-dimethylphenyl)-2,3-dihydro-1 H-inden-1 -one
• a microwave vial a mixture of 4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-2,3- dihydro-1 H-inden-1 -one (610 mg), 4-bromo-3,5-dimethylphenol (475 mg), Na 2 CO3 (8 ml_ of a 1 M aqueous solution), toluene (8 ml_) and ethanol (2.5 ml_) is purged for 5 minutes with argon. Tetrakis-triphenylphosphine-palladium-(O) (140 mg) is added, the vial is sealed and the mixture is stirred at 1 10°C for 12 hours.
• Step 3 4-(2,6-Dimethyl-4-(3-(methylsulfonyl)propoxy)phenyl)-2,3-dihydro-1 H-inden- 1 -one
• Step 4 (S)-4-(2,6-Dimethyl-4-(3-(methylsulfonyl)propoxy)phenyl)-2,3-dihydro-1 H- inden-1 -ol
• Step 5 Methyl 2-((S)-6-((R)-4-(2,6-dimethyl-4-(3-(methylsulfonyl)propoxy)phenyl)- 2,3-dihydro-1 H-inden-1 -yloxy)-2,3-dihydrobenzofuran-3-yl)acetate
• Step 1 3-(tert-Butyldimethylsilyloxy)-2,6-dimethylphenol 2,4-Dimethylbenzene-1 ,3-diol (1 .5 g) and triethylamine (2.3 mL) are dissolved in dichloromethane (15 mL) , c o o l e d t o 0 ° C a n d t r e a t e d w i t h tert- butylchlorodimethylsilane (1 .7 g) and 4-dimethylaminopyridine (133 mg).
• Step 2 3-(tert-Butyldimethylsilyloxy)-2,6-dimethylphenyl trifluoromethane-sulfonate 3-(tert-Butyldimethylsilyloxy)-2,6-dimethylphenol (2.1 g) and 2,6-dimethylpyridine (lutidine) (2 mL) are dissolved in dichloromethane (20 mL) cooled to 0°C and treated with trifluoromethanesulfonic anhydride (1 .6 mL). The mixture is stirred for 3 hours at room temperature, diluted with dichloromethane and washed with saturated aqueous NH CI solution and brine.
• Step 4 Methyl 2-((3S)-6-((1 R)-4-(3-hydroxy-2,6-dimethylphenyl)-2,3-dihydro-1 H- inden-1 -yloxy)-2,3-dihydrobenzofuran-3-yl)acetate
• Step 5 Methyl 2-((3S)-6-((1 R)-4-(2,6-dimethyl-3-(3-(methylsulfonyl)propoxy)phenyl)- 2,3-dihydro-1 H-inden-1 -yloxy)-2,3-dihydrobenzofuran-3-yl)acetate
• Step 3 Methyl 2-((S)-6-((R)-4-(2,6-dimethyl-4-((R)-tetrahydrofuran-3-yloxy)phenyl)- 2,3-dihydro-1 H-inden-1 -yloxy)-2,3-dihydrobenzofuran-3-yl)acetate
• the title compound is prepared from 3-methylbutane-1 ,3-diol and 4-methylbenzene- 1 -sulfonyl chloride following a procedure analogous to that described in Step 4 of Intermediate 1 .
• Step 1 (4-Bromo-3,5-dimethylphenoxy)(tert-butyl)dimethylsilane
• Step 2 Methyl 2-((S)-6-((R)-4-(4-(tert-butyldimethylsilyloxy)-2,6-dimethylphenyl)-2,3- dihydro-1 H-inden-1 -yloxy)-2,3-dihydrobenzofuran-3-yl)acetate
• Step 3 Methyl 2-((S)-6-((R)-4-(4-hydroxy-2,6-dimethylphenyl)-2,3-dihydro-1 H-inden-
• Step 4 Methyl 2-((S)-6-((R)-4-(4-(2-methoxyethoxy)-2,6-dimethylphenyl)-2,3-dihydro- 1 H-inden-1 -yloxy)-2,3-dihydrobenzofuran-3-yl)acetate
• methyl 2-((S)-6-((R)-4-(4-hydroxy-2,6-dimethylphenyl)-2,3-dihydro- 1 H-inden-1 -yloxy)-2,3-dihydrobenzofuran-3-yl)acetate 37 mg
• K2CO3 24 mg
• N,N-dimethylformamide (2 ml_) 1 -bromo-2-methoxyethane (1 0 ⁇ _).
• Step 3 1 -Bromo-3-(2-methoxyethoxy)-2-methyl benzene
• Step 2 Methyl 2-((3S)-6-((1 R)-4-(3-(2-hydroxyethoxy)-2-methylphenyl)-2,3-dihydro- 1 H-inden-1 -yloxy)-2,3-dihydrobenzofuran-3-yl)acetate
• Step 1 3-((4-Bromo-3,5-dimethylphenoxy)methyl)-3-methyloxetane
• Step 3 Methyl 2-((S)-6-((R)-4-bromo-7-fluoro-2,3-dihydro-1 H-inden-1 -yloxy)-2,3- dihydrobenzofuran-3-yl)acetate
• Step 4 Methyl 2-((S)-6-((R)-7-fluoro-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)- 2,3-dihydro-1 H-inden-1 -yloxy)-2,3-dihydrobenzofuran-3-yl)acetate
• Step 5 Methyl 2-((S)-6-((R)-4-(2,6-dimethyl-4-((3-methyloxetan-3- yl)methoxy)phenyl)-7-fluoro-2,3-dihydro-1 H-inden-1 -yloxy)-2,3-dihydrobenzofuran-3- yl)acetate
• the title compound is prepared from 4-bromo-3,5-dimethylphenol and 3-
• Step 4 Methyl 2-((3S)-6-((1 R)-4-(2,6-dimethyl-4-((tetrahydrofuran-3- yl)methoxy)phenyl)-7-fluoro-2,3-dihydro-1 H-inden-1 -yloxy)-2,3-dihydrobenzofuran-3- yl)acetate
• Step 1 1 -(2-Bromophenyl)cyclopropanecarbonitrile

Landscapes

• Health & Medical Sciences (AREA)
• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Animal Behavior & Ethology (AREA)
• General Health & Medical Sciences (AREA)
• Life Sciences & Earth Sciences (AREA)
• Pharmacology & Pharmacy (AREA)
• Public Health (AREA)
• Veterinary Medicine (AREA)
• Medicinal Chemistry (AREA)
• Epidemiology (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Engineering & Computer Science (AREA)
• General Chemical & Material Sciences (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Diabetes (AREA)
• Cardiology (AREA)
• Heart & Thoracic Surgery (AREA)
• Obesity (AREA)
• Hematology (AREA)
• Child & Adolescent Psychology (AREA)
• Hospice & Palliative Care (AREA)
• Urology & Nephrology (AREA)
• Vascular Medicine (AREA)
• Emergency Medicine (AREA)
• Endocrinology (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Plural Heterocyclic Compounds (AREA)
• Furan Compounds (AREA)
• Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
• Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Priority Applications (2)

Applications Claiming Priority (2)

Publications (1)

Family

ID=48013980

Family Applications (2)

Family Applications After (1)

Country Status (23)

Cited By (9)

Families Citing this family (21)

Citations (5)

Family Cites Families (8)

• 2013
  • 2013-03-14 US US13/803,237 patent/US8642585B2/en active Active
  • 2013-03-22 UY UY0001034704A patent/UY34704A/es unknown
  • 2013-03-25 SG SG11201405713UA patent/SG11201405713UA/en unknown
  • 2013-03-25 AU AU2013241926A patent/AU2013241926A1/en not_active Abandoned
  • 2013-03-25 HK HK15101722.6A patent/HK1201260A1/xx unknown
  • 2013-03-25 CN CN201380026597.0A patent/CN104321319A/zh active Pending
  • 2013-03-25 JP JP2015502285A patent/JP6131492B2/ja not_active Expired - Fee Related
  • 2013-03-25 TW TW102110560A patent/TW201400466A/zh unknown
  • 2013-03-25 KR KR20147030011A patent/KR20140139088A/ko not_active Withdrawn
  • 2013-03-25 JP JP2015502284A patent/JP6040486B2/ja active Active
  • 2013-03-25 WO PCT/EP2013/056313 patent/WO2013144098A1/en not_active Ceased
  • 2013-03-25 PE PE2014001462A patent/PE20142019A1/es not_active Application Discontinuation
  • 2013-03-25 EP EP13724175.8A patent/EP2831053B1/en not_active Not-in-force
  • 2013-03-25 WO PCT/EP2013/056312 patent/WO2013144097A1/en not_active Ceased
  • 2013-03-25 AR ARP130100969A patent/AR090493A1/es unknown
  • 2013-03-25 CA CA2868474A patent/CA2868474A1/en not_active Abandoned
  • 2013-03-25 AP AP2014007903A patent/AP2014007903A0/xx unknown
  • 2013-03-25 EP EP13712760.1A patent/EP2831064B1/en active Active
  • 2013-03-25 EA EA201401053A patent/EA201401053A1/ru unknown
  • 2013-03-25 MX MX2014011465A patent/MX2014011465A/es unknown
  • 2013-03-25 MA MA37429A patent/MA20150065A1/fr unknown
• 2014
  • 2014-09-22 TN TNP2014000398A patent/TN2014000398A1/fr unknown
  • 2014-09-25 PH PH12014502141A patent/PH12014502141A1/en unknown
  • 2014-09-25 CL CL2014002556A patent/CL2014002556A1/es unknown
  • 2014-09-26 CO CO14213969A patent/CO7091175A2/es unknown
  • 2014-10-17 EC ECIEPI201423238A patent/ECSP14023238A/es unknown

Patent Citations (5)

Non-Patent Citations (2)

Also Published As

Similar Documents

Legal Events