WO2004058733A1 - Anti-inflammatoires non steroidiens - Google Patents
Anti-inflammatoires non steroidiens Download PDFInfo
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- WO2004058733A1 WO2004058733A1 PCT/EP2003/014081 EP0314081W WO2004058733A1 WO 2004058733 A1 WO2004058733 A1 WO 2004058733A1 EP 0314081 W EP0314081 W EP 0314081W WO 2004058733 A1 WO2004058733 A1 WO 2004058733A1
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- 0 COc1c(C(*)(*)CC(C(F)(F)F)(C(Nc(cc2C(C*)=NO3)ccc2C3=O)=O)O)c(*)c(*)c(*)c1* Chemical compound COc1c(C(*)(*)CC(C(F)(F)F)(C(Nc(cc2C(C*)=NO3)ccc2C3=O)=O)O)c(*)c(*)c(*)c1* 0.000 description 4
- BJAXAWZUNNKJPJ-UHFFFAOYSA-N CC(CC(C(F)(F)F)(C(Nc(cc1C(C)=NO2)ccc1C2=O)=O)O)(c1c2)Oc1ccc2Br Chemical compound CC(CC(C(F)(F)F)(C(Nc(cc1C(C)=NO2)ccc1C2=O)=O)O)(c1c2)Oc1ccc2Br BJAXAWZUNNKJPJ-UHFFFAOYSA-N 0.000 description 1
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- 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
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
- C07D265/02—1,2-Oxazines; Hydrogenated 1,2-oxazines
Definitions
- the present invention relates to non-steroidal compounds and the use of the non-steroidal compounds for the manufacture of medicaments for the treatment of inflammation.
- non-steroidal compounds which bind to the glucocorticoid receptor, but for which no anti-inflammatory effect has so far been shown [cf. Nature Medicin 4 (1998) 92, Mol. Pharmacol. 52 (1997) 571]. Furthermore, non-steroidal compounds have been described which are derived from steroidal compounds, have affinity for the glucocorticoid receptor and are likely to have an anti-inflammatory effect mediated by receptors [J. Med. Chem. 36, (1993), 3278-3285]. However, these compounds did not show any advantages over steroidal glucocorticoids in animal experiments, i.e. the anti-inflammatory effects of metabolic effects, e.g. Suppression of adrenal function to separate.
- the object was therefore to provide new non-steroidal anti-inflammatories which show a better dissociation of action than the compounds of the prior art with at least comparable, if not improved, potency.
- the compounds found are a selection from WO 00/32584.
- Nonsteroidal compounds have now been found which bind well to the glucocorticoid receptor and, through this binding, bring about an anti-inflammatory effect.
- these compounds show significantly better or at least equally good dissociations of action between anti-inflammatory and undesirable effects and are superior to the non-steroidal glucocorticoids described so far or at least have an equally good effect.
- R 1 and R 2 are the same or different and are for a C 1 -C 2 -alkyl group or, together with the C atom of the chain, for a ring with a total of 3 to 4 links,
- R 3 represents a hydrogen atom or a C 1 -C 2 alkyl group
- R 4 represents a hydrogen atom or a C 1 -C 2 alkyl group
- R 5 to R 8 are identical or different from one another and are selected from hydrogen or halogen atoms, and R4 and R5 together represent a 5-membered heterocyclic ring which may optionally contain a further oxygen or nitrogen atom in addition to the oxygen atom, as well as their pure enantiomers and racemates.
- the compounds of general formula I according to the invention can exist as different stereoisomers due to the presence of asymmetry centers. Both the racemates and the separately present stereoisomers belong to the subject of the present invention.
- the (+) enantiomers are preferred.
- a compound is known from WO 98/54159 which is very similar to the compounds mentioned here, but shows very pronounced activity as progestogen.
- the absolute configuration of this compound could be determined by X-ray structure analysis with (R). Because of the high bond similarity of these substances from WO 98/54159 and the compounds present here, the f configuration is also assumed for the (+) enantiomers present here.
- the C 1 -C 2 -alkyl groups can all be a methyl or ethyl group.
- a halogen atom can be a fluorine, chlorine, bromine or iodine atom.
- R1 and R2 together with the carbon atom of the chain form a 3-4-membered ring, this is a cyclopropyl or butyl ring.
- R 4 and R 5 form a common ring, then the 1,3-dioxol, furanyl, dihydrofuranyl and 1,3-oxazole ring systems are particularly preferred.
- the substituents R 4 to R 8 can independently of one another denote hydrogen atoms or halogen atoms or together form a ring as described above. The aromatic character of the phenyl ring is retained.
- racemic mixtures mentioned in the invention can be separated into the pure, optically active forms by the racemate separation methods which are known to the person skilled in the art.
- the racemic mixtures can be chromatographed on a self-optically active one
- CHIRALPAK AD® Separate the carrier material (CHIRALPAK AD®) into the pure isomers. It is also possible to esterify the free hydroxyl group in a racemic compound of the general formula I with an optically active acid and to separate the diastereoisomeric esters obtained by fractional crystallization or chromatographically and to saponify the separated esters to give the optically pure isomers.
- an optically active acid for example, mandelic acid, camphorsulfonic acid or tartaric acid can be used as the optically active acid.
- mandelic acid, camphorsulfonic acid or tartaric acid can be used as the optically active acid.
- R 1 and R 2 are the same or different and represent a methyl or ethyl group, further together with the carbon atom of the chain represent a cyclopropyl or cyclobutyl ring, and / or R 3 is a hydrogen atom or a methyl group, and / or
- R 4 R 4 is a hydrogen atom or a methyl group and / or
- R 5 to R 8 R 5 to R 8 represent a hydrogen atom and optionally fluorine, chlorine, bromine or iodine atoms in one or two positions, and / or
- R 4 and R 5 together including the phenyl ring atoms 2 and 3 for a furan, a dihydrofuran, a 1,3-dioxole or a 1,3-oxazole ring and R 6 , R 7 and R 8 for a hydrogen atom or optionally in one or two positions for a fluorine, chlorine, bromine or iodine atom
- the table can be read as follows:
- Another embodiment of the present invention comprises precisely the compounds of the formula I listed in Table 1, taking into account their stated stereochemistry.
- a particular embodiment relates to the (+) enantiomers of compounds 1-36 in the table above.
- glucocorticoid receptor The binding of the substances to the glucocorticoid receptor (GR) is checked with the aid of a recombinantly produced receptor. Cytosol preparations from Sf9 cells which had been infected with recombinant baculoviruses which code for the GR are used for the binding studies. Compared to the reference substance [ 3 H] -dexamethasone, the substances show a high to very high affinity for GR.
- these compounds show in the mineral corticoid receptor (MR) binding test using cytosol preparations from Sf9 cells which are associated with Baculoviruses coding for the MR were infected, and of [ 3 H] -aldosterone as reference substance affinities for the MR.
- MR mineral corticoid receptor
- GR-mediated inhibition of the transcription of cytokines, adhesion molecules, enzymes and other pro-inflammatory factors is regarded as an essential molecular mechanism for the anti-inflammatory effect of glucocorticoids. This inhibition is caused by an interaction of the GR with other transcription factors, e.g. AP-1 and NF-kappa- B, effects (for an overview see Cato, AGB and Wade E, BioEssays 18, 371-378 1996).
- the compounds of the general formula I according to the invention inhibit the secretion of the cytokine IL-8 triggered by lipopolysaccharide (LPS) in the human monocyte cell line THP-1.
- LPS lipopolysaccharide
- the compounds of formula I are distinguished by their ability to address the transrepresentation mechanism via the GR more strongly (lower potency) than the transactivation mechanism. This was measured by determining transactivation and transrepression using reporter gene tests in human HeLa cells.
- the MMTV promoter (transactivation) and the IL-6 promoter (transrepression) were each upstream of the gene coding for the luciferase. By means of the photometric determination of the enzyme activity of the luciferase, it was possible to measure the activation of the transcription (MMTV promoter construct) or the inhibition of the transcription (IL-6 promoter construct) by the GR.
- the anti-inflammatory activity of the compounds of the general formula I were tested in animal experiments by testing in croton oil-induced inflammation in the rat and the mouse (J. Exp. Med. (1995), 182, 99-108).
- croton oil was applied topically to the ears in ethanolic solution.
- the test substances were also applied topically or systemically at the same time or two hours before the croton oil.
- ear weight as a measure of inflammatory edema
- peroxidase activity as a measure of immigration of granulocytes
- elastase activity as a measure of immigration of neutrophil granulocytes were measured.
- the compounds of the general formula I inhibit the three above-mentioned inflammation parameters in this test both after topical and after systemic application.
- glucocorticoid therapy One of the most common undesirable effects of glucocorticoid therapy is the so-called "steroid diabetes" [cf. Hatz, HJ, Glucocorticoide: Basic Immunology, Pharmacology and Therapy Guidelines, Horschafliche Verlagsgesellschaft mbH, Stuttgart, 1998].
- the reason for this is the stimulation of gluconeogenesis in the liver by induction of the enzymes responsible for this and by free amino acids that result from the breakdown of proteins (catabolic effect of the glucocorticoids).
- a key enzyme of the catabolic metabolism in the liver is tyrosine aminotranferase (TAT).
- TAT tyrosine aminotranferase
- the animals are sacrificed 8 hours after the administration of the test substances, the liver is removed and the TAT activity in the Homogenate measured.
- the compounds of the general formula I do not induce the tyrosine aminotransferase, or do so only to a small extent, in which they are anti-inflammatory.
- the new compounds of general formula I show the following compared to the steroidal glucocorticoids previously used
- Non-steroidal structure ie the substances are still effective in patients who are no longer accessible for therapy with them due to an allergic reaction to the steroid basic structures of conventional glucocorticoids (cf.Lutz, ME, el-Azhary RA, Mayo Clin. Proc. 72 , 1141-1144, 1997). - similarly good anti-inflammatory effect with little metabolic effect
- the compounds of general formula I according to the invention can be used as medicaments for the treatment or prophylaxis of the following disease states in mammals and humans:
- the term “DISEASE” stands for the following indications:
- kidney diseases associated with inflammatory, allergic and / or proliferative processes (vi) kidney diseases associated with inflammatory, allergic and / or proliferative processes:
- liver diseases associated with inflammatory, allergic and / or proliferative processes (vii) liver diseases associated with inflammatory, allergic and / or proliferative processes:
- liver cell disintegration - acute hepatitis of various origins, e.g. viral, toxic, drug-induced
- Gastroenteritis of other genesis e.g. native sprue
- Otitis externa e.g. due to contact xem. Infection etc.
- - Acquired primary adrenal insufficiency e.g. Addison's disease, autoimmune adrenalitis, post-infectious, tumors, metastases etc.
- congenital secondary adrenal insufficiency e.g. congenital hypopitutitarianism - acquired secondary adrenal insufficiency, e.g. post-infectious, tumors etc.
- the compounds of general formula I according to the invention can be used for the therapy and prophylaxis of other disease states not mentioned above, for which synthetic glucocorticoids are used today (see also Hatz, HJ, glucocorticoids: immunological bases, pharmacology and therapy guidelines, Academicliche Verlagsgesellschaft mbH, Stuttgart , 1998).
- the suitable dose for the therapeutic effects in the abovementioned disease states is different and depends, for example, on the potency of the compound of the general formula I, the host, the mode of administration and the type and severity of the conditions to be treated, and on the use as a prophylactic or therapeutic agent.
- the invention further encompasses
- the daily doses comprise a range from 1 ⁇ g to 100,000 ⁇ g of the compound according to the invention per kg of body weight.
- a recommended daily dose is in the range of 1 ⁇ g to 100,000 ⁇ g per kg body weight.
- a dose of 10 to 30,000 ⁇ g per kg body weight is preferred, more preferably a dose of 10 to 10,000 ⁇ g per kg body weight.
- this dose is conveniently administered several times a day.
- acute shock e.g. anaphylactic shock
- single doses can be given that are clearly above the doses mentioned above.
- the pharmaceutical preparations based on the new compounds are formulated in a manner known per se by processing the active ingredient with the carrier substances, fillers, disintegrants, binders, humectants, lubricants, absorbents, diluents, flavoring agents, colorants, etc. customary in galenics and converted into the desired application form. It is on
- Tablets, coated tablets, capsules, pills, powders, granules, pastilles, suspensions, emulsions or solutions are particularly suitable for oral administration. Injection and infusion preparations are possible for parenteral administration.
- Appropriately prepared crystal suspensions can be used for intra-articular injection.
- Aqueous and oily injection solutions or suspensions and corresponding depot preparations can be used for intramuscular injection.
- the new compounds in the form of suppositories, capsules, solutions (e.g. in the form of clysms) and ointments can be used for both systemic and local therapy.
- the pulmonary application of the new compounds can be used in the form of aerosols and inhalants.
- the new compounds can be used as drops, ointments and tinctures in appropriate pharmaceutical preparations for local use on the eyes, external auditory canal, middle ear, nasal cavity and paranasal sinuses.
- formulations in gels, ointments, fatty ointments, creams, pastes, powder, milk and tinctures are possible.
- the dosage of the compounds of the general formula I should be 0.01% to 20% in these preparations in order to achieve a sufficient pharmacological effect.
- the invention also encompasses the compounds of the general formula I according to the invention as a therapeutic active ingredient.
- the invention furthermore relates to the compounds of the general formula I according to the invention as a therapeutic active ingredient together with pharmaceutically acceptable and acceptable excipients and carriers.
- the invention also comprises a pharmaceutical composition which is one of the pharmaceutical contains active compounds according to the invention or a mixture thereof and a pharmaceutically acceptable salt or pharmaceutically acceptable adjuvants and carriers.
- Process for the preparation of the compounds according to the invention The processes for the preparation of compounds according to general formula I known from WO98 / 54159, WO00 / 32584 and WO02 / 10143 can also be used for the preparation of the compounds according to the invention in this patent application.
- the nitriles (VII) required for the production processes described in WO98 / 54159, WO00 / 32584 and WO02 / 10143, the following processes can be obtained.
- Carboxylic acids of the general formula II are converted into the corresponding ester with R9 using an appropriate alkyl halide or with an appropriate alcohol using methods known to those skilled in the art under basic or acidic conditions.
- R9 stands for a C1-C5 alkyl chain.
- the resulting carboxylic acid esters (III) are with complex hydride reagents such as. B. implemented lithium aluminum hydride to arrive at compounds of formula IV.
- the alcohols of the general formula IV are mixed with an inorganic mixed acid anhydride, such as, for. B. SOCI 2 , PCI 3 or PBr 3 implemented to arrive at compounds of formula V.
- the Benzyl halides of the general formula V are reacted with an inorganic cyanide salt in order to obtain compounds of the formula VI.
- an inorganic cyanide salt such as sodium hydride, potassium carbonate, cesium carbonate or lithium diisopropylamine and a corresponding alkyl halide.
- a strong base such as sodium hydride, potassium carbonate, cesium carbonate or lithium diisopropylamine and a corresponding alkyl halide.
- the radicals R1, R2, R4-R8 of the compounds II-VII in Scheme 1 have the meaning given in formula I.
- nitriles of the formula VI can be obtained by the following process.
- Phenols of the general formula VIII are reacted with acetic anhydride to give the corresponding acetates IX and, for example, with a Lewis acid.
- B. aluminum trichloride to the compounds of general formula X implemented.
- the compounds of the general formula X are reacted with a base such as potassium carbonate and an alkyl halide to give compounds of the general formula XI.
- the compounds of general formula XI are then converted to phenylacetic acid derivatives of general formula XII by a method according to Willgerodt and Kindler (Brown EV, Synthesis 1975, pp. 358-375).
- an inorganic mixed acid anhydride such as. B.
- acetophenone derivatives of the general formula XI are by reaction with a metal alkyl compound such as. B. implemented methyl magnesium chloride or methyl magnesium bromide to the compounds of general formula XIV.
- the reaction mixture is poured into water, extracted with ethyl acetate, washed with brine, dried (Na 2 SO 4 ) and concentrated.
- the crude product is in 137 ml of a solution of 1 N sodium hydroxide solution in ethanol / water 2: 1 at RT. Stirred for 12 hours.
- the mixture is concentrated in vacuo and the remaining solution is extracted with diethyl ether.
- the water phase is acidified with 1 M hydrochloric acid and with diethyl ether extracted. 2.95 g of acid are obtained, which is heated with 55 ml of 2N sulfuric acid and 10 ml of glacial acetic acid with vigorous stirring under reflux for several hours.
- (+/-) - 6- [3- (benzo [1, 3] dioxol-4-yl) cyclobutyl-2-hydroxy-2-trifluoromethyl-propionyl-amino] -4-methyl-2,3- benzoxazin-1-one:
- the enantiomer mixture is separated by chromatography on a chiral support material (CHIRALPAK AD®, DAICEL) with hexane / ethanol (93: 7, vvv).
- CHIRALPAK AD®, DAICEL hexane / ethanol
- (+/-) - 6- [4- (5-Bromo-2-methoxyphenyl) -2-hydroxy-4-methyl-2- (trifluoromethyl) valeroylamino] -4-methyl-2,3-benzoxazin-1-one
- (+/-) - 6- [4- (5-Bromo-2-methoxyphenyl) -2-hydroxy-4-methyl-2- (trifluoromethyl) valeroylamino] -4-methyl-2,3-benzoxazin-1-one is produced according to the analogous procedure from Example 1. Mp 175-176 ° C
- (+/-) - 4-ethyl-6- [4- (7-benzofuranyl) -2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino] -2,3-benzoxazin-1-one 930 mg ( ⁇ ) -4-ethyl-6- [4- (2,3-dihydrobenzofuran-7-yl) -2-hydroxy-4-methyl-2-trifluoromethyl-valeroylamino] -2,3-benzoxazin-1-one and 680 mg of 2,3-dichloro-5,6-dicyano-p-benzoquinone in 90 ml of dioxane are boiled under reflux for 20 hours, water is added and the mixture is filtered off with suction.
- (+) - 6- [4- (2-Methoxy-3-fluoro-phenyl) -cyclopropyI-2-hydroxy-2-trifluoromethyl-propanoylamino] -4-methyl-2,3-benzoxazin-1-one is started from (2-methoxy-3-fluoro-phenyl) -cyclopropyl-carbonitrile obtained by the method described in Example 3.
- the potency of the anti-inflammatory is determined by inhibiting the secretion of the cytokine IL-8 in a cellular test.
- the compounds of the general formula I according to the invention inhibit the secretion of IL-8 triggered by lipopolysaccharide (LPS) in the human monocyte cell line THP-1.
- LPS lipopolysaccharide
- the concentration of the cytokine in the supernatant was determined using commercially available ELISA kits.
- the compounds of the formula I show a high to very high potency and activity (> 50%) in inhibition (see Table 4).
- the potency of the racemates is significantly lower than that of the pure enantiomers.
- the compounds of formula I are able to preferentially induce transrepression by the GR and to a lesser extent the transactivation. This dissociation of the mechanisms of action was determined with the help of reporter gene tests in stably transfected human HeLa cells.
- the MMTV promoter which is placed in front of a luciferase gene, was used to determine the transactivation induced by the GR. By photometric determination of the luciferase activity it was possible to determine the transactivation activities of the GR after binding of the test compounds.
- the inhibition of the transcription of the luciferase gene induced by tetradecanoyl phorbol acetate (TPA) under the control of the IL-6 promoter or the collagenase promoter (transrepression) by the GR after binding of the test substances was also determined by measuring the luciferase activity in HeLa cells.
- the compounds of formula I show a more than 5-fold better potency in transrepression (IL-6 promoter) than in transactivation (MMTV promoter) and at least 60% inhibition of IL-6 or collagenase promoter activity , In transrepression, the pure enantiomers show better activity (potency) compared to the racemic compounds.
- the anti-inflammatory activity of the compounds of the general formula I were tested in animal experiments in croton oil-induced inflammation in the mouse and in the rat (J. Exp. Med. (1995), 182, 99-108).
- croton oil was applied topically to the ears in ethanolic solution.
- the test substances were applied systemically two hours before the croton oil. After 16-24 h the ear weight was measured as a measure of the inflammatory edema.
- the compounds of formula I show a comparable and sometimes stronger inhibition of the inflammation induced by croton oil to the standard (prednisolone) (see Table 8).
- TAT tyrosine aminotransferase
- TAT tyrosine aminotransferase
- the induction factor stands for the corresponding n-fold increase in the enzyme activity of tyrosine aminotransferase in treated animals compared to untreated control animals
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Abstract
Priority Applications (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP03789227A EP1572671A1 (fr) | 2002-12-20 | 2003-12-11 | Anti-inflammatoires non steroidiens |
AU2003293843A AU2003293843A1 (en) | 2002-12-20 | 2003-12-11 | Non-steroidal anti-inflammatory agents |
JP2004562728A JP2006512382A (ja) | 2002-12-20 | 2003-12-11 | 非ステロイド性抗炎症剤 |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE10261874A DE10261874A1 (de) | 2002-12-20 | 2002-12-20 | Nichtsteroidale Entzündungshemmer |
DE10261874.7 | 2002-12-20 |
Publications (1)
Publication Number | Publication Date |
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WO2004058733A1 true WO2004058733A1 (fr) | 2004-07-15 |
Family
ID=32478137
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/EP2003/014081 WO2004058733A1 (fr) | 2002-12-20 | 2003-12-11 | Anti-inflammatoires non steroidiens |
Country Status (5)
Country | Link |
---|---|
EP (1) | EP1572671A1 (fr) |
JP (1) | JP2006512382A (fr) |
AU (1) | AU2003293843A1 (fr) |
DE (1) | DE10261874A1 (fr) |
WO (1) | WO2004058733A1 (fr) |
Cited By (2)
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WO2007040166A1 (fr) * | 2005-09-30 | 2007-04-12 | Dainippon Sumitomo Pharma Co., Ltd. | Nouveau dérivé pyrrole condensé |
US9365552B2 (en) | 2010-03-19 | 2016-06-14 | Novartis Ag | Pyridine and pyrazine derivative for the treatment of CF |
Families Citing this family (37)
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GB0401334D0 (en) | 2004-01-21 | 2004-02-25 | Novartis Ag | Organic compounds |
GB0411056D0 (en) | 2004-05-18 | 2004-06-23 | Novartis Ag | Organic compounds |
WO2006000398A1 (fr) * | 2004-06-28 | 2006-01-05 | Glaxo Group Limited | Derives de 2,3-benzoxazine utilises en tant que modulateurs non steroidiens du recepteur glucocorticoide |
WO2006000401A1 (fr) * | 2004-06-28 | 2006-01-05 | Glaxo Group Limited | Oxazines substituees utilisees comme modulateurs du recepteur glucocorticoide |
GB0418045D0 (en) | 2004-08-12 | 2004-09-15 | Glaxo Group Ltd | Compounds |
GT200500281A (es) | 2004-10-22 | 2006-04-24 | Novartis Ag | Compuestos organicos. |
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GB0507577D0 (en) | 2005-04-14 | 2005-05-18 | Novartis Ag | Organic compounds |
AR058104A1 (es) | 2005-10-21 | 2008-01-23 | Novartis Ag | Compuestos organicos |
GB0526244D0 (en) | 2005-12-22 | 2006-02-01 | Novartis Ag | Organic compounds |
GB0601951D0 (en) | 2006-01-31 | 2006-03-15 | Novartis Ag | Organic compounds |
AR060607A1 (es) | 2006-04-21 | 2008-07-02 | Novartis Ag | Derivados de purina,composiciones farmaceuticas que los contienen, metodo de preparacion y usos en enfermedades obstructivas o inflamatorias de las vias respiratorias. |
ATE493174T1 (de) | 2007-01-10 | 2011-01-15 | Irm Llc | Verbindungen und zusammensetzungen als kanal- aktivierende proteasehemmer |
MX2009012077A (es) | 2007-05-07 | 2009-11-19 | Novartis Ag | Compuestos organicos. |
PT2444120T (pt) | 2007-12-10 | 2018-01-03 | Novartis Ag | Análogos da amilorida espirocíclicos como bloqueadores de enac |
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EP2490687A1 (fr) | 2009-10-22 | 2012-08-29 | Vertex Pharmaceuticals Incorporated | Compositions destinées au traitement de la mucoviscidose et d'autres maladies chroniques |
US8637516B2 (en) | 2010-09-09 | 2014-01-28 | Irm Llc | Compounds and compositions as TRK inhibitors |
WO2012034095A1 (fr) | 2010-09-09 | 2012-03-15 | Irm Llc | Composés et compositions comme inhibiteurs de trk |
US8372845B2 (en) | 2010-09-17 | 2013-02-12 | Novartis Ag | Pyrazine derivatives as enac blockers |
CA2828219A1 (fr) | 2011-02-25 | 2012-08-30 | Irm Llc | Composes et compositions en tant qu'inhibiteurs de trk |
US8883819B2 (en) | 2011-09-01 | 2014-11-11 | Irm Llc | Bicyclic heterocycle derivatives for the treatment of pulmonary arterial hypertension |
WO2013038381A1 (fr) | 2011-09-16 | 2013-03-21 | Novartis Ag | Dérivés d'amide pyridine/pyrazine |
US9034879B2 (en) | 2011-09-16 | 2015-05-19 | Novartis Ag | Heterocyclic compounds for the treatment of CF |
WO2013038378A1 (fr) | 2011-09-16 | 2013-03-21 | Novartis Ag | Dérivés pyridinamides |
ES2882807T3 (es) | 2011-09-16 | 2021-12-02 | Novartis Ag | Heterociclil carboxamidas N-sustituidas |
WO2013038373A1 (fr) | 2011-09-16 | 2013-03-21 | Novartis Ag | Dérivés pyrimidinamides |
US8809340B2 (en) | 2012-03-19 | 2014-08-19 | Novartis Ag | Crystalline form |
US9073921B2 (en) | 2013-03-01 | 2015-07-07 | Novartis Ag | Salt forms of bicyclic heterocyclic derivatives |
US10155001B2 (en) | 2013-06-14 | 2018-12-18 | Inserm (Institut National De La Sante Et De La Recherche Medicale) | RAC1 inhibitors for inducing bronchodilation |
EA201692140A1 (ru) | 2014-04-24 | 2017-04-28 | Новартис Аг | Производные аминопиридина в качестве ингибиторов фосфатидилинозитол 3-киназы |
ES2667424T3 (es) | 2014-04-24 | 2018-05-10 | Novartis Ag | Derivados de pirazina como inhibidores de fosfatidil-inositol-3-quinasa |
CA2945212A1 (fr) | 2014-04-24 | 2015-10-29 | Novartis Ag | Derives amines de pyrazine utilisables en tant qu'inhibiteurs de la phosphatidylinositol 3-kinase |
IT201800010643A1 (it) | 2018-11-28 | 2020-05-28 | Ima Spa | Macchina per la formazione di sacchetti filtro per prodotti da infusione. |
US20200383960A1 (en) | 2019-06-10 | 2020-12-10 | Novartis Ag | Pyridine and Pyrazine derivative for the Treatment of CF, COPD, and Bronchiectasis |
JP2022547427A (ja) | 2019-08-28 | 2022-11-14 | ノバルティス アーゲー | 置換1,3-フェニルヘテロアリール誘導体及び疾患の治療におけるその使用 |
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WO1998054159A1 (fr) * | 1997-05-30 | 1998-12-03 | Schering Aktiengesellschaft | Acylanilides non steroidiques heterocycliquement substitues a effet mixte gestagene et androgene |
WO2000032584A2 (fr) * | 1998-11-27 | 2000-06-08 | Schering Aktiengesellschaft | Inhibiteurs d'inflammation non steroidiques |
-
2002
- 2002-12-20 DE DE10261874A patent/DE10261874A1/de not_active Withdrawn
-
2003
- 2003-12-11 JP JP2004562728A patent/JP2006512382A/ja active Pending
- 2003-12-11 AU AU2003293843A patent/AU2003293843A1/en not_active Abandoned
- 2003-12-11 WO PCT/EP2003/014081 patent/WO2004058733A1/fr not_active Application Discontinuation
- 2003-12-11 EP EP03789227A patent/EP1572671A1/fr not_active Withdrawn
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
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WO1998054159A1 (fr) * | 1997-05-30 | 1998-12-03 | Schering Aktiengesellschaft | Acylanilides non steroidiques heterocycliquement substitues a effet mixte gestagene et androgene |
WO2000032584A2 (fr) * | 1998-11-27 | 2000-06-08 | Schering Aktiengesellschaft | Inhibiteurs d'inflammation non steroidiques |
Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2007040166A1 (fr) * | 2005-09-30 | 2007-04-12 | Dainippon Sumitomo Pharma Co., Ltd. | Nouveau dérivé pyrrole condensé |
US9365552B2 (en) | 2010-03-19 | 2016-06-14 | Novartis Ag | Pyridine and pyrazine derivative for the treatment of CF |
USRE46757E1 (en) | 2010-03-19 | 2018-03-20 | Novartis Ag | Pyridine and pyrazine derivative for the treatment of CF |
US10117858B2 (en) | 2010-03-19 | 2018-11-06 | Novartis Ag | Pyridine and pyrazine derivative for the treatment of CF |
US11911371B2 (en) | 2010-03-19 | 2024-02-27 | Novartis Ag | Pyridine and pyrazine derivative for the treatment of chronic bronchitis |
Also Published As
Publication number | Publication date |
---|---|
DE10261874A1 (de) | 2004-07-08 |
EP1572671A1 (fr) | 2005-09-14 |
JP2006512382A (ja) | 2006-04-13 |
AU2003293843A1 (en) | 2004-07-22 |
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