WO2003053930A1 - 1,4-dihydro-1,4-diphenylpyridine derivatives - Google Patents
1,4-dihydro-1,4-diphenylpyridine derivatives Download PDFInfo
- Publication number
- WO2003053930A1 WO2003053930A1 PCT/EP2002/013931 EP0213931W WO03053930A1 WO 2003053930 A1 WO2003053930 A1 WO 2003053930A1 EP 0213931 W EP0213931 W EP 0213931W WO 03053930 A1 WO03053930 A1 WO 03053930A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- compounds
- general formula
- amino
- methyl
- mmol
- Prior art date
Links
- 0 CCC(C)(C=C*)*(*)=N Chemical compound CCC(C)(C=C*)*(*)=N 0.000 description 3
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/80—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D211/84—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen directly attached to ring carbon atoms
- C07D211/90—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
Definitions
- the present invention relates to novel l,4-dihydro-l,4-diphenylpyridine derivatives, processes for their preparation, and their use in medicaments, especially for the treat- ment of chronic obstructive pulmonary diseases.
- the fibrous protein elastin which comprises an appreciable percentage of all protein content in some tissues, such as the arteries, some ligaments and the lungs, can be hydrolysed or otherwise destroyed by a select group of enzymes classified as elastases.
- Human leukocyte elastase HLE, EC 3.4.21.37
- HNE human neutrophil elastase
- PMN human polymorphonuclear leukocytes
- HNE is capable of degrading a wide range of matrix proteins including elastin, and in addition to these actions on connective tissue HNE has a. broad range of inflammatory actions including upregulation of IL-8 gene expression, oedema formation, mucus gland hyperplasia and mucus hypersecretion.
- Pulmonary diseases where HNE is believed to play a role include lung fibrosis, pneumonia, acute respiratory distress syndrome (ARDS), pulmonary emphysema, including smoking-induced emphysema, chronic obstructive pulmonary diseases
- HNE chronic obstructive pulmonary diseases
- COPD chronic obstructive pulmonary diseases
- the present invention relates to compounds of the general formula (I)
- R 1 , R 2 , R 3 , R 8 , R 9 and R 10 independently from each other represent hydrogen, halogen, nitro, cyano, trifluoromethyl, Ci-Cg-alkyl, CjrC 6 -alkanoyL hydroxy, Ci-C ⁇ -alkoxy, trifluoromethoxy, amino, mono- or di-CrC ⁇ -alkylamino,
- R 4 represents C ⁇ -C 6 -alkyl, trifluoromethyl or phenyl
- R 5 represents C 1 -C -alkyl, which can be substituted with one to three identical or different radicals selected from the group consisting of hydroxy, C ⁇ -C 4 - alkoxy, amino, mono- and di-C ⁇ -C 4 -alkylamino
- R 6 represents cyano, aminocarbonyl, mono- and di-C ⁇ -C 4 -alkylaminocarbonyl, carboxyl or CrCe-alkoxycarbonyl, wherein the alkoxy moiety can be further substituted with a radical selected from the group consisting of hydroxy, - C 4 -alkoxy, amino, mono- and di-C 1 -C 4 -alkylamino,
- R > 6 represents a moiety of the formula
- R A is selected from the group consisting of hydrogen and C ⁇ -C 6 - alkyl
- R , 7 represents hydrogen, C 1 -C 4 -alkyl or amino
- X 1 , X 2 , X 3 and X 4 independently from each other represent CH or N, wherein ring A contains either 0, 1 or 2 nitrogen atoms,
- Y 1 , Y 2 , Y 3 , Y 4 and Y 5 independently from each other represent CH or N, wherein ring B contains either 0, 1 or 2 nitrogen atoms.
- the present invention relates to compounds of general formula (I), wherein R 1 represents hydrogen,
- R 2 , R 3 , R 9 and R 10 independently from each other represent hydrogen, halogen, nitro, cyano, trifluoromethyl, C 1 -C 4 -alkyl, C 1 -C 4 -alkanoyl, hydroxy, C ⁇ -C 4 -alkoxy, trifluoromethoxy, amino, C ⁇ -C 4 -dialkylamino, C ⁇ -C 4 -acylamino, methoxy- carbonylamino, tert.-butoxycarbonylamino, carboxyl, methoxycarbonyl or ethoxycarbonyl, wherein C 1 -C -alkyl, C 1 -C 4 -alkanoyl, C ⁇ -C 4 -alkoxy, C 1 -C - dialkylamino and C 1 -C -acylamino can be further substituted with one to two identical or different radicals selected from the group consisting of hydroxy, methoxy, ethoxy, amino, dimethylamin
- R 4 represents methyl, ethyl, trifluoromethyl or phenyl
- R 5 represents methyl or ethyl
- R 6 represents cyano, aminocarbonyl, methylaminocarbonyl, dimethylaminocarb- onyl, carboxyl or C 1 -C 4 -alkoxycarbonyl, wherein the alkoxy moiety can be further substituted with a radical selected from the group consisting of hydroxy, methoxy, ethoxy, amino, mono- and di-C ⁇ -C 4 -alkylamino,
- R 7 represents hydrogen, methyl, ethyl or amino
- R represents hydrogen
- X 1 , X 2 and X 3 represent CH
- X 4 represents CH or N
- Y 1 , Y 2 , Y 3 , Y 4 and Y 5 represent CH.
- the present invention relates to compounds of general formula (I), wherein
- R 1 and R 2 represent hydrogen
- R 3 represents fluoro, chloro, bromo, nitro, cyano, trifluoromethyl, methyl, methoxy or hydroxy
- R 4 represents methyl or trifluoromethyl
- R 5 represents methyl
- R represents cyano, aminocarbonyl, methylaminocarbonyl, dimethylamino- carbonyl, carboxyl, methoxycarbonyl or ethoxycarbonyl,
- R 7 represents hydrogen, methyl or amino
- R 8 and R 9 represent hydrogen
- R represents fluoro, chloro, bromo, nitro, cyano, trifluoromethyl or methyl
- X ⁇ X 2 X 3 and X 4 represent CH
- Y 1 , Y 2 , Y 3 , Y 4 and Y 5 represent CH.
- the present invention relates to compounds according to general formula (I), which have the following structure:
- R 1 , R 2 , R 3 , R 8 , R 9 and R 10 independently firom each other represent hydrogen, halogen, nitro, cyano, trifluoromethyl, C ⁇ -Cg-allcyl, C ⁇ -C 6 -alkanoyl, hydroxy, C ⁇ -C 6 -alkoxy, trifluoromethoxy, amino, mono- or di-C ⁇ -C 6 - alkylamino, C ⁇ -C 6 -acylamino, C ⁇ -C 6 -alkoxycarbonylamino, carboxyl, C ⁇ -C 6 -alkoxycarbonyl or phenyl, wherein Ci-C ⁇ -alkyl, C ⁇ -C 6 - alkanoyl, C ⁇ -C 6 -alkoxy, mono- or di-Ci-C ⁇ -alkylamino and C ⁇ -C 6 - acylamino can be further substituted with one to three identical or different radicals selected from the group consisting of hydroxy, C ⁇
- R 4 represents Ci-C ⁇ -alkyl, trifluoromethyl or phenyl
- R >5 represents C ⁇ -C 4 -alkyl
- R 6 represqnts cyano, carboxyl or C ⁇ -C 6 -alkoxycarbonyl, wherein the alkoxy moiety can be further substituted with a radical selected firom the group consisting of hydroxy, C ⁇ -C 4 -alkoxy, amino, mono- and di- C ⁇ -C 4 -alkylamino,
- R 7 represents hydrogen, C 1 -C 4 -alkyl or amino.
- the present invention relates to compounds according to general formula (I), wherein R is cyano, which is located m para-position relativ to the 1,4-dihydropyridine ring.
- the present invention relates to compounds according to general formula (I), wherein R 4 is methyl.
- the present invention relates to compounds according to general formula (I), wherein R 5 is methyl.
- the present invention relates to compounds according to general formula (I), wherein R 6 is methoxycarbonyl or ethoxycarbonyl.
- the present invention relates to compounds according to general formula (I), wherein R 7 is hydrogen, methyl or amino.
- the present invention relates to compounds according to general formula (I), wherein R 10 is trifluoromethyl, which is attached to Y 2 .
- the compounds according to this invention can also be present in the form of their • salts, hydrates and/or solvates.
- Physiologically acceptable salts are preferred in the context of the present invention.
- Physiologically acceptable salts according to the invention are non-toxic salts which in general are accessible by reaction of the compounds (I) with an inorganic or organic base or acid conventionally used for this purpose.
- Non-limiting examples of pharmaceutically acceptable salts of compounds (I) include the alkali metal salts, e.g.
- the alkaline earth metal salts such as magnesium and calcium salts
- the quaternary ammonium salts such as, for example, triethyl ammonium salts, acetates, benzene sulphonates, benzoates, dicarbonates, disulphates, ditartrates, borates, bromides, carbonates, chlorides, citrates, dihydrochlorides, fumarates, gluconates, glutamates, hexyl resorcinates, hydrobromides, hydro- chlorides, hydroxynaphthoates, iodides, isothionates, lactates, laurates, malates, maleates, mandelates, mesylates, methylbromides, methylnitrates, methylsulphates, nitrates, oleates, oxalates, palmitates, pantothenates, phosphates, diphosphates, polygalacturonates,
- Hydrates of the compounds of the invention or their salts are stoichiometric compositions of the compounds with water, such as for example hemi-, mono-, or dihydrates.
- Solvates of the compounds of the invention or their salts are stoichiometric compositions of the compounds with solvents.
- the present invention includes both the individual enantiomers or diastereomers and the corresponding racemates or diastereomeric mixtures of the compounds according to the invention and their respective salts.
- all possible tautomeric forms of the compounds described above are included according to the present invention.
- the diastereomeric mixtures can be separated into the individual isomers by chromatographic processes.
- the racemates can be resolved into the respective enantiomers either by chromatographic processes on chiral phases or by resolution.
- Alkyl in general represents a straight-chain or branched hydrocarbon radical having 1 to 6, preferably 1 to 4 carbon atoms.
- Non-limiting examples include methyl, ethyl, n- propyl, isopropyl, n-butyl, isobutyl, sec. -butyl, tert.-butyl, pentyl, isopentyl, hexyl, isohexyl.
- radicals such as alkoxy, alkylamino, alkoxycarbonyl and alkoxycarbonylamino.
- Acyl or Alkanoyl in general represents a straight-chain or branched hydrocarbon radical having 1 to 6, preferably 1 to 4 carbon atoms which has a carbonyl function at the position of attachment.
- Non-limiting examples include formyl, acetyl, n-propionyl, n-butyryl, isobutyryl, pivaloyl, n-hexanoyl.
- radicals such as acylamino.
- Alkylamino represents an alkylamino radical having one or two (independently selected) alkyl substituents, illustratively and preferably representing methylamino, ethylamino, n-propylamino, isopropylamino, tert-butylamino, n-pentylamino, n-hexyl- amino, NN-dimethylamino, NN-diethylamino, N-ethyl-N-methylamino, N-methyl-N- n-propylamino, N-isopropyl-N-n-propylamino, N-t-butyl-N-methylamino, N-ethyl-N- n-pentylamino and N-n-hexyl-N-methylamino.
- Alkylaminocarbonyl represents an allylaminocarbonyl radical having one or two
- alkyl substituents illustratively and preferably representing methylaminocarbonyl, ethylaminocarbonyl, n-propylaminocarbonyl, isopropylamino- carbonyl, tert-butylaminocarbonyl, n-pentylaminocarbonyl, n-hexylaminocarbonyl, N, N-dimethylaminocarbonyl, N N-diethylaminocarbonyl, N-e yl-N-methylamino- carbonyl, N-methyl-N-n-propylarninocarbonyl, N-isopropyl-N-n-propylarninocarbonyl,
- N-t-butyl-N-methylaminocarbonyl N-ethyl-N-n-pentylamino-carbonyl and N-n-hexyl- N-methylaminocarbonyl.
- R 1 , R 2 , R 3 or R 8 , R 9 and R 10 respectively.
- a * symbol next to a bond denotes the point of attachment in the molecule.
- the present invention relates to processes for synthesizing the compounds of general formula (I), characterized in that either
- R 11 represents cyano or Ci-C ⁇ -alkoxycarbonyL
- R 12 represents Ci-C ⁇ -alkyl
- R , 13 represents Cj-C 4 -alkyl
- Suitable solvents for the processes [A] to [C] are generally customary organic solvents which do not change under the reaction conditions. These include ethers such as diethyl ether, diisopropyl ether, 1,2-dimethoxyethane, dioxan or tetrahydrofuran, ethylacetate, acetone, acetonitrile, dimethylsulfoxide, dimethylformamide, or alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol or t-butanol, or hydrocarbons such as pentane, hexane, cyclohexane, benzene, toluene or xylene, or halogeno-hydro- carbons such as dichloromethane, dichloroethane, trichloromethane or chlorobenzene.
- ethers such as diethyl ether, diisopropyl ether,
- acetic acid can be employed as solvent. It is also possible to use mixtures of the above-mentioned solvents.
- Preferred for process [A] is ethanol or a mixture of n-propanol and dimethylsulfoxide.
- acetic acid or diisopropyl ether are preferred.
- Suitable bases for process [A] and [C] are generally inorganic or organic bases. These preferably include cyclic amines, such as, for example, piperidine, mo holine, N- methylmorpholine, pyridine or 4-N,N-dimethylaminopyridine, or amines, such as, for example, triethylamine or diisopropylethylamine. Preference is given to piperidine.
- the base is employed in an amount from 0.1 mol to 10 mol, preferably from 1 mol to 3 mol, relative to 1 mol of the compound of the general formula (II).
- Suitable acids for process [B] and [C] are generally inorganic or organic acids. These preferably include carboxylic acids, such as, for example acetic acid or trifluoroacetic acid, or sulfonic acids, such as, for example, methanesulfonic acid or p-toluenesulfonic acid. Preference for process [B] and [C] is given to acetic acid or trifluoroacetic acid. The acid is employed in an amount from 0.25 mol to 100 mol, relative to 1 mol of the compounds of the general formulas (V) and VTT), respectively.
- the processes [A] to [C] are in general carried out in a temperature range from +20°C to +150°C, preferably from +60°C to +130°C.
- the compounds of general formula (II) can be synthesized by reacting compounds of general formula (VII) with compounds of the general (VIII)
- the compounds of the present invention show human neutrophil elastase (HNE) inhibitory activity and are therefore suitable for the preparation of medicaments for the treatment of diseases associated with HNE activity.
- HNE human neutrophil elastase
- They may thus provide an effective treatment of acute and chronic inflammatory processes, such as rheumatoid arthritis, atherosclerosis, and especially of acute and chronic pulmonary diseases, such as lung fibrosis, cystic fibrosis, pneumonia, acute respiratory distress syndrome (ARDS), in particular pulmonary emphysema, including smoking-induced emphysema, and chronic obstructive pulmonary diseases (COPD).
- ARDS acute respiratory distress syndrome
- COPD chronic obstructive pulmonary diseases
- They may also provide an effective treatment of brain trauma, cancer and other conditions in which neutrophil participation is involved.
- the compounds of formula (I) according to the invention can therefore be used as active compound components for the production of medicaments.
- they can be converted into the customary formulations such as tablets, coated tablets, aerosols, pills, granules, syrups, emulsions, suspensions and solutions in a known manner using inert, non-toxic, pharmaceutically suitable excipients or solvents.
- the compounds according to the invention are used here in an amount such that their concentration in the total mixture is approximately 0.5% to approximately 90% by weight, the concentration, inter alia, being dependent on the corresponding indication of the medicament.
- formulations are produced, for example, by extending the active compounds with solvents and/or excipients having the above properties, where, if appropriate, additionally emulsifiers or dispersants and, in the case of water as the solvent, alternatively an organic solvent, have to be added.
- Administration is carried out in a customary manner, preferably orally, transdermally or parenterally, for example perlingually, buccally, intravenously, nasally, rectally or by inhalation.
- oral administration in the case of oral administration, it is recommendable to administer doses of from 0.001 to 50 mg/kg, preferably of 0.01 mg/kg to 20 mg/kg.
- parenteral administration such as, for example, intravenously or via mucous membranes nasally, buccally or inhalationally, it is recommendable to use doses of 0.001 mg/kg to 0.5 mg/kg.
- HNE human neutrophil elastase
- the elastase substrate MeOSuc-Ala-Ala-Pro-Val-AMC (#324740, Calbiochem-Novabiochem Corporation, Merck KgaA, Darmstadt, Germany) is used.
- the test solution is prepared by mixing 10 ⁇ l of test compound dilution, 20 ⁇ l of HNE enzyme dilution (final concentration 8 - 0.4 ⁇ U/ml, routinely 2.1 ⁇ U/ml) and
- the preparation examples had IC 50 values within the range of 20 nM - 20 ⁇ M in this assay. Representative data are given in table 1 :
- the elastase substrate elastin-fluorescein (#100620, ICN Biomedicals GmbH, Eschwege, Germany) is used.
- the test solution is prepared by mixing 3 ⁇ l of test compound dilution, 77 ⁇ l of HNE enzyme dilution (final concentration 0.22 U/ml - 2.2 mU/ml, routinely 21.7 ⁇ U/ml) and 80 ⁇ l substrate suspension (final concentration 2 mg/ml).
- the suspension is incubated for 0 - 16 hrs at 37°C (routinely four hours) under slightly shaking conditions.
- 160 ⁇ l of 0.1 M acetic acid are added to the test solution (final concentration 50 mM).
- the polymeric elastin-fluorescein is pulled down by centrifugation (Eppendorf 5804 centrifuge, 3.000 rpm, 10 min). The supernatant is transferred into a new MTP and the fluorescence of the liberated peptide fluorescein due to the enzymatic reaction is measured (BMG Fluostar plate reader). The rate of fluorescence (ex. 490 nm, em. 520 nm) is proportional to elastase activity. IC 50 values are determined by RFU- versus-[I] plots.
- This assay is used to determine the elasto lyric potential of human polymorphonuclear cells (PMNs) and assess the proportion of degradation due to neutrophil elastase [cf. Z.W. She et al., Am. J. Respir. Cell. Mol. Biol. 9, 386-392 (1993)].
- PMNs human polymorphonuclear cells
- Tritiated elastin in suspension, is coated on to a 96 well plate at 10 ⁇ g per well.
- Test and reference [ZD-0892 (J. Med. Chem. 40, 1876-1885, 3173-3181 (1997), WO
- ⁇ l protease inhibitor ( ⁇ lPI)] compounds are added to the wells at the appropriate concentrations.
- Human PMNs are separated from peripheral venous blood of healthy donors and resuspended in culture media.
- the neutrophils are added to the coated wells at concentrations ranging between 1 x 10 to 1 x 10 cells per well.
- Porcine pancreatic elastase (1.3 ⁇ M) is used as a positive control for the assay, and ⁇ lPI (1.2 ⁇ M) is used as the positive inhibitor of neutrophil elastase.
- the cellular control is PMNs without compound at each appropriate cell density.
- the cells plus compounds are incubated in a humidified incubator at 37°C for 4 hours.
- the plates are centrifuged to allow the harvest of cell supernatant only.
- the supernatant is transferred in 75 ⁇ l volumes to corresponding wells of a 96 well
- LumaplateTM solid scintillant containing plates. The plates are dried until no liquid is visible in the wells and read in a beta counter for 3 minutes per well.
- Elastolysis of the H-elastin results in an increase in counts in the supernatant.
- An inhibition of this elastolysis shows a decrease, from the cellular control, of tritium in the supernatant.
- ZD-0892 is a selective inhibitor of PMN elastase along with the data from lPI inhibition, these results indicate that the majority of elastin degradation by PMNs is due to the release of neutrophil elastase, and not to another elastolytic enzyme such as matrix metalloproteases (MMPs).
- MMPs matrix metalloproteases
- HNE human neutrophil elastase
- Rats are anaesthetised with Hypnorm/Hypnovel/water and instilled with HNE or saline delivered by microsprayer into the lungs.
- Test compounds are administered by intravenous injection, by oral gavage or by inhalation at set times prior to the administration of HNE.
- Sixty minutes after the administration of elastase animals are killed by an anaesthetic overdose (sodium pentobarbitone) and the lungs lavaged with 2 ml heparinised phosphate buffered saline (PBS).
- Bronchoalveolar lavage (BAL) volume is recorded and the samples kept on ice. Each BAL sample is centrifuged at 900 r.p.m.
- the absorbance of the well contents is measured at 415 nm using a spectrophotometer.
- a standard curve is constructed by measuring the OD at 415 nm of different concentrations of blood in 0.1% CTAB/PBS. Blood content values are calculated by comparison to the standard curve (included in each plate) and normalised for the volume of BAL fluid retrieved.
- the compounds of this invention are evaluated intravenously, orally or by inhalation for their inhibitory activity in this model of HNE-induced haemorrhage in the rat.
- the reaction mixture is refluxed for 7 h with a Dean-Stark trap to remove water.
- Example 1A 4.8 g (21.8 mmol) of Example 1A are dissolved in 30 ml ethanol, 4.0 g (21.8 mmol) 4-bromobenzaldehyde, 2.47 g (21.8 mmol) ethyl cyanoacetate, and 3.71 g
- Example 2A 150 mg (0.62 mmol) of Example 2A are dissolved in 2 ml ethanol, 114 mg (0.62 mmol) 4-bromobenzaldehyde, 70 mg (0.62 mmol) ethyl cyanoacetate, and 105 mg (1.23 mmol) piperidine are added. The reaction mixture is stirred under reflux overnight. After cooling down to room temperature, the solvent is removed in vacuo and the residue is purified by column chromatography on silica with eluent dichloromethane.
- Example 2A 100 mg (0.41 mmol) of Example 2A are dissolved in 2 ml ethanol, 54 mg (0.41 mmol) 4-cyanobenzaldehyde, 47 mg (0.41 mmol) ethyl cyanoacetate, and 70 mg (0.82 mmol) piperidine are added. The reaction mixture is stirred under reflux overnight. After cooling down to room temperature, the solvent is removed in vacuo and the residue is purified by column chromatography on silica with eluent dichloromethane. Yield: 26 mg (14%)
- Example 4 The enantiomers of Example 4 are separated by chiral HPLC [silane modified poly(N-methacryloyl-L-leucin-l-menthylamide) fixed on silica; 250 x 20 mm column] with iso-hexane/ethylacetate 4:1 as eluent (20 ml/min).
- (+)-Enantiomer (Example 5):
- Example 2A 150 mg (0.62 mmol) of Example 2A are dissolved in 2 ml acetic acid, 114 mg
- Example 2A 100 mg (0.41 mmol) of Example 2A are dissolved in 2 ml acetic acid, 54 mg (0.41 mmol) 4-cyanobenzaldehyde, and 40 mg (0.41 mmol) ethyl propiolate are added. The reaction mixture is stirred under reflux overnight. After cooling down to room temperature, the solvent is removed in vacuo and the residue is purified by column chromatography on silica with eluent dichloromethane. Yield: 20 mg (11%)
- Example 3A 100 mg (0.37 mmol) of Example 3A, 60 mg (0.46 mmol) 4-cyanobenzaldehyde, 31 mg (0.31 mmol) 2,4-pentanedione, and 70 mg (0.61 mmol) trifluoroacetic acid are dissolved in 2 ml diisopropyl ether. The reaction mixture is stirred under reflux over- night. After cooling down to room temperature, the solvent is removed in vacuo and the residue is purified by preparative HPLC. Yield: 7 mg (5%)
- Example 2A 100 mg (0.41 mmol) of Example 2A are dissolved in 2 ml ethanol, 72 mg (0.41 mmol) 4-(trifluoromethyl)benzaldehyde, 47 mg (0.41 mmol) ethyl cyanoacetate, and 70 mg (0.82 mmol) piperidine are added. The reaction mixture is stirred under reflux overnight. After cooling down to room temperature, the solvent is removed in vacuo and the residue is purified by column chromatography on silica with eluent dichloromethane.
- Example 4A 100 mg (0.53 mmol) of Example 4A are dissolved in 2 ml ethanol, 69 mg
- Example 2A 750 mg (3.08 mmol) of Example 2A are dissolved in 5 ml ethanol, 404 mg
- Example 2A 750 mg (3.08 mmol) of Example 2A are dissolved in 5 ml ethanol, 404 mg
- Example 5A 200 mg (0.54 mmol) of Example 5A are dissolved in 2.5 ml ethanol, 71.1 mg (0.54 mmol) 4-cyanobenzaldehyde, 61.3 mg (0.54 mmol) ethyl cyanoacetate, and 4.6 mg (0.05 mmol) piperidine are added. The reaction mixture is stirred under reflux for 30 h. After cooling down to room temperature, the solvent is removed in vacuo and the residue is purified by column chromatography on silica with eluent cylclo- hexane/ethyl acetate. The solid obtained by column chromatography is dissolved in ethanol. Water is added until a solid precipitates. The suspension is filtered and the solvent of the filtrate is removed in vacuo. Yield: 18 mg (5%)
- Example 7A 200 mg (0.73 mmol) of Example 7A are dissolved in 2.5 ml ethanol, 95.9 mg (0.73 mmol) 4-cyanobenzaldehyde, 82.8 mg (0.73 mmol) ethyl cyanoacetate, and 6.2 mg (0.07 mmol) piperidine are added. The reaction mixture is stirred under reflux overnight. After cooling down to room temperature, the solvent is removed in vacuo and the residue is purified by preparative HPLC with eluent acetonitrile/water. Yield: 59 mg (15%)
- Example 8A 200 mg (0.77 mmol) of Example 8A are dissolved in 2.5 ml ethanol, 107 mg (0.77 mmol) 4-cyanobenzaldehyde, 87.6 mg (0.77 mmol) ethyl cyanoacetate, and 20 mg (0.23 mmol) piperidine are added. The reaction mixture is stirred under reflux overnight. After cooling down to room temperature, the solvent is removed in vacuo and the residue is purified by preparative HPLC with eluent acetonitrile/water. Yield: 50.5 mg (12%)
- Example 2A 100 mg (0.41 mmol) of Example 2A are dissolved in 5 ml ethanol, 44 mg
- the compounds according to the invention can be converted into pharmaceutical preparations as follows:
- Example 1 100 mg of the compound of Example 1, 50 mg of lactose (monohydrate), 50 mg of maize starch (native), 10 mg of polyvinylpyrrolidone (PNP 25) (from BASF, Ludwigshafen, Germany) and 2 mg of magnesium stearate.
- the mixture of active component, lactose and starch is granulated with a 5% solution (m/m) of the PVP in water. After drying, the granules are mixed with magnesium stearate for 5 min. This mixture is moulded using a customary tablet press (tablet format, see above). The moulding force applied is typically 15 k ⁇ .
- composition Composition:
- Rhodigel is suspended in ethanol and the active component is added to the suspension.
- the water is added with stirring. Stirring is continued for about 6h until the swelling of the Rhodigel is complete.
Landscapes
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pain & Pain Management (AREA)
- Rheumatology (AREA)
- Pulmonology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Hydrogenated Pyridines (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
Description
Claims
Priority Applications (6)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CA002470813A CA2470813A1 (en) | 2001-12-20 | 2002-12-09 | 1,4-dihydro-1,4-diphenylpyridine derivatives |
DE60214428T DE60214428T2 (en) | 2001-12-20 | 2002-12-09 | 1, 4-DIHYDRO-1, 4-DIPHENYLPYRIDINE DERIVATIVES |
AU2002361992A AU2002361992A1 (en) | 2001-12-20 | 2002-12-09 | 1,4-dihydro-1,4-diphenylpyridine derivatives |
EP02796589A EP1458682B1 (en) | 2001-12-20 | 2002-12-09 | 1,4-dihydro-1,4-diphenylpyridine derivatives |
JP2003554646A JP4486817B2 (en) | 2001-12-20 | 2002-12-09 | 1,4-dihydro-1,4-diphenylpyridine derivative |
US10/498,967 US7199136B2 (en) | 2001-12-20 | 2002-12-09 | 1,4-dihydro-1,4-diphenylpyridine derivatives |
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB0130553A GB2383326A (en) | 2001-12-20 | 2001-12-20 | Antiinflammatory dihydropyridines |
GB0130553.1 | 2001-12-20 | ||
GB0216664A GB2390849A (en) | 2002-07-17 | 2002-07-17 | 3-Acyl-1,4-dihydro-1,4-di(phenyl/azinyl/diazinyl)pyridine derivatives for use as human neutrophil elastase inhibitors |
GB0216664.3 | 2002-07-17 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2003053930A1 true WO2003053930A1 (en) | 2003-07-03 |
Family
ID=26246892
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/EP2002/013931 WO2003053930A1 (en) | 2001-12-20 | 2002-12-09 | 1,4-dihydro-1,4-diphenylpyridine derivatives |
Country Status (8)
Country | Link |
---|---|
US (1) | US7199136B2 (en) |
EP (1) | EP1458682B1 (en) |
JP (1) | JP4486817B2 (en) |
AU (1) | AU2002361992A1 (en) |
CA (1) | CA2470813A1 (en) |
DE (1) | DE60214428T2 (en) |
ES (1) | ES2271365T3 (en) |
WO (1) | WO2003053930A1 (en) |
Cited By (47)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2004020412A1 (en) * | 2002-08-27 | 2004-03-11 | Bayer Healthcare Ag | Dihydropyridine derivatives for use as human neutrophil elastase inhibitors |
WO2005082864A1 (en) * | 2004-02-26 | 2005-09-09 | Bayer Healthcare Ag | 1,4-diaryl-dihydropyrimidin-2-ones and their use as human neutrophil elastase inhibitors |
WO2005082863A2 (en) | 2004-02-26 | 2005-09-09 | Bayer Healthcare Ag | 1,4 diaryl-dihydropyrimidin-2 ones and their use as a human neutrophil elastase inhibitors |
JP2007505902A (en) * | 2003-09-18 | 2007-03-15 | アストラゼネカ・アクチエボラーグ | 2-pyridone derivatives and their use as neutrophil elastase inhibitors |
JP2007523105A (en) * | 2004-02-19 | 2007-08-16 | バイエル・ヘルスケア・アクチェンゲゼルシャフト | Dihydropyridinone derivatives |
DE102007019690A1 (en) | 2007-04-26 | 2008-10-30 | Bayer Healthcare Ag | Use of cyclic substituted furopyrimidine derivatives for the treatment of pulmonary arterial hypertension |
DE102007019691A1 (en) | 2007-04-26 | 2008-10-30 | Bayer Healthcare Ag | Use of acyclically substituted furopyrimidine derivatives for the treatment of pulmonary arterial hypertension |
DE102007027800A1 (en) | 2007-06-16 | 2008-12-18 | Bayer Healthcare Ag | Substituted bicyclic heteroaryl compounds and their use |
DE102007027799A1 (en) | 2007-06-16 | 2008-12-18 | Bayer Healthcare Ag | Substituted furopyrimidines and their use |
DE102007051762A1 (en) | 2007-10-30 | 2009-05-07 | Bayer Healthcare Ag | Substituted pyrrolotriazines and their use |
DE102007054786A1 (en) | 2007-11-16 | 2009-05-20 | Bayer Healthcare Ag | Trisubstituted Furopyrimidines and their Use |
WO2009077728A1 (en) | 2007-12-14 | 2009-06-25 | Argenta Discovery Limited | Indoles and their therapeutic use |
DE102008007400A1 (en) | 2008-02-04 | 2009-08-06 | Bayer Healthcare Ag | Substituted furans and their use |
WO2010094956A1 (en) | 2009-02-17 | 2010-08-26 | Pulmagen Therapeutics (Inflammation) Limited. | Triazolopyridine derivatives as p38 map kinase inhibitors |
WO2010094955A1 (en) | 2009-02-17 | 2010-08-26 | Pulmagen Therapeutics (Inflammation) Limited | Pyrimidopyridazine derivatives useful as p38 mapk inhibitors |
EP2280006A1 (en) | 2005-08-08 | 2011-02-02 | Pulmagen Therapeutics (Synergy) Limited | Pharmaceutical composition for inhalation comprising an oxazole or thiazole m3 muscarinic receptor antagonist |
EP2281813A1 (en) | 2005-08-08 | 2011-02-09 | Pulmagen Therapeutics (Synergy) Limited | Bicyclo[2.2.1]hept-7-ylamine derivatives and their uses |
WO2011051672A1 (en) | 2009-10-28 | 2011-05-05 | Vantia Limited | Azaindole derivatives |
WO2011051673A1 (en) | 2009-10-28 | 2011-05-05 | Vantia Limited | Aminothiazole derivatives useful as klk1 inhibitors |
WO2011051671A1 (en) | 2009-10-28 | 2011-05-05 | Vantia Limited | Aminopyridine derivatives as kallikrein inhibitors |
WO2011154738A1 (en) | 2010-06-10 | 2011-12-15 | Chiesi Farmaceutici S.P.A. | Urea derivatives and their therapeutic use in the treatment of, inter alia, diseases of the respiratory tract |
WO2013083604A1 (en) | 2011-12-09 | 2013-06-13 | Chiesi Farmaceutici S.P.A. | Kinase inhibitors |
WO2013083206A1 (en) | 2011-12-09 | 2013-06-13 | Chiesi Farmaceutici S.P.A. | Derivatives of 4-hydroxy-1,2,3,4-tetrahydronaphtalen-1-yl urea and their use in the treatment of, inter alia, diseases of the respiratory tract |
WO2013083606A1 (en) | 2011-12-09 | 2013-06-13 | Chiesi Farmaceutici S.P.A. | Kinase inhibitors |
WO2014122160A1 (en) | 2013-02-06 | 2014-08-14 | Boehringer Ingelheim International Gmbh | Substituted bicyclic dihydropyrimidinones and their use as inhibitors of neutrophil elastase activity |
WO2014135414A1 (en) | 2013-03-04 | 2014-09-12 | Boehringer Ingelheim International Gmbh | Substituted bicyclic dihydropyrimidinones and their use as inhibitors of neutrophil elastase activity |
WO2014195402A1 (en) | 2013-06-06 | 2014-12-11 | Chiesi Farmaceutici S.P.A. | Kinase inhibitors |
WO2016016366A1 (en) * | 2014-07-31 | 2016-02-04 | Boehringer Ingelheim International Gmbh | Substituted dihydropyrimidinones and their use as inhibitors of neutrophil elastase activity |
US9440930B2 (en) | 2014-07-31 | 2016-09-13 | Boehringer Ingelheim International Gmbh | Substituted bicyclic dihydropyrimidinones and their use as inhibitors of neutrophil elastase activity |
US9458113B2 (en) | 2014-07-31 | 2016-10-04 | Boehringer Ingelheim International Gmbh | Substituted bicyclic dihydropyrimidinones and their use as inhibitors of neutrophil elastase activity |
US9475779B2 (en) | 2014-07-31 | 2016-10-25 | Boehringer Ingelheim International Gmbh | Substituted bicyclic dihydropyrimidinones and their use as inhibitors of neutrophil elastase activity |
US9657015B2 (en) | 2014-07-31 | 2017-05-23 | Boehringer Ingelheim International Gmbh | Substituted bicyclic dihydropyrimidinones and their use as inhibitors of neutrophil elastase activity |
WO2017089390A1 (en) | 2015-11-23 | 2017-06-01 | F. Hoffmann-La Roche Ag | Janus kinases inhibitors, compositions thereof and use thereof |
WO2017108737A1 (en) | 2015-12-23 | 2017-06-29 | Chiesi Farmaceutici S.P.A. | 1-(3-tert-butyl-phenyl)-3-(4-([1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-1,2,3,4-tetrahydro- naphthalen-1-yl)-urea derivatives and their use as p38 mapk inhibitors |
WO2017108736A1 (en) | 2015-12-23 | 2017-06-29 | Chiesi Farmaceutici S.P.A. | N-[3-(3-{4-[[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl} -ureido)-phenyl]-methanesulfonamide derivatives and their use as p38 mapk inhibitors |
WO2017108738A1 (en) | 2015-12-23 | 2017-06-29 | Chiesi Farmaceutici S.P.A. | 1-(3-tert-butyl-2h-pyrazol-5-yl or 5-tert-butyl-isoxaol-3-yl)-3-(4-([1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-1,2,3,4-tetrahydro-naphthalenyl) urea derivatives and their use as p38 mapk inhibitors |
WO2017191098A1 (en) | 2016-05-05 | 2017-11-09 | F. Hoffmann-La Roche Ag | Pyrazole derivatives, compositions and therapeutic use thereof |
WO2018046409A1 (en) | 2016-09-06 | 2018-03-15 | F. Hoffmann-La Roche Ag | 8-(azetidin-1-yl)-[1,2,4]triazolo[1,5-a]pyridinyl compounds, compositions and methods of use thereof |
WO2018122212A1 (en) | 2016-12-29 | 2018-07-05 | F. Hoffmann-La Roche Ag | Pyrazolopyrimidine compounds and methods of use thereof |
WO2018166993A2 (en) | 2017-03-14 | 2018-09-20 | F. Hoffmann-La Roche Ag | Pyrazolochlorophenyl compounds, compositions and methods of use thereof |
WO2018215390A1 (en) | 2017-05-22 | 2018-11-29 | F. Hoffmann-La Roche Ag | Therapeutic compounds and compositions, and methods of use thereof |
WO2018215389A1 (en) | 2017-05-22 | 2018-11-29 | F. Hoffmann-La Roche Ag | Therapeutic compounds and compositions, and methods of use thereof |
WO2018224423A1 (en) | 2017-06-07 | 2018-12-13 | Chiesi Farmaceutici S.P.A. | (4-(([1,2,4]triazolo[4,3-a]pyridine-6-yl)oxy)-1,2,3,4-tetrahydronaphthalen-1-yl) ureido derivatives as anti-inflammatory p38 mapk inhibitors for treating diseases of the respiratory tract |
WO2019139714A1 (en) | 2018-01-15 | 2019-07-18 | Genentech, Inc. | Pyrazolopyrimidine compounds as jak inhibitors |
WO2020257143A1 (en) | 2019-06-18 | 2020-12-24 | Genentech, Inc. | Pyrazolopyrimidine aryl ether inhibitors of jak kinases and uses thereof |
WO2020257145A1 (en) | 2019-06-18 | 2020-12-24 | Genentech, Inc. | Pyrazolopyrimidine sulfone inhibitors of jak kinases and uses thereof |
WO2020257142A1 (en) | 2019-06-18 | 2020-12-24 | Genentech, Inc. | Tetrazole-substituted pyrazolopyrimidine inhibitors of jak kinases and uses thereof |
Families Citing this family (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP1539710B1 (en) * | 2002-09-10 | 2010-10-27 | Bayer Schering Pharma Aktiengesellschaft | Heterocyclic derivatives |
DE102009004197A1 (en) * | 2009-01-09 | 2010-07-15 | Bayer Schering Pharma Aktiengesellschaft | Heterocyclic fused diaryldihydropyrimidine derivatives and their use |
US9958484B2 (en) * | 2015-07-08 | 2018-05-01 | Qualcomm Incorporated | Apparatus and method for measuring load current by applying compensated gain to voltage derived from drain-to-source voltage of power gating device |
JP2020015705A (en) * | 2018-07-27 | 2020-01-30 | 住友化学株式会社 | Method for producing aniline compound |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR2528425A1 (en) * | 1982-06-15 | 1983-12-16 | Bayer Ag | 1,4-DIHYDROPYRIDINES AND PHARMACEUTICAL COMPOSITION CONTAINING THEM |
EP0451654A2 (en) * | 1990-04-11 | 1991-10-16 | Bayer Ag | Use of N-alkylated 1,4-dihydropyridine carboxylic acid esters as drugs, new compounds and process for their preparation |
WO1995005823A1 (en) * | 1993-08-27 | 1995-03-02 | Bayer Aktiengesellschaft | Use of n-alkylated 1,4-dihydropyridine dicarboxylic acid esters as medicaments |
JPH0840904A (en) * | 1994-07-29 | 1996-02-13 | Nikken Chem Co Ltd | 1,4-dihydropyridine compound |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE2753946A1 (en) * | 1977-12-03 | 1979-06-13 | Bayer Ag | 1-N-ARYL-1,4-DIHYDROPYRIDINE AND THEIR USE AS A MEDICINAL PRODUCT |
-
2002
- 2002-12-09 US US10/498,967 patent/US7199136B2/en not_active Expired - Fee Related
- 2002-12-09 WO PCT/EP2002/013931 patent/WO2003053930A1/en active IP Right Grant
- 2002-12-09 DE DE60214428T patent/DE60214428T2/en not_active Expired - Lifetime
- 2002-12-09 AU AU2002361992A patent/AU2002361992A1/en not_active Abandoned
- 2002-12-09 ES ES02796589T patent/ES2271365T3/en not_active Expired - Lifetime
- 2002-12-09 CA CA002470813A patent/CA2470813A1/en not_active Abandoned
- 2002-12-09 EP EP02796589A patent/EP1458682B1/en not_active Expired - Fee Related
- 2002-12-09 JP JP2003554646A patent/JP4486817B2/en not_active Expired - Fee Related
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR2528425A1 (en) * | 1982-06-15 | 1983-12-16 | Bayer Ag | 1,4-DIHYDROPYRIDINES AND PHARMACEUTICAL COMPOSITION CONTAINING THEM |
EP0451654A2 (en) * | 1990-04-11 | 1991-10-16 | Bayer Ag | Use of N-alkylated 1,4-dihydropyridine carboxylic acid esters as drugs, new compounds and process for their preparation |
WO1995005823A1 (en) * | 1993-08-27 | 1995-03-02 | Bayer Aktiengesellschaft | Use of n-alkylated 1,4-dihydropyridine dicarboxylic acid esters as medicaments |
JPH0840904A (en) * | 1994-07-29 | 1996-02-13 | Nikken Chem Co Ltd | 1,4-dihydropyridine compound |
Non-Patent Citations (1)
Title |
---|
DATABASE CA [online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; SEKI, TAKEJI ET AL: "Preparation of 1,4-dihydropyridine compounds as antiallergics and antiinflammatories", XP002235303, retrieved from STN Database accession no. 124:343126 * |
Cited By (56)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7691854B2 (en) | 2002-08-27 | 2010-04-06 | Bayer Schering Pharma Aktiengesellschaft | Dihydropyridine derivatives for use as human neutrophil elastase inhibitors |
WO2004020412A1 (en) * | 2002-08-27 | 2004-03-11 | Bayer Healthcare Ag | Dihydropyridine derivatives for use as human neutrophil elastase inhibitors |
JP2007505902A (en) * | 2003-09-18 | 2007-03-15 | アストラゼネカ・アクチエボラーグ | 2-pyridone derivatives and their use as neutrophil elastase inhibitors |
JP2007523105A (en) * | 2004-02-19 | 2007-08-16 | バイエル・ヘルスケア・アクチェンゲゼルシャフト | Dihydropyridinone derivatives |
WO2005082864A1 (en) * | 2004-02-26 | 2005-09-09 | Bayer Healthcare Ag | 1,4-diaryl-dihydropyrimidin-2-ones and their use as human neutrophil elastase inhibitors |
WO2005082863A2 (en) | 2004-02-26 | 2005-09-09 | Bayer Healthcare Ag | 1,4 diaryl-dihydropyrimidin-2 ones and their use as a human neutrophil elastase inhibitors |
WO2005082863A3 (en) * | 2004-02-26 | 2005-12-22 | Bayer Healthcare Ag | 1,4 diaryl-dihydropyrimidin-2 ones and their use as a human neutrophil elastase inhibitors |
US8101615B2 (en) | 2004-02-26 | 2012-01-24 | Bayer Pharma Aktiengesellschaft | 1,4-diaryl-dihydropyrimidin-2-ones and their use as human neutrophil elastase inhibitors |
US7893073B2 (en) | 2004-02-26 | 2011-02-22 | Bayer Schering Pharma Aktiengesellschaft | Heterocyclic derivatives |
EP2281813A1 (en) | 2005-08-08 | 2011-02-09 | Pulmagen Therapeutics (Synergy) Limited | Bicyclo[2.2.1]hept-7-ylamine derivatives and their uses |
EP2280006A1 (en) | 2005-08-08 | 2011-02-02 | Pulmagen Therapeutics (Synergy) Limited | Pharmaceutical composition for inhalation comprising an oxazole or thiazole m3 muscarinic receptor antagonist |
DE102007019690A1 (en) | 2007-04-26 | 2008-10-30 | Bayer Healthcare Ag | Use of cyclic substituted furopyrimidine derivatives for the treatment of pulmonary arterial hypertension |
DE102007019691A1 (en) | 2007-04-26 | 2008-10-30 | Bayer Healthcare Ag | Use of acyclically substituted furopyrimidine derivatives for the treatment of pulmonary arterial hypertension |
DE102007027799A1 (en) | 2007-06-16 | 2008-12-18 | Bayer Healthcare Ag | Substituted furopyrimidines and their use |
DE102007027800A1 (en) | 2007-06-16 | 2008-12-18 | Bayer Healthcare Ag | Substituted bicyclic heteroaryl compounds and their use |
DE102007051762A1 (en) | 2007-10-30 | 2009-05-07 | Bayer Healthcare Ag | Substituted pyrrolotriazines and their use |
DE102007054786A1 (en) | 2007-11-16 | 2009-05-20 | Bayer Healthcare Ag | Trisubstituted Furopyrimidines and their Use |
EP2327693A1 (en) | 2007-12-14 | 2011-06-01 | Pulmagen Therapeutics (Asthma) Limited | Indoles and their therapeutic use |
WO2009077728A1 (en) | 2007-12-14 | 2009-06-25 | Argenta Discovery Limited | Indoles and their therapeutic use |
DE102008007400A1 (en) | 2008-02-04 | 2009-08-06 | Bayer Healthcare Ag | Substituted furans and their use |
WO2010094956A1 (en) | 2009-02-17 | 2010-08-26 | Pulmagen Therapeutics (Inflammation) Limited. | Triazolopyridine derivatives as p38 map kinase inhibitors |
WO2010094955A1 (en) | 2009-02-17 | 2010-08-26 | Pulmagen Therapeutics (Inflammation) Limited | Pyrimidopyridazine derivatives useful as p38 mapk inhibitors |
WO2011051673A1 (en) | 2009-10-28 | 2011-05-05 | Vantia Limited | Aminothiazole derivatives useful as klk1 inhibitors |
WO2011051671A1 (en) | 2009-10-28 | 2011-05-05 | Vantia Limited | Aminopyridine derivatives as kallikrein inhibitors |
WO2011051672A1 (en) | 2009-10-28 | 2011-05-05 | Vantia Limited | Azaindole derivatives |
WO2011154738A1 (en) | 2010-06-10 | 2011-12-15 | Chiesi Farmaceutici S.P.A. | Urea derivatives and their therapeutic use in the treatment of, inter alia, diseases of the respiratory tract |
WO2013083606A1 (en) | 2011-12-09 | 2013-06-13 | Chiesi Farmaceutici S.P.A. | Kinase inhibitors |
WO2013083206A1 (en) | 2011-12-09 | 2013-06-13 | Chiesi Farmaceutici S.P.A. | Derivatives of 4-hydroxy-1,2,3,4-tetrahydronaphtalen-1-yl urea and their use in the treatment of, inter alia, diseases of the respiratory tract |
WO2013083604A1 (en) | 2011-12-09 | 2013-06-13 | Chiesi Farmaceutici S.P.A. | Kinase inhibitors |
WO2014122160A1 (en) | 2013-02-06 | 2014-08-14 | Boehringer Ingelheim International Gmbh | Substituted bicyclic dihydropyrimidinones and their use as inhibitors of neutrophil elastase activity |
WO2014135414A1 (en) | 2013-03-04 | 2014-09-12 | Boehringer Ingelheim International Gmbh | Substituted bicyclic dihydropyrimidinones and their use as inhibitors of neutrophil elastase activity |
WO2014195402A1 (en) | 2013-06-06 | 2014-12-11 | Chiesi Farmaceutici S.P.A. | Kinase inhibitors |
US9290457B2 (en) | 2014-07-31 | 2016-03-22 | Boehringer Ingelheim International Gmbh | Substituted dihydropyrimidinones and their use as inhibitors of neutrophil elastase activity |
WO2016016366A1 (en) * | 2014-07-31 | 2016-02-04 | Boehringer Ingelheim International Gmbh | Substituted dihydropyrimidinones and their use as inhibitors of neutrophil elastase activity |
US9440930B2 (en) | 2014-07-31 | 2016-09-13 | Boehringer Ingelheim International Gmbh | Substituted bicyclic dihydropyrimidinones and their use as inhibitors of neutrophil elastase activity |
US9458113B2 (en) | 2014-07-31 | 2016-10-04 | Boehringer Ingelheim International Gmbh | Substituted bicyclic dihydropyrimidinones and their use as inhibitors of neutrophil elastase activity |
US9475779B2 (en) | 2014-07-31 | 2016-10-25 | Boehringer Ingelheim International Gmbh | Substituted bicyclic dihydropyrimidinones and their use as inhibitors of neutrophil elastase activity |
US9657015B2 (en) | 2014-07-31 | 2017-05-23 | Boehringer Ingelheim International Gmbh | Substituted bicyclic dihydropyrimidinones and their use as inhibitors of neutrophil elastase activity |
EP3604308A1 (en) | 2014-07-31 | 2020-02-05 | Boehringer Ingelheim International GmbH | Substituted bicyclic dihydropyrimidinones and their use as inhibitors of neutrophil elastase activity |
EP3539952A1 (en) | 2014-07-31 | 2019-09-18 | Boehringer Ingelheim International GmbH | Substituted bicyclic dihydropyrimidinones and their use as inhibitors of neutrophil elastase activity |
WO2017089390A1 (en) | 2015-11-23 | 2017-06-01 | F. Hoffmann-La Roche Ag | Janus kinases inhibitors, compositions thereof and use thereof |
WO2017108738A1 (en) | 2015-12-23 | 2017-06-29 | Chiesi Farmaceutici S.P.A. | 1-(3-tert-butyl-2h-pyrazol-5-yl or 5-tert-butyl-isoxaol-3-yl)-3-(4-([1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-1,2,3,4-tetrahydro-naphthalenyl) urea derivatives and their use as p38 mapk inhibitors |
WO2017108736A1 (en) | 2015-12-23 | 2017-06-29 | Chiesi Farmaceutici S.P.A. | N-[3-(3-{4-[[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl} -ureido)-phenyl]-methanesulfonamide derivatives and their use as p38 mapk inhibitors |
WO2017108737A1 (en) | 2015-12-23 | 2017-06-29 | Chiesi Farmaceutici S.P.A. | 1-(3-tert-butyl-phenyl)-3-(4-([1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-1,2,3,4-tetrahydro- naphthalen-1-yl)-urea derivatives and their use as p38 mapk inhibitors |
WO2017191098A1 (en) | 2016-05-05 | 2017-11-09 | F. Hoffmann-La Roche Ag | Pyrazole derivatives, compositions and therapeutic use thereof |
WO2018046409A1 (en) | 2016-09-06 | 2018-03-15 | F. Hoffmann-La Roche Ag | 8-(azetidin-1-yl)-[1,2,4]triazolo[1,5-a]pyridinyl compounds, compositions and methods of use thereof |
EP4198036A1 (en) | 2016-09-06 | 2023-06-21 | F. Hoffmann-La Roche AG | 8-(azetidin-1-yl)-[1,2,4]triazolo[1,5-a] pyridinyl compounds, compositions and methods of use thereof |
WO2018122212A1 (en) | 2016-12-29 | 2018-07-05 | F. Hoffmann-La Roche Ag | Pyrazolopyrimidine compounds and methods of use thereof |
WO2018166993A2 (en) | 2017-03-14 | 2018-09-20 | F. Hoffmann-La Roche Ag | Pyrazolochlorophenyl compounds, compositions and methods of use thereof |
WO2018215389A1 (en) | 2017-05-22 | 2018-11-29 | F. Hoffmann-La Roche Ag | Therapeutic compounds and compositions, and methods of use thereof |
WO2018215390A1 (en) | 2017-05-22 | 2018-11-29 | F. Hoffmann-La Roche Ag | Therapeutic compounds and compositions, and methods of use thereof |
WO2018224423A1 (en) | 2017-06-07 | 2018-12-13 | Chiesi Farmaceutici S.P.A. | (4-(([1,2,4]triazolo[4,3-a]pyridine-6-yl)oxy)-1,2,3,4-tetrahydronaphthalen-1-yl) ureido derivatives as anti-inflammatory p38 mapk inhibitors for treating diseases of the respiratory tract |
WO2019139714A1 (en) | 2018-01-15 | 2019-07-18 | Genentech, Inc. | Pyrazolopyrimidine compounds as jak inhibitors |
WO2020257143A1 (en) | 2019-06-18 | 2020-12-24 | Genentech, Inc. | Pyrazolopyrimidine aryl ether inhibitors of jak kinases and uses thereof |
WO2020257145A1 (en) | 2019-06-18 | 2020-12-24 | Genentech, Inc. | Pyrazolopyrimidine sulfone inhibitors of jak kinases and uses thereof |
WO2020257142A1 (en) | 2019-06-18 | 2020-12-24 | Genentech, Inc. | Tetrazole-substituted pyrazolopyrimidine inhibitors of jak kinases and uses thereof |
Also Published As
Publication number | Publication date |
---|---|
US7199136B2 (en) | 2007-04-03 |
JP4486817B2 (en) | 2010-06-23 |
JP2005517666A (en) | 2005-06-16 |
DE60214428T2 (en) | 2007-09-20 |
AU2002361992A1 (en) | 2003-07-09 |
EP1458682B1 (en) | 2006-08-30 |
DE60214428D1 (en) | 2006-10-12 |
EP1458682A1 (en) | 2004-09-22 |
US20050165014A1 (en) | 2005-07-28 |
ES2271365T3 (en) | 2007-04-16 |
CA2470813A1 (en) | 2003-07-03 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US7199136B2 (en) | 1,4-dihydro-1,4-diphenylpyridine derivatives | |
US7691854B2 (en) | Dihydropyridine derivatives for use as human neutrophil elastase inhibitors | |
US8173665B2 (en) | I-pheny 1-3,4-dihydropyrimidin-2(1H)-one derivatives and their use | |
US8097629B2 (en) | Dihydropyridinone derivatives | |
US7687510B2 (en) | Pyrimidinone derivatives as therapeutic agents against acute and chronic inflammatory, ischaemic and remodelling processes | |
US6124279A (en) | Therapeutic heterocycles | |
Atwal et al. | Dihydropyrimidine calcium channel blockers: 2-heterosubstituted 4-aryl-1, 4-dihydro-6-methyl-5-pyrimidinecarboxylic acid esters as potent mimics of dihydropyridines | |
US8101615B2 (en) | 1,4-diaryl-dihydropyrimidin-2-ones and their use as human neutrophil elastase inhibitors | |
GB2383326A (en) | Antiinflammatory dihydropyridines | |
GB2390849A (en) | 3-Acyl-1,4-dihydro-1,4-di(phenyl/azinyl/diazinyl)pyridine derivatives for use as human neutrophil elastase inhibitors |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
AK | Designated states |
Kind code of ref document: A1 Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NO NZ OM PH PL PT RO RU SD SE SG SK SL TJ TM TN TR TT TZ UA UG US UZ VC VN YU ZA ZM ZW |
|
AL | Designated countries for regional patents |
Kind code of ref document: A1 Designated state(s): GH GM KE LS MW MZ SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE BG CH CY CZ DE DK EE ES FI FR GB GR IE IT LU MC NL PT SE SI SK TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG |
|
121 | Ep: the epo has been informed by wipo that ep was designated in this application | ||
DFPE | Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101) | ||
WWE | Wipo information: entry into national phase |
Ref document number: 2002796589 Country of ref document: EP |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2470813 Country of ref document: CA |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2003554646 Country of ref document: JP |
|
WWP | Wipo information: published in national office |
Ref document number: 2002796589 Country of ref document: EP |
|
WWE | Wipo information: entry into national phase |
Ref document number: 10498967 Country of ref document: US |
|
WWG | Wipo information: grant in national office |
Ref document number: 2002796589 Country of ref document: EP |