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WO2001081324A1 - Derives de benzoxazine et de benzothiazine presentant des proprietes d'inhibition de nos et d'antioxydation - Google Patents

Derives de benzoxazine et de benzothiazine presentant des proprietes d'inhibition de nos et d'antioxydation

Info

Publication number
WO2001081324A1
WO2001081324A1 PCT/EP2001/004282 EP0104282W WO0181324A1 WO 2001081324 A1 WO2001081324 A1 WO 2001081324A1 EP 0104282 W EP0104282 W EP 0104282W WO 0181324 A1 WO0181324 A1 WO 0181324A1
Authority
WO
WIPO (PCT)
Prior art keywords
alkyl
hydrogen
chr
tert
methyl
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.)
Ceased
Application number
PCT/EP2001/004282
Other languages
German (de)
English (en)
Other versions
WO2001081324B1 (fr
Inventor
Peter Hölscher
Rolf Jautelat
Hartmut Rehwinkel
Stefan Jaroch
Detlev Sülzle
Margrit Hillmann
Gerardine Anne Burton
Fiona Mcdougall Mcdonald
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Bayer Pharma AG
Original Assignee
Schering AG
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Schering AG filed Critical Schering AG
Priority to AU2001262200A priority Critical patent/AU2001262200A1/en
Publication of WO2001081324A1 publication Critical patent/WO2001081324A1/fr
Publication of WO2001081324B1 publication Critical patent/WO2001081324B1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
    • C07D265/34—1,4-Oxazines; Hydrogenated 1,4-oxazines condensed with carbocyclic rings
    • C07D265/36—1,4-Oxazines; Hydrogenated 1,4-oxazines condensed with carbocyclic rings condensed with one six-membered ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D279/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one sulfur atom as the only ring hetero atoms
    • C07D279/10—1,4-Thiazines; Hydrogenated 1,4-thiazines
    • C07D279/14—1,4-Thiazines; Hydrogenated 1,4-thiazines condensed with carbocyclic rings or ring systems
    • C07D279/16—1,4-Thiazines; Hydrogenated 1,4-thiazines condensed with carbocyclic rings or ring systems condensed with one six-membered ring

Definitions

  • the invention relates to benzoxazine and benzothiazine derivatives, the process for their preparation and their use in pharmaceuticals.
  • NOS nitric oxide synthases
  • NOS inhibitors and in particular selective inhibitors of NOS 1, NOS 2 or NOS 3 are therefore suitable for the therapy of various diseases which are caused or exacerbated by pathological concentrations of NO in cells.
  • a number of reviews provide information on the effects and inhibitors of NO synthases. Examples include: Drugs 1, 321 (1998) or Current Pharmac. Design 3,
  • ROS reactive oxygen species
  • SO 2 ' " superoxide radical anions
  • OH ' hydroxyl radicals
  • heterocycles substituted according to the invention have both NOS-inhibitory and also radical-scavenging / antioxidative properties and can therefore be used particularly advantageously as medicaments.
  • the invention relates to the compounds of formula I, their tautomeric and isomeric forms and salts
  • R 2 is hydrogen or
  • R1 and R2 together with two adjacent carbon atoms form a 5-, 6-, 7- or ⁇ -membered ring which is monocyclic or bicyclic, saturated or unsaturated and in which 1 or 2 CH 2 groups can be replaced by oxygen or carbonyl and the is substituted with - (CHR 9 ) r -NR 7 -A-NR 8 -B, - (CHR 9 ) n -B or - (CHR 9 ) r -NR 8 -B,
  • R3 is hydrogen or NR 15 R 16 ,
  • R 4 is hydrogen or acyl
  • R 5 and R 6 independently of one another are hydrogen, C 3-7 cycloalkyl, phenyl, C 1-6 alkyl, C 2-6 alkenyl or C 2-6 alkynyl radicals, which can each be substituted by halogen, OH, Ode-alkyl, SH, SC 1-6- alkyl, NR 15 R 16 , 5- or ⁇ -membered heteroaryl with 1-3 N, O or S atoms, phenyl or C 3-7 cycloalkyl,
  • R 7 and R 8 independently of one another are hydrogen, C 1-6 -alkyl, which may be substituted by phenyl, COOC 1-6 -alkyl or CO-C 1-6 -alkyl,
  • R 8 together with the adjacent nitrogen atom forms a 5-7-membered saturated heterocycle which can contain a further oxygen, nitrogen or sulfur atom or forms an unsaturated ⁇ -membered heterocycle which can contain 1-3 N atoms,
  • R 7 together with the neighboring nitrogen atom forms a 5-7-membered saturated heterocycle which can contain a further oxygen, nitrogen or sulfur atom,
  • R 9 and R 1ü are hydrogen or C 1-6 alkyl
  • R 11 and R are hydrogen, hydroxy, C 1-6 alkyl or C 1-6 alkoxy
  • R 1b and R 1b are hydrogen, -6 alkyl, phenyl or benzyl, or
  • R 15 , R 16 together with the nitrogen atom form a saturated 5-, 6- or 7-membered ring which may contain a further nitrogen, oxygen or sulfur atom and which may be substituted by C 1-4 alkyl, phenyl, benzyl or benzoyl.
  • the compounds of the formula can exist as tautomers, stereoisomers or geometric isomers.
  • the invention also encompasses all possible isomers, such as E and Z isomers, S and R enantiomers, diastereomers, racemates and mixtures thereof, including the tautomeric compounds of the formulas Ia and Ib.
  • the physiologically acceptable salts can be formed with inorganic and organic acids such as oxalic acid, lactic acid, citric acid, fumaric acid, acetic acid, maleic acid, tartaric acid, phosphoric acid, HCl, HBr, sulfuric acid, p-toluenesulfonic acid, methanesulfonic acid and others.
  • inorganic and organic acids such as oxalic acid, lactic acid, citric acid, fumaric acid, acetic acid, maleic acid, tartaric acid, phosphoric acid, HCl, HBr, sulfuric acid, p-toluenesulfonic acid, methanesulfonic acid and others.
  • the inorganic or organic bases which are known for the formation of physiologically compatible salts, such as, for example, alkali metal hydroxides, such as sodium and potassium hydroxide, alkaline earth metal hydroxides such as calcium hydroxide, ammonia, amines such as ethanolamine, diethanolamine, triethanolamine, N-methylglucamine, Tris, are also suitable for salt formation of acid groups - (hydroxymethyl) methylamine etc.
  • physiologically compatible salts such as, for example, alkali metal hydroxides, such as sodium and potassium hydroxide, alkaline earth metal hydroxides such as calcium hydroxide, ammonia, amines such as ethanolamine, diethanolamine, triethanolamine, N-methylglucamine, Tris, are also suitable for salt formation of acid groups - (hydroxymethyl) methylamine etc.
  • Alkyl means in each case a straight-chain or branched alkyl group such as e.g. Methyl, ethyl, propyl, isopropyl, n-butyl, sec. Butyl, tert. Butyl, n-pentyl, sec. Pentyl, tert. Pentyl, neopentyl, n-hexyl, sec. Hexyl, heptyl, octyl.
  • alkyl means in each case a straight-chain or branched alkyl group such as e.g. Methyl, ethyl, propyl, isopropyl, n-butyl, sec. Butyl, tert. Butyl, n-pentyl, sec. Pentyl, tert. Pentyl, neopentyl, n-hexyl, sec. Hexyl, heptyl,
  • Alkenyl and alkynyl substituents preferably contain a double bond and are each straight-chain or branched.
  • the following radicals may be mentioned: vinyl, 2-propenyl, 1-propenyl, 2-butenyl, 1-butenyl, 3-butenyl, 2-methyl-2-propenyl, 2-pentenyl, 4-hexenyl, ethynyl, 1-propynyl , 2-propynyl, 1-butynyl, 2-butynyl.
  • Cycloalkyl is understood to mean cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.
  • Halogen means fluorine, chlorine, bromine or iodine.
  • Aryl is to be understood in each case as naphthyl or phenyl, which can be substituted one to three times in the same or different ways.
  • the following 5- and 6-ring heteroaromatics may be mentioned as examples of heteroaryl radicals which can be bonded via the hetero atom or a carbon atom:
  • Piperidine, pyrrolidine, morpholine, thiomorpholine, hexahydroazepine and piperazine may be mentioned as a saturated heterocycle.
  • the heterocycle can be substituted 1-3 times with C 1-4 alkyl or an optionally substituted with halogen phenyl, benzyl or benzoyl. Examples include: N-methylpiperazine, 2,6-dimethylmorpholine, phenylpiperazine or 4- (4-fluorobenzoyl) piperidine.
  • the substituent Q can be linked at any point via a carbon atom or, if appropriate, via an nitrogen atom.
  • R 1 and R 2 form a ring together with two adjacent carbon atoms, this ring can be in position 5, 6 or 7, 8 or in particular 6, 7 of the benzoxazine or benzothiazine and has the formula
  • E represents a 3 - membered ring, the 1 - 2fold with
  • the acyl radical R is derived from straight-chain or branched aliphatic C * -6 -carboxylic acids such as, for example, formic acid, acetic acid, propionic acid, butyric acid, trimethyl acetic acid or caproic acid or from known benzenesulfonic acids, which can be substituted by halogen or C 1-4 alkyl, and C 1- alkanesulfonic acids such as methanesulfonic acid, p-toluenesulfonic acid.
  • straight-chain or branched aliphatic C * -6 -carboxylic acids such as, for example, formic acid, acetic acid, propionic acid, butyric acid, trimethyl acetic acid or caproic acid or from known benzenesulfonic acids, which can be substituted by halogen or C 1-4 alkyl, and C 1- alkanesulfonic acids such as methanesulfonic acid, p-toluene
  • R 4 , R 7 and R 8 each preferably represent hydrogen.
  • n C 1-6 alkylene, especially methylene or ethylene,
  • R 11 and R 12 hydroxy, C- ⁇ . 6 -A! Koxy or in particular C 1-6 alkyl,
  • R 1 for R 1 : - (CHR 9 ) n -NR 7 -A-NR 8 -B or - (CHR 9 ) n -NR 8 -B.
  • the invention also relates to the use of the compounds according to the invention for the manufacture of a medicament for the treatment of diseases which are caused by the action of nitrogen monoxide in pathological concentrations and by reactive oxygen species.
  • diseases which are caused by the action of nitrogen monoxide in pathological concentrations and by reactive oxygen species.
  • Examples include: cerebral ischemia, hypoxia and other neurodegenerative diseases that are associated with inflammation, such as multiple sclerosis, amyotrophic lateral sclerosis and comparable skierotic diseases, Parkinson's disease, Huntington's disease, Korksakoff's disease, epilepsy, vomiting, sleep disorders, schizophrenia, depression, Stress, pain, migraines, hypoglycemia, dementia such as Alzheimer's disease, HIV dementia and presenile dementia.
  • autoimmune and / or inflammatory diseases such as hypotension, ARDS (adult respiratory distress syndrome), sepsis or septic shock, rheumatoid arthritis, osteoarthritis, and insulin-dependent diabetes mellitus (IDDM) , pelvic / bowel inflammatory disease, meningitis, glomerulonephritis, acute and chronic liver diseases, rejection diseases (e.g. allogeneic heart, kidney or liver transplants) or inflammatory skin diseases such as psoriasis and others.
  • ARDS adult respiratory distress syndrome
  • sepsis or septic shock rheumatoid arthritis
  • osteoarthritis osteoarthritis
  • IDDM insulin-dependent diabetes mellitus
  • the compounds according to the invention are brought into the form of a pharmaceutical preparation which, in addition to the active substance, is suitable for vehicles, enteral or parenteral administration, with carriers, auxiliaries and / or additives. contains substances.
  • the application can be administered orally or sublingually as a solid in the form of capsules or tablets or as a liquid in the form of solutions, suspensions, elixirs, aerosols or emulsions or rectally in the form of suppositories or in the form of injection solutions which can optionally be used subcutaneously or intravenously or topically in Form of aerosols or transdermal systems or intrathecally.
  • auxiliaries for the desired pharmaceutical formulation are the inert organic and inorganic carrier materials known to the person skilled in the art, such as, for example, water, gelatin, gum arabic, lactose, starch, magnesium stearate, talc, vegetable oils, polyalkylene glycols, etc. If necessary, preservatives and stabilizers can also be used -, wetting agents, emulsifiers or salts for changing the osmotic pressure or buffers may be included.
  • Injection solutions or suspensions in particular aqueous solutions of the active compounds in polyhydroxyethoxylated castor oil, are particularly suitable for parenteral use.
  • Surfactant auxiliaries such as salts of bile acids or animal or vegetable phospholipids, but also mixtures thereof and liposomes or their components can also be used as carrier systems.
  • Tablets, coated tablets or capsules with talc and / or hydrocarbon carriers or binders, such as lactose, corn or potato starch, are particularly suitable for oral use. It can also be used in liquid form, for example as juice, to which a sweetener may be added.
  • the compounds according to the invention have a synergistic neuroprotective effect and can be administered as combination preparations, where the active compounds can be present in a formulation or in separate formulations, and the dose, depending on the route of administration, and the weight of the patient and the type and severity of the disease varies (CA Hicks et al. Eur. J. of Pharm. 381, 113-119 (1999)).
  • the dosage of the active ingredients can vary depending on the route of administration, age and weight of the patient, type and severity of the disease to be treated and similar factors.
  • the daily dose is 1 - 2000 mg, preferably 20 - 500 mg, whereby the dose can be given as a single dose to be administered once or divided into two or more daily doses.
  • the NOS inhibitory activity of the compounds of the formula I and their physiologically tolerable salts can be determined by the methods of Bredt and Snyder in Proc. Natl. Acad. Be. USA 86: 9030-9033 (1989).
  • the compounds of the invention are prepared by adding a compound of the formula II or its salt
  • R 1 , R 2 , R 3 , R 5 , R 6 and X are as defined above, Z is oxygen or sulfur and R is C-
  • reaction with ammonia is carried out under pressure in autoclaves with excess ammonia at low temperatures (-76 ° C.) or by stirring in methanol saturated with ammonia at room temperature.
  • Thiolactams are preferably reacted.
  • the imine ether or iminothioether is first prepared as an intermediate compound (e.g. with methyl iodide or methyl sulfate) from the lactam or thiolactam and is reacted with or without isolation of the intermediate compound with the corresponding amines or their salts.
  • amino protecting groups are carbamates such as tert. Butoxycarbonyl, benzyloxycarbonyl or acetyl suitable.
  • esters are saponified at the precursors, acids are esterified, hydroxyl groups are etherified or acylated, amines are acylated, alkylated, diazotized, halogenated, NO2 introduced or reduced, reacted with isocyanates or isothiocyanates, the isomers are separated or the salts are formed.
  • the saponification of an ester group can be carried out in a basic or acidic manner by hydrolyzing at room temperature or elevated temperature to the boiling point of the reaction mixture in the presence of alkali metal hydroxides in ethanol or other alcohols or by means of acids such as hydrochloric acid and, if appropriate, further processing salts of the aminobenzoxazines or thiazines.
  • the carboxylic acid is esterified in a manner known per se with diazomethane or the corresponding alcohol in acid or in the presence of an activated acid derivative.
  • suitable acid derivatives are acid chloride, imidazolide or anhydride.
  • a nitro group or halogen, especially bromine can be introduced by electrophilic aromatic substitution.
  • the resulting mixtures can be separated in the usual way, also by means of HPLC. If a nitrile is present, it can be saponified by known methods or converted into the corresponding amine, tetrazole or amidoxime, or it becomes a substituted amidine by attacking substituted anilines or amines.
  • Friedel-Crafts acylation is successfully used for type Ila lactams, and then the lactam can be selectively converted to the thiolactam or the acylation product can be reductively aminated.
  • Suitable catalysts are metals such as Raney nickel or noble metal catalysts such as palladium or platinum, optionally in the presence of barium sulfate or on supports.
  • metals such as Raney nickel or noble metal catalysts such as palladium or platinum, optionally in the presence of barium sulfate or on supports.
  • ammonium formate or formic acid can also be used in a known manner.
  • Reducing agents such as tin-Il chloride can be used as well as complex metal hydrides possibly in the presence of heavy metal salts. It may be advantageous to reduce the Introduce ester group as in formula V.
  • the reduction with zinc or iron in acetic acid has proven effective for nitro groups.
  • alkylation can be carried out using alkyl halides, for example, using conventional methods.
  • the lactam group may need to be protected as an anion by a second equivalent base or by a suitable protective group.
  • the amino group is acylated in a customary manner, for example using an acid halide or acid anhydride, if appropriate in the presence of a base.
  • the introduction of the halogens chlorine, bromine or iodine via the amino group can also be carried out, for example, according to Sandmeyer by reacting the diazonium salts formed intermediately with nitrites with Cu (l) chloride or Cu (l) bromide in the presence of the corresponding acid such as hydrochloric acid or hydrobromic acid reacted with potassium iodide.
  • benzyl alcohols can be converted into the corresponding benzyl halides using methanesulfonyl chloride.
  • N ⁇ 2 group succeeds through a number of known nitration methods.
  • nitrates or with nitrronium tetrafluoroborate can be nitrated in inert solvents such as halogenated hydrocarbons or in sulfolane or glacial acetic acid. It is also possible to introduce e.g. by nitrating acid in water or conc. Sulfuric acid as a solvent at temperatures between -10 ° C and 30 ° C.
  • the isomer mixtures can be converted into the enantiomers or E / Z by conventional methods such as, for example, crystallization, chromatography or salt formation.
  • the salts are prepared in a customary manner by adding a solution of the compound of the formula I - optionally also with protected amino groups - with the equivalent amount or an excess of an acid, which is optionally in solution, and removing the precipitate or in a conventional manner worked up the solution.
  • the corresponding benzylamines provide nucleophilic substitution of benzyl halides with secondary amines.
  • Meerwein reagent trimethyioxonium tetrafluoroborate
  • the invention also relates to the intermediate compounds of the formulas IIa and IIb and their salts
  • R 1, R 2, R 3, R 5, R 6 and X have the above meaning, Z is oxygen or sulfur and R C ⁇ -6 alkyl.
  • the compounds of the formula IIIa can be prepared, for example, by adding a compound of the formula III
  • R ⁇ and R have the meaning given above and Y is a reactive carboxyl group such as acid halide, nitrile, carboxylic acid ester and optionally reductively cyclized or by reacting a compound of formula V.
  • Aromatic thiols of type III are obtained, among other things, as described in Chem. Pharm. Bull. 39, 2888 (1991) and the literature mentioned there, by rearrangement of the corresponding dimethylaminothiocarbamates.
  • the substituents R 1 -R 3 can be introduced at the stage of the compounds of the formula III or II.
  • the aldehyde or the ketone of the corresponding 1,4-benzoxazin-3-one or 1,4-benzothiazin-3-one can be reductively aminated. This is also possible twice with diamonds chosen appropriately. Diamines can also be reacted with the aldehyde of 1,4-benzoxazin-3-one and, at the same time, with other aldehydes chosen appropriately.
  • Diamines are obtained, as described in the literature (Synthesis 11; 917-918 (1988)), also by reacting benzamides with diamine with the release of ammonia, or by forming amides via the carboxylic acid after customary activation, for example using carbonyldiimidazole ( CDI).
  • CDI carbonyldiimidazole
  • the corresponding halogen derivative can be substituted nucleophilically. Is a primary or secondary
  • Amino group present it may be advantageous to protect it as an intermediate, for example by introducing a tert. Butoxycarbonylou, which is split off after the amidine formation in the usual way.
  • New compounds were characterized by one or more of the following methods: melting point, mass spectroscopy, NMR.
  • NMR spectra were measured with a Bruker 300 MHz device, the (deuterated) solvents are abbreviated as follows: CDCI3 (chloroform), DMSO (dimethyl sulfoxide). Shifts are given in delta and ppm. They mean: m (multiplet, multiple signals), s (singlet), d (doublet), dd (double doublet, etc.), tr (triplet), q (quartet), H (hydrogen protons), J (coupling constant).

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne des composés de formule (I), leurs formes tautomères et isomères, ainsi que leurs sels. Dans la formule (I), X représente O ou S, R<1> représente (CHR<9>)n-NR<7>-A-NR<8>-B, -(CHR<9>)n-NR<8>-B ou (CHR<9>)n-B, R<2> représente hydrogène ou R<1> et R<2> forment, conjointement avec deux atomes de carbone voisins, un cycle à 5, 6, 7 ou 8 éléments, monocyclique ou bicyclique, saturé ou insaturé, dans lequel 1 ou 2 groupes CH2 peuvent être remplacés par oxygène ou carbonyle et qui peut être substitué par (CHR<9>)r-NR<7>-A-NR<8>-B, -(CHR<9>)n-B ou -(CHR<9>)r-NR<8>-B, R<3> représente hydrogène ou NR<15>R<16>, R<4> représente hydrogène ou acyle, R<5> et R<6> représentent, indépendamment l'un de l'autre, hydrogène, des radicaux cycloalkyle C3-7, phényle, alkyle C1-6, alcényle C2-6 ou alcynyle C2-6, pouvant chacun être substitué par halogène, OH, O-alkyle C1-6, SH, S-alkyle C1-6, NR<15>R<16>, hétéroaryle à 5 ou 6 éléments et à 1-3 atomes de N, O ou S, phényle ou cycloalkyle C3-7, A représente alkylène C1-6 à chaîne droite ou ramifiée ou (CH2)p-Q-(CH2)q- et B représente (II) ou (III). La présente invention concerne également le procédé de production de ces composés, ainsi que leur utilisation dans des médicaments.
PCT/EP2001/004282 2000-04-25 2001-04-12 Derives de benzoxazine et de benzothiazine presentant des proprietes d'inhibition de nos et d'antioxydation Ceased WO2001081324A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2001262200A AU2001262200A1 (en) 2000-04-25 2001-04-12 Benzoxazine derivatives and benzothiazine derivatives having nos-inhibitory and antioxidant properties

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE10021244 2000-04-25
DE10021244.1 2000-04-25

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WO2001081324B1 WO2001081324B1 (fr) 2002-02-28

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014011047A1 (fr) * 2012-07-12 2014-01-16 Khondrion B.V. Dérivés de chromanyle destinés au traitement de la maladie mitochondriale
US9388156B2 (en) 2012-07-12 2016-07-12 Khondiron IP B.V. Chromanyl derivatives for treating mitochondrial disease

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999012915A1 (fr) * 1997-09-08 1999-03-18 Schering Aktiengesellschaft Derives de benzoxazine et de benzothiazine et leur utilisation dans des medicaments
WO2000017173A1 (fr) * 1998-09-18 2000-03-30 Schering Aktiengesellschaft Derives de benzoxazine et de benzothiazine et leur utilisation dans des produits pharmaceutiques

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999012915A1 (fr) * 1997-09-08 1999-03-18 Schering Aktiengesellschaft Derives de benzoxazine et de benzothiazine et leur utilisation dans des medicaments
WO2000017173A1 (fr) * 1998-09-18 2000-03-30 Schering Aktiengesellschaft Derives de benzoxazine et de benzothiazine et leur utilisation dans des produits pharmaceutiques

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
CHEMICAL ABSTRACTS, vol. 59, no. 12, 1963, Columbus, Ohio, US; abstract no. 13482g, BASSIGNANA P ET AL: "Infrared spectra of some compounds with thiazole and oxazole rings. The C:N bond." column 2; XP002176522 *
SPECTROCHIM. ACTA, vol. 19, no. 11, 1963, pages 1885 - 1897 *

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014011047A1 (fr) * 2012-07-12 2014-01-16 Khondrion B.V. Dérivés de chromanyle destinés au traitement de la maladie mitochondriale
KR20150036035A (ko) * 2012-07-12 2015-04-07 콘드리온 아이피 비.브이. 미토콘드리아 질환을 치료하기 위한 크로마닐 유도체
CN104662011A (zh) * 2012-07-12 2015-05-27 康尊知识产权公司 治疗线粒体疾病的色满衍生物
JP2015522067A (ja) * 2012-07-12 2015-08-03 コンドリオン アイピー ビー．ブイ．Ｋｈｏｎｄｒｉｏｎ Ｉｐ Ｂ．Ｖ． ミトコンドリア病を治療するためのクロマニル誘導体
US9388156B2 (en) 2012-07-12 2016-07-12 Khondiron IP B.V. Chromanyl derivatives for treating mitochondrial disease
EP2872497B1 (fr) 2012-07-12 2017-03-08 Khondrion Ip B.V. Dérivés chromanyles pour le traitement de maladies mitochondriales
CN104662011B (zh) * 2012-07-12 2017-09-29 康尊知识产权公司 治疗线粒体疾病的色满衍生物
AU2013287347B2 (en) * 2012-07-12 2017-11-30 Khondrion Ip B.V. Chromanyl derivatives for treating mitochondrial disease
KR102137450B1 (ko) * 2012-07-12 2020-07-27 콘드리온 아이피 비.브이. 미토콘드리아 질환을 치료하기 위한 크로마닐 유도체

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AU2001262200A1 (en) 2001-11-07
WO2001081324B1 (fr) 2002-02-28

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