EP1742949A1 - Neue 2-(piperazin-1-yl)- und 2-(¬1,4|diazepan-1-yl)- imidazo¬4,5-d|pyridazin-4-one, deren herstellung und deren verwendung als arzneimittel zur bekämpfung von diabetes mellitus - Google Patents
Neue 2-(piperazin-1-yl)- und 2-(¬1,4|diazepan-1-yl)- imidazo¬4,5-d|pyridazin-4-one, deren herstellung und deren verwendung als arzneimittel zur bekämpfung von diabetes mellitusInfo
- Publication number
- EP1742949A1 EP1742949A1 EP04803766A EP04803766A EP1742949A1 EP 1742949 A1 EP1742949 A1 EP 1742949A1 EP 04803766 A EP04803766 A EP 04803766A EP 04803766 A EP04803766 A EP 04803766A EP 1742949 A1 EP1742949 A1 EP 1742949A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- methyl
- pyridazin
- group
- piperazin
- butyn
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
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Definitions
- the present invention relates to new substituted imidazo [4,5-d] pyridazin-4-ones of the general formula
- DPP-IV dipeptidylpeptidase-IV
- the Production their use for the prevention or treatment of diseases or conditions which are associated with increased DPP-IV activity or which can be prevented or alleviated by reducing the DPP-IV activity, in particular of type I or type II diabetes mellitus, the a compound of the general formula (I) or a medicament containing a physiologically acceptable salt thereof and process for their preparation.
- DPP-IV dipeptidylpeptidase-IV
- R 1 is a heteroaryl-cis-alkyl group, where under the term heteroaryl a pyridinyl, pyrimidinyl, phenylpyridinyl, phenylpyrimidinyl, benzoxazolyl, 1-methyl-1H-benzotriazolyl, benzo [1, 2.5] thiadiazolyl, [1, 2.4 ] Triazolo [4,3-a] pyridinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, naphthyridinyl or phenanthridinyl group is to be understood and the heteroaryl groups mentioned above by R 10 , R 11 and R 12 are substituted, where R 10 is a hydrogen atom, a fluorine, chlorine or bromine atom or a methyl, difluoromethyl, trifluoromethyl, phenyl, cyano, methoxy, difluoromethoxy, trifluoromethoxy
- R 13 is a hydrogen atom, a fluorine, chlorine or bromine atom or a methyl, difluoromethyl, trifluoromethyl
- R 14 represents a hydrogen atom or a methyl, methoxy or cyano group
- R 2 represents a hydrogen atom or a methyl group
- R 3 is a 2-butyn-1-yl group or a 1-buten-1-yl, 2-buten-1-yl or 3-methyl-2-buten-1-yl group,
- n is the number 1 or 2, being the connections
- Preferred compounds of the general formula I are those in which
- R 1 is a heteroarylmethyl group, the term heteroaryl being a pyridinyl, pyrimidinyl, benzoxazolyl, 1-methyl-1H-benzotriazolyl, benzo [1, 2.5] thiadiazoiyl, [1, 2.4] Triazolo [4,3-apyridinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, naphthyridinyl or phenanthridinyl group and the above-mentioned heteroaryl groups are substituted by R 10 , R 11 and R 12 , where R 10 is a hydrogen atom or a fluorine atom or a methyl, difluoromethyl, trifluoromethyl, phenyl, cyano, methoxy, difluoromethoxy, trifluoromethoxy, dimethylamino, pyrrolidin-1-yl, piperidine 1- yl or morpholin-4-yl
- R 13 is a hydrogen atom, a fluorine, chlorine or bromine atom or a methyl, difluoromethyl, trifluoromethyl, cyano, methoxy
- R 14 represents a hydrogen atom or a cyano group
- R 2 represents a hydrogen atom or a methyl group
- R 3 is a 2-butyn-1-yl group or a 1-buten-1-yl, 2-buten-1-yl or 3-methyl-2-buten-1-yl group
- n represents the number 1 or 2
- Preferred subgroups relate in each case to those compounds of the general formula I in which R 1 , R 2 and n are defined as mentioned above and R 3 is a 2-butyn-1-yl group, their tautomers, their enantiomers, their diastereomers, their Mixtures and their salts.
- R 1 is a heteroarylmethyl group, the term heteroaryl being a pyridinyl, pyrimidinyl, benzoxazolyl, 1-methyl-1H-benzotriazolyl, benzo [1, 2.5] thiadiazolyl, [1, 2.4] Triazolo [4,3-apyridinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, naphthyridinyl or phenanthridinyl group and the above-mentioned heteroaryl groups are substituted by R 10 , R 11 and R 12 , where R 10 represents a hydrogen atom or a fluorine atom or a methyl, phenyl, cyano, methoxy, dimethylamino, pyrrolidin-1-yl, piperidin-1-yl or morpholin-4-yl group, R 11 represents a hydrogen atom or a methyl or cyano group and R 12 represents a hydrogen
- R 3 is a 2-butyn-1-yl group
- n represents the number 1 or 2
- R is a methyl group which is replaced by a fluomaphthyl, bromnaphthyl, methoxynaphthyl, cyanonaphthyl, dicyanonaphthyl, methylpyridinyl, cyanopyridinyl, dimethylpyrimidinyl, phenylpyrimidinyl, methylbenzoxazolyl, 1-methyl-1-H-benzyl , Benzo [1, 2.5] thiadiazolyl, [1, 2.4] triazolo [4,3-a] pyridinyl, quinolinyl, fluoroquinolinyl, methylquinolinyl, cyanoquinolinyl, methylisoquinolinyl, cyanoisoquinoline -, Quinazolinyl, methylquinazolinyl, phenylquinazolinyl, (dimethylamino) quinazolinyl, (morpholin-4
- R 2 is a hydrogen atom
- R 3 is a 2-butyn-1-yl group
- n represents the number 1 or 2
- R 1 is a methyl group which is substituted by a cyanonaphthyl, methylbenzoxazolyl, 1-methyl-1H-benzotriazolyl, benzo [1, 2.5] thiadiazolyl, methylisoquinolinyl, methylquinazolinyl or trimethylquinoxalinyl group,
- R 2 is a hydrogen atom, R is a 2-butyn-1-yl group and
- n the number 1 or 2
- R 1 , R 2 and R 3 are as defined above
- n the number 1
- a second preferred subgroup are those compounds of the general formula I in which
- R 1 , R 2 and R 3 are as defined above
- n is the number 2
- the compounds of the general formula I are obtained by processes known per se, for example by the following processes:
- R 1 to R 3 are defined as mentioned at the outset and
- Z 1 is a leaving group such as a halogen atom, a substituted hydroxy, mercapto,
- Sulfinyl, sulfonyl or sulfonyloxy group such as a chlorine or bromine atom, a
- the reaction is advantageously carried out in a solvent such as isopropanol, butanol, tetrahydrofuran, dioxane, dimethylformamide, dimethyl sulfoxide, ethylene glycol monomethyl ether, ethylene glycol diethyl ether or sulfolane, optionally in the presence of an inorganic or tertiary organic base, for example sodium carbonate, potassium carbonate or potassium hydroxide, a tertiary organic base, e.g.
- Triethylamine or in the presence of N-ethyl-diisopropylamine (Hünig base), these organic bases can also serve as solvents at the same time, and optionally in the presence of a reaction accelerator such as an alkali metal halide or a palladium-based catalyst at temperatures between -20 and 180 ° C, but preferably at temperatures between -10 and 120 ° C.
- a reaction accelerator such as an alkali metal halide or a palladium-based catalyst at temperatures between -20 and 180 ° C, but preferably at temperatures between -10 and 120 ° C.
- the reaction can also be carried out without a solvent or in an excess of piperazine or [1, 4] diazepane.
- R, R 2 , R 3 and n are defined as mentioned at the beginning.
- the tert-butyloxycarbonyl radical is preferably cleaved off by treatment with an acid such as trifluoroacetic acid or hydrochloric acid or by treatment with bromotrimethylsilane or iodotrimethylsilane, optionally using a solvent such as methylene chloride, ethyl acetate, dioxane, methanol, isopropanol or diethyl ether at temperatures between 0 and 80 ° C. ,
- any reactive groups present such as amino, alkylamino or imino groups, can be protected during the reaction by customary protective groups, which are split off again after the reaction.
- protective residues for an amino, alkylamino or imino group are the formyl, acetyl, trifluoroacetyl, ethoxycarbonyl, tert-butoxycarbonyl, Benzyloxycarbonyl, benzyl, methoxybenzyl or 2,4-dimethoxybenzyl group and, in addition, the phthalyl group for the amino group.
- the subsequent subsequent splitting off of a protective residue used takes place, for example, hydrolytically in an aqueous solvent, e.g. in water, isopropanol / water, acetic acid water, tetrahydrofuran / water or dioxane water, in the presence of an acid such as trifluoroacetic acid, hydrochloric acid or sulfuric acid or in the presence of an alkali base such as sodium hydroxide or potassium hydroxide or aprotic, e.g. in the presence of iodotrimethylsilane, at temperatures between 0 and 120 ° C, preferably at temperatures between 10 and 100 ° C.
- an aqueous solvent e.g. in water, isopropanol / water, acetic acid water, tetrahydrofuran / water or dioxane water
- an acid such as trifluoroacetic acid, hydrochloric acid or sulfuric acid
- an alkali base such as sodium hydroxide or potassium
- a benzyl, methoxybenzyl or benzyloxycarbonyl radical is cleaved off, for example, by hydrogenolysis, e.g. with hydrogen in the presence of a catalyst such as palladium / carbon in a suitable solvent such as methanol, ethanol, ethyl acetate or glacial acetic acid, optionally with the addition of an acid such as hydrochloric acid at temperatures between 0 and 100 ° C, but preferably at room temperatures between 20 and 60 ° C, and at a hydrogen pressure of 1 to 7 bar, but preferably from 3 to 5 bar.
- a 2,4-dimethoxybenzyl radical is preferably cleaved in trifluoroacetic acid in the presence of anisole.
- a tert-butyl or tert-butyloxycarbonyl radical is preferably cleaved off by treatment with an acid such as trifluoroacetic acid or hydrochloric acid or by treatment with iodotrimethylsilane, optionally using a solvent such as methylene chloride, dioxane, methanol or diethyl ether.
- a trifluoroacetyl radical is preferably split off by treatment with an acid such as hydrochloric acid, if appropriate in the presence of a solvent such as acetic acid at temperatures between 50 and 120 ° C. or by treatment with sodium hydroxide solution optionally in the presence of a solvent such as tetrahydrofuran at temperatures between 0 and 50 ° C.
- a phthalyl radical is preferably cleaved in the presence of hydrazine or a primary amine such as methylamine, ethylamine or n-butylamine in a solvent such as methanol, ethanol, isopropanol, toluene / water or dioxane at temperatures between 20 and 50 ° C.
- the compounds of general formula I obtained can be separated into their enantiomers and / or diastereomers.
- cis / trans mixtures can be separated into their ice and trans isomers, and compounds with at least one optically active carbon atom can be separated into their enantiomers.
- the cis / trans mixtures obtained can be chromatographed into their cis and trans isomers, the compounds of general formula I obtained which occur in racemates, according to methods known per se (see Allinger NL and Eliel EL in " Topics in Stereochemistry ", Vol. 6, Wiley Interscience, 1971) in their optical antipodes and compounds of general formula I with at least 2 asymmetric carbon atoms due to their physico-chemical differences according to methods known per se, for example by chromatography and / or fractional crystallization, into their diastereomers, which, if they occur in racemic form, can then be separated into the enantiomers as mentioned above.
- the enantiomers are separated preferably by column separation on chiral phases or by recrystallization from an optically active solvent or by reaction with an optically active substance which forms salts or derivatives, such as esters or amides, for example esters or amides, in particular acids and their activated derivatives or alcohols, and Separation of the diastereomeric salt mixture or derivative obtained in this way, for example on the basis of different solubilities, it being possible for the free antipodes to be released from the pure diastereomeric salts or derivatives by the action of suitable agents.
- an optically active substance which forms salts or derivatives, such as esters or amides, for example esters or amides, in particular acids and their activated derivatives or alcohols
- optically active acids are, for example, the D and L forms of tartaric acid or dibenzoyl tartaric acid, di-op-toluoyl tartaric acid, malic acid, mandelic acid, Camphorsulfonic acid, glutamic acid, aspartic acid or quinic acid.
- suitable optically active alcohol are (+) - or (-) - menthol and optically active acyl radicals in amides are, for example, (+) - or (-) - menthyloxycarbonyl.
- the compounds of the formula I obtained can be converted into their salts, in particular for pharmaceutical use into their physiologically tolerable salts with inorganic or organic acids.
- suitable acids for this purpose are hydrochloric acid, hydrobromic acid, sulfuric acid, methanesulfonic acid, phosphoric acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid or maleic acid.
- the compounds of the general formula I according to the invention and their physiologically tolerable salts have valuable pharmacological properties, in particular an inhibitory effect on the enzyme DPP-IV.
- the cell extract was solubilized in a buffer (10 mM Tris HCl, 0.15 M NaCl, 0.04 tiu aprotinin, 0.5% Nonidet-P40, pH 8.0) by centrifugation at 35,000 g for 30 minutes at 4 ° C (to remove cell debris) won.
- the DPP-IV assay was carried out as follows:
- AFC amido-4-trifluoromethylcoumarin
- 20 ⁇ l assay buffer final concentrations 50 mM Tris HCl pH 7.8, 50 mM NaCl, 1% DMSO
- the reaction was started by adding 30 ⁇ l solubilized Caco-2 protein (final concentration 0.14 ⁇ g protein per well).
- the test substances to be checked were typically added pre-diluted in 20 ⁇ l, the assay buffer volume then being reduced accordingly.
- the reaction was carried out at room temperature, the incubation period was 60 minutes.
- the compounds prepared according to the invention are well tolerated, since no changes in the behavior of the animals could be observed, for example, after oral administration of 10 mg / kg of the compound of Example 1 to rats.
- the compounds of general formula I according to the invention and their corresponding pharmaceutically acceptable salts are suitable for influencing all those conditions or diseases which can be influenced by inhibiting DPP-IV activity . It is therefore to be expected that the compounds according to the invention for the prevention or treatment of diseases or conditions such as diabetes mellitus type 1 and type 2, prediabetes, reduction in glucose tolerance or changes in fasting blood sugar, diabetic complications (such as retinopathy, nephropathy or neuropathies) , metabolic acidosis or ketosis, reactive hypoglycaemia, insulin resistance, metabolic syndrome, dyslipidemia of various origins, arthritis, atherosclerosis and related diseases, obesity, allograft transplantation and osteoporosis caused by calcitonin are suitable.
- diseases or conditions such as diabetes mellitus type 1 and type 2, prediabetes, reduction in glucose tolerance or changes in fasting blood sugar, diabetic complications (such as retinopathy, nephropathy or neuropathies) , metabolic acidosis or ketosis, reactive hypogly
- these substances are suitable for preventing B cell degeneration such as apoptosis or necrosis of pancreatic B cells.
- the substances are also suitable for improving or restoring the functionality of pancreatic cells, and also increasing the number and size of pancreatic B cells.
- the compounds according to the invention are suitable, inter alia, for achieving a sedative or anxiolytic effect to be able to influence catabolic conditions after operations or hormonal stress responses favorably or to reduce mortality and morbidity after myocardial infarction.
- the compounds according to the invention are suitable for the treatment of all conditions which are related to the above-mentioned effects and are mediated by GLP-1 or GLP-2.
- the compounds according to the invention can also be used as diuretics or antihypertensives and are suitable for the prevention and treatment of acute kidney failure.
- the compounds according to the invention can be used to treat inflammatory diseases of the respiratory tract. They are the same suitable for the prevention and therapy of chronic inflammatory bowel diseases such as irritable bowel syndrome (IBS), Crohn's disease or ulcerative colitis as well as for pancreatitis.
- IBS irritable bowel syndrome
- Crohn's disease Crohn's disease
- ulcerative colitis as well as for pancreatitis.
- it is expected that they can be used for any type of injury or impairment in the gastrointestinal tract, such as, for example, with colitis and enterids.
- DPP-IV inhibitors and thus also the compounds according to the invention can be used to treat infertility or to improve fertility in humans or in the mammalian organism, in particular if the infertility is related to an insulin resistance or with a polycystic Ovarian syndrome stands.
- these substances are suitable for influencing sperm motility and can therefore be used as contraceptives for use in men.
- the substances are suitable for influencing growth hormone deficiency states that are associated with short stature, and can be used sensibly in all indications in which growth hormone can be used.
- the compounds according to the invention are also suitable for the treatment of various autoimmune diseases such as, for example, rheumatoid arthritis, multiple sclerosis, thyroditides and Graves ' disease, etc.
- autoimmune diseases such as, for example, rheumatoid arthritis, multiple sclerosis, thyroditides and Graves ' disease, etc.
- viral diseases such as, for example, in HIV infections for the stimulation of blood formation, for benign prostatic hyperplasia, for gingivitis, as well as for the treatment of neuronal defects and neurodegenerative diseases such as Alzheimer's disease.
- Compounds described are also to be used for the therapy of tumors, in particular for changing tumor invasion, as well as metastatisation.
- T-cell lymphomas examples here are the use in T-cell lymphomas, acute lymphoblastic leukemia, cell-based thyroid carcinomas, basal cell carcinomas or breast carcinomas.
- Other indications are stroke, ischemia of various origins, Parkinson's disease and migraines.
- further areas of indication are follicular and epidermal hyperkeratosis, increased keratinocyte proliferation, psoriasis, encephalomyelitis, glomerulonephritis, lipodystrophy, and psychosomatic, depressive and neuropsychiatric diseases of various origins.
- the compounds according to the invention can also be used in combination with other active ingredients.
- Therapeutics suitable for such a combination include, for example, antidiabetic agents such as metformin, sulfonylureas (e.g. glibenclamide, tolbutamide, glimepiride), nateglinide, repaglinide, thiazolidinedione (e.g. rosiglitazone, pioglitazone), PPAR-gamma agonists (e.g.
- Gl 262570 and antagonists, PPAR-gamma / alpha modulators (eg KRP 297), PPAR-gamma / alpha / delta modulators, AMPK activators, ACC1 and ACC2 inhibitors, DGAT inhibitors, SMT3 receptor agonists, H ß-HSD inhibitors , FGF1 9 agonists or mimetics, alpha-glucosidase inhibitors (eg acarbose, Voglibose), other DPPIV inhibitors, alpha2-antagonists, insulin and insulin analogues, GLP-1 and GLP-1 analogues (eg exendin-4) or amylin.
- PPAR-gamma / alpha modulators eg KRP 297
- PPAR-gamma / alpha / delta modulators AMPK activators
- ACC1 and ACC2 inhibitors eg PPAR-gamma / alpha / delta modulators
- SGLT2 inhibitors such as T-1095 or KGT-1251 (869682), inhibitors of protein tyrosine phosphatase 1, substances which influence deregulated glucose production in the liver, such as inhibitors of glucose-6-phosphatase, or fructose-1, 6- bisphosphatase, the glycogen phosphorylase, glucagon receptor antagonists and inhibitors of the phosphoenolpyruvate carboxykinase, the glycogen synthase kinase or the pyruvate dehydrokinase, lipid lowering agents such as HMG-CoA reductase inhibitors (eg Simvastatinate, fibrinate), fibrinate, fibrinate, fibrinate, fibrinate, fibrinate, fibrinate, fibrinate, fibrinate, fibrinate, fibrinate, fibrinate, fibrinate, fibrinate, fibrinate, fibrinate, fibrinate, fibrinate, fibrinate, fibrinate, fibrinate, fibrinate, fibrinate, fibrinate, fibrinate, fibrinate, fibrinate, fibrinate, fibrinate, fibrinate,
- the dosage required to achieve a corresponding effect is expediently 1 to 100 mg, preferably 1 to 30 mg for intravenous administration, and 1 to 1000 mg, preferably 1 to 100 mg, in each case 1 to 4 times a day for oral administration.
- the compounds of formula I prepared according to the invention optionally in combination with other active substances, together with one or more inert customary carriers and / or diluents, e.g.
- Example III Methyl 2-bromo-3- (2-butyn-1-yl) -5-formyl-3H-imidazole-4-carboxylate 43 ml of a solution of 13.5 g of 2-bromo-1- (2-butyn-1-yl) -1 H -imidazole-4,5-dicarboxylic acid dimethyl ester in 220 ml of tetrahydrofuran are placed under an argon atmosphere at -70 ° C a 1 M solution of diisobutyl aluminum hydride in tetrahydrofuran was added dropwise within 20 minutes.
- 1 coated tablet contains: active substance 75.0 mg calcium phosphate 93.0 mg maize starch 35.5 mg polyvinylpyrrolidone 10.0 mg hydroxypropylmethyl cellulose 15.0 mg magnesium stearate 1.5 mq 230.0 mg
- the active substance is mixed with calcium phosphate, corn starch, polyvinylpyrrolidone, hydroxypropylmethyl cellulose and half of the stated amount of magnesium stearate. Pressings with a diameter of approx. 13 mm are produced on a tableting machine, these are rubbed on a suitable machine through a sieve with a 1.5 mm mesh size and with the remaining amount Magnesium stearate mixed. This granulate is pressed on a tablet machine into tablets of the desired shape. Core weight: 230 mg stamp: 9 mm, curved
- the dragee cores thus produced are coated with a film consisting essentially of hydroxypropylmethyl cellulose.
- the finished film coated tablets are polished with beeswax. Drage weight: 245 mg.
- 1 tablet contains: Active substance 100.0 mg milk sugar 80.0 mg corn starch 34.0 mg polyvinylpyrrolidone 4.0 mg magnesium stearate 2.0 mq 220.0 mg
- 1 tablet contains: active substance 150.0 mg milk sugar powder 89.0 mg corn starch 40.0 mg colloids silica 10.0 mg polyvinylpyrrolidone 10.0 mg magnesium stearate 1.0 mq 300.0 mg
- the active substance mixed with milk sugar, corn starch and silica is moistened with a 20% aqueous polyvinylpyrrolidone solution and passed through a sieve
- the granules dried at 45 ° C are rubbed through the same sieve again and mixed with the specified amount of magnesium stearate. The mixture becomes
- 1 capsule contains: Active ingredient 150.0 mg corn starch dr. approx. 180.0 mg powdered milk sugar approx. 87.0 mg magnesium stearate 3.0 mq approx. 420.0 mg
- the active ingredient is mixed with the excipients, through a sieve of
- the final mix is filled into size 1 hard gelatin capsules.
- Capsule filling approx. 320 mg capsule shell: hard gelatin capsule size 1.
- 1 suppository contains: Active ingredient 150.0 mg polyethylene glycol 1500 550.0 mg polyethylene glycol 6000 460.0 mg polyoxyethylene sorbitan monostearate 840.0 mo 2000.0 mg
- 5 ml of suspension contain 50 mg of active ingredient.
- composition active ingredient 10.0 mg 0.01 n hydrochloric acid sq Aqua bidest ad 2.0 ml production:
- the active substance is dissolved in the required amount of 0.01N HCl, made isotonic with sodium chloride, sterile filtered and filled into 2 ml ampoules.
- composition active ingredient 50.0 mg 0.01 N hydrochloric acid s.q. Aqua bidest to 10.0 ml
- the active substance is dissolved in the required amount of 0.01N HCl, made isotonic with sodium chloride, sterile filtered and filled into 10 ml ampoules.
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Abstract
Description
Claims
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
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DE10359098A DE10359098A1 (de) | 2003-12-17 | 2003-12-17 | Neue 2-(Piperazin-1-yl)- und 2-([1,4]Diazepan-1-yl)-imidazo[4,5-d]pyridazin-4-one, deren Herstellung und deren Verwendung als Arzneimittel |
PCT/EP2004/014125 WO2005058901A1 (de) | 2003-12-17 | 2004-12-11 | Neue 2-(piperazin-1-yl)- und 2-([1,4]diazepan-1-yl)- imidazo[4,5-d]pyridazin-4-one, deren herstellung und deren verwendung als arzneimittel zur bekämpfung von diabetes mellitus |
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EP1742949A1 true EP1742949A1 (de) | 2007-01-17 |
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EP04803766A Withdrawn EP1742949A1 (de) | 2003-12-17 | 2004-12-11 | Neue 2-(piperazin-1-yl)- und 2-(¬1,4|diazepan-1-yl)- imidazo¬4,5-d|pyridazin-4-one, deren herstellung und deren verwendung als arzneimittel zur bekämpfung von diabetes mellitus |
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EP (1) | EP1742949A1 (de) |
JP (1) | JP2007513989A (de) |
CA (1) | CA2543074A1 (de) |
DE (1) | DE10359098A1 (de) |
WO (1) | WO2005058901A1 (de) |
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EP2854812A1 (de) | 2012-05-24 | 2015-04-08 | Boehringer Ingelheim International GmbH | Xanthinderivat als dpp-4-inhibitor zur behandlung von autoimmundiabetes, insbesondere lada |
WO2014045266A1 (en) | 2012-09-24 | 2014-03-27 | Ulf Eriksson | Treatment of type 2 diabetes and related conditions |
IN2015DN03795A (de) | 2012-10-24 | 2015-10-02 | Inserm Inst Nat De La Santé Et De La Rech Médicale | |
JP2016510795A (ja) | 2013-03-15 | 2016-04-11 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | 心臓保護及び腎臓保護の抗糖尿病治療におけるリナグリプチンの使用 |
ES2950384T3 (es) | 2014-02-28 | 2023-10-09 | Boehringer Ingelheim Int | Uso médico de un inhibidor de DPP-4 |
US10426818B2 (en) | 2015-03-24 | 2019-10-01 | Inserm (Institut National De La Sante Et De La Recherche Medicale) | Method and pharmaceutical composition for use in the treatment of diabetes |
EP4233840A3 (de) | 2016-06-10 | 2023-10-18 | Boehringer Ingelheim International GmbH | Kombinationen aus linagliptin und metformin |
US11285180B2 (en) | 2016-12-06 | 2022-03-29 | Inserm (Institut National De La Sante Et De La Recherche Medicale) | Methods of enhancing the potency of incretin-based drugs in subjects in need thereof |
WO2024091863A1 (en) | 2022-10-25 | 2024-05-02 | Starrock Pharma Llc | Combinatorial, and rotational combinatorial therapies for obesity and other diseases |
Family Cites Families (6)
Publication number | Priority date | Publication date | Assignee | Title |
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JP2004502690A (ja) * | 2000-07-04 | 2004-01-29 | ノボ ノルディスク アクティーゼルスカブ | 酵素dpp−ivのインヒビターである複素環式化合物 |
AU2002234640B8 (en) * | 2001-02-24 | 2009-11-05 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Xanthine derivative, production and use thereof as a medicament |
JP2003300977A (ja) * | 2002-04-10 | 2003-10-21 | Sumitomo Pharmaceut Co Ltd | キサンチン誘導体 |
EP1514552A4 (de) * | 2002-06-06 | 2008-04-02 | Eisai R&D Man Co Ltd | Neues kondensiertes imidazolderivativ |
UY28103A1 (es) * | 2002-12-03 | 2004-06-30 | Boehringer Ingelheim Pharma | Nuevas imidazo-piridinonas sustituidas, su preparación y su empleo como medicacmentos |
DE10327439A1 (de) * | 2003-06-18 | 2005-01-05 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Neue Imidazopyridazinon- und Imidazopyridonderivate, deren Herstellung und deren Verwendung als Arzneimittel |
-
2003
- 2003-12-17 DE DE10359098A patent/DE10359098A1/de not_active Withdrawn
-
2004
- 2004-12-11 EP EP04803766A patent/EP1742949A1/de not_active Withdrawn
- 2004-12-11 JP JP2006544293A patent/JP2007513989A/ja not_active Ceased
- 2004-12-11 CA CA002543074A patent/CA2543074A1/en not_active Abandoned
- 2004-12-11 WO PCT/EP2004/014125 patent/WO2005058901A1/de active Application Filing
Non-Patent Citations (1)
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See references of WO2005058901A1 * |
Also Published As
Publication number | Publication date |
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WO2005058901A8 (de) | 2006-04-27 |
WO2005058901A1 (de) | 2005-06-30 |
JP2007513989A (ja) | 2007-05-31 |
DE10359098A1 (de) | 2005-07-28 |
CA2543074A1 (en) | 2005-06-30 |
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